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Sökning: WFRF:(Holmberg Monica)

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1.
  • Einarsdottir, Elisabet, et al. (författare)
  • A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception.
  • 2004
  • Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 13:8, s. 799-805
  • Tidskriftsartikel (refereegranskat)abstract
    • Identification of genes associated with pain insensitivity syndromes can increase the understanding of the pathways involved in pain and contribute to the understanding of how sensory pathways relate to other neurological functions. In this report we describe the mapping and identification of the gene responsible for loss of deep pain perception in a large family from northern Sweden. The loss of pain perception in this family is characterized by impairment in the sensing of deep pain and temperature but with normal mental abilities and with most other neurological responses intact. A severe reduction of unmyelinated nerve fibers and a moderate loss of thin myelinated nerve fibers are observed in the patients. Thus the cases in this study fall into the class of patients with loss of pain perception with underlying peripheral neuropathy. Clinically they best fit into HSAN V. Using a model of recessive inheritance we identified an 8.3 Mb region on chromosome 1p11.2-p13.2 shared by the affected individuals in the family. Analysis of functional candidate genes in the disease critical region revealed a mutation in the coding region of the nerve growth-factor beta (NGFB) gene specific for the disease haplotype. This NGF mutation seems to separate the effects of NGF involved in development of central nervous system functions such as mental abilities, from those involved in peripheral pain pathways. This mutation could therefore potentially provide an important tool to study different roles of NGF, and of pain control.
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2.
  • Einarsdottir, Elisabet, et al. (författare)
  • The CTLA4 region as a general autoimmunity factor: an extended pedigree provides evidence for synergy with the HLA locus in the etiology of type 1 diabetes mellitus, Hashimoto's thyroiditis and Graves' disease
  • 2003
  • Ingår i: European Journal of Human Genetics. - : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 11:1, s. 81-84
  • Tidskriftsartikel (refereegranskat)abstract
    • We have identified a large family in the northern part of Sweden with multiple cases of autoimmune diseases, namely type 1 diabetes (T1D), Graves' disease (GD) and Hashimoto's thyroiditis (HT). The family members affected by any of these diseases share a region of 2.4 Mb that comprises among others the CTLA4 gene. We determined that all affected members of the family shared the HLA susceptibility haplotype (DR4-DQA1*0301-DQB1*0302). Analysis of genetic interaction conditioning for HLA haplotype provided strong evidence that the critical region which includes the CTLA4 gene acts together with the HLA locus on the etiology of disease (lodscore 4.20 (theta=0.0). The study of this family allowed us to: (1) reinforce a number of reports on linkage and association of the CTLA4 region to T1D and AITD; (2) demonstrate that a single haplotypic variant in this region constitutes an etiological factor to disease susceptibility in T1D, GD and HT; (3) reveal a strong genetic interaction of the CTLA4 and HLA loci in the genetic architecture of autoimmune disease; (4) emphasise the value of large pedigrees drawn from isolated populations as tools to single out the effect of individual loci in the etiology of complex diseases.
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4.
  • Berntman, Monica, et al. (författare)
  • Bus travel safety - a travel chain perspective
  • 2010
  • Konferensbidrag (refereegranskat)abstract
    • The injury risk for bus passengers is low compared to car users. However, bus passengers also run the risk of sustaining injuries as vulnerable road users: as pedestrians or cyclists to and from the bus stop. Among vulnerable road users, seniors are a particularly important group. Hitherto, injury data have mainly been based on police-reported accidents. These accidents reveal bus occupant safety, rarely covering the whole travel chain. The aim of this study is therefore to incorporate all links in the travel chain, in order to better assess the risks in local and regional bus services. Instead of using only police data, both police- and hospital-registered injuries are collected, which will cover not only on-board injuries but also transport to and from the vehicle and during boarding and alighting. Four emergency departments in a southern Swedish county (Skåne) have been collecting data on bus-related injuries between 2006 and 2009. Follow-up studies (postal surveys) are made in order to assess longterm effects and medical costs. In order to assess incidence rates, injury data are complemented by using ongoing extensive travel surveys. The preliminary findings (with data from 2006 to 2008) from this study underscore the need for a holistic perspective when it comes to safety issues. A substantial number of bus-related injuries are sustained to and from the bus stops, and among these injuries older people are over-represented. These injuries are results of so-called single accidents, i.e. not directly involving external violence. Further results will target exposure, risk estimates, and societal costs for the group of elderly passengers as well as all user groups.
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6.
  • Blomstedt, Patric, et al. (författare)
  • A family with a hereditary form of torsion dystonia from northern Sweden treated with bilateral pallidal deep brain stimulation
  • 2009
  • Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 24:16, s. 2415-2419
  • Tidskriftsartikel (refereegranskat)abstract
    • To evaluate pallidal DBS in a non-DYT1 form of hereditary dystonia. We present the results of pallidal DBS in a family with non-DYT1 dystonia where DYT5 to 17 was excluded. The dystonia is following an autosomal dominant pattern. Ten members had definite dystonia and five had dystonia with minor symptoms. Four patients received bilateral pallidal DBS. Mean age was 47 years. The patients were evaluated before surgery, and "on" stimulation after a mean of 2.5 years (range 1-3) using the Burke-Fahn-Marsden scale (BFM). Mean BFM score decreased by 79 % on stimulation, from 42.5 +/- 24 to 9 +/- 6.5 at the last evaluation. Cervical involvement improved by 89%. The 2 patients with oromandibular dystonia and blepharospasm demonstrated a reduction of 95% regarding these symptoms. The present study confirms the effectiveness of pallidal DBS in a new family with hereditary primary segmental and generalized dystonia.
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7.
  • Carlsson, Ninni, 1962, et al. (författare)
  • ”Visa i handling vad arbetet mot mäns våld är värt”
  • 2019
  • Ingår i: Svenska Dagbladet. ; 2019:4 april
  • Tidskriftsartikel (populärvet., debatt m.m.)abstract
    • Mitt i debatten om Josefin Nilsson och det våld mot henne som närstående berättar om i SVT-dokumentären ”Älska mig för den jag är”, tillkännager regeringen, C och L att de föreslår 45 miljoner i vårbudget för att bekämpa mäns våld mot kvinnor. Flera medier kallar det en storsatsning men är det verkligen det, frågar våldsforskare, #metoo-upprop och organisationer. Med hjälp av aktuell forskning argumenterar de för att detta är långt ifrån tillräckligt, kräver större vårbudget mot mäns våld mot kvinnor och bjuder in riksdag och regering till dialog.
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8.
  • Colleoni, Marco, et al. (författare)
  • Site of primary tumor has a prognostic role in operable breast cancer: the international breast cancer study group experience.
  • 2005
  • Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 0732-183X. ; 23:7, s. 1390-400
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: Cancer presenting at the medial site of the breast may have a worse prognosis compared with tumors located in external quadrants. For medial tumors, axillary lymph node staging may not accurately reflect the metastatic potential of the disease. PATIENTS AND METHODS: Eight-thousand four-hundred twenty-two patients randomly assigned to International Breast Cancer Study Group clinical trials between 1978 and 1999 were classified as medial site (1,622; 19%) or lateral, central, and other sites (6,800; 81%). Median follow-up was 11 years. RESULTS: A statistically significant difference was observed for patients with medial tumors versus those with nonmedial tumors in disease-free survival (DFS; 10-year DFS, 46% v 48%; HR, 1.10; 95% CI, 1.02 to 1.18; P = .01) and overall survival (10-year OS 59% v 61%; HR, 1.09; 1.01 to 1.19; P = .04). This difference increased after adjustment for other prognostic factors (HR, 1.22; 95% CI, 1.13 to 1.32 for DFS; and HR, 1.24; 95% CI, 1.14 to 1.35 for OS; both P = .0001). The risk of relapse for patients with medial presentation was largest for the node-negative cohort and for patients with tumors larger than 2 cm. In the subgroup of 2,931 patients with negative axillary lymph nodes, 10-year DFS was 61% v 67%, and OS was 73% v 80% for medial versus nonmedial sites, respectively (HR 1.33; 95% CI, 1.15 to 1.54; P = .0001 for DFS; and HR 1.40; 95% CI, 1.17 to 1.67; P = .0003 for OS). CONCLUSION: Tumor site has a significant prognostic utility, especially for axillary lymph node-negative disease, that should be considered in therapeutic algorithms. New staging procedures such as biopsy of the sentinel internal mammary nodes or novel imaging methods should be further studied in patients with medial tumors.
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10.
  • Gruber, Günther, et al. (författare)
  • Prognostic value of extracapsular tumor spread for locoregional control in premenopausal patients with node-positive breast cancer treated with classical cyclophosphamide, methotrexate, and fluorouracil: long-term observations from International Breast Cancer Study Group Trial VI.
  • 2005
  • Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 0732-183X. ; 23:28, s. 7089-97
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: We sought to determine retrospectively whether extracapsular spread (ECS) might identify a subgroup that could benefit from radiotherapy after mastectomy, especially patients with 1 to 3 positive lymph nodes (LN1-3+). PATIENTS AND METHODS: We randomized 1,475 premenopausal women with node-positive breast cancer to three, six, or nine courses of "classical" CMF (cyclophosphamide, methotrexate, and fluorouracil). After a review of all pathology forms, 933 patients (63%) had information on the presence or absence of ECS. ECS was present in 49.5%. The median follow-up was 10 years. RESULTS: In univariate analyses, ECS was associated with worse disease-free survival (DFS) and overall survival (OS). In multivariate analyses adjusting for tumor size, vessel invasion, surgery type, and age group, ECS remained significant (DFS: hazard ratio, 1.61; 95% CI, 1.34 to 1.93; P < .0001; OS: 1.67; 95% CI, 1.34 to 2.08; P < .0001). However, ECS was not significant when the number of positive nodes was added. The locoregional failure rate +/- distant failure (LRF +/- distant failure) within 10 years was estimated at 19% (+/- 2%) without ECS, versus 27% (+/- 2%) with ECS. The difference was statistically significant in univariate analyses, but not after adjusting for the number of positive nodes. No independent effect of ECS on DFS, OS, or LRF could be confirmed within the subgroup of 382 patients with LN1-3+ treated with mastectomy without radiotherapy. CONCLUSION: Our results do not support an independent prognostic value of ECS, nor its use as an indication for irradiation in premenopausal patients with LN1-3+ treated with classical CMF. However, we could not examine whether extensive ECS is of prognostic importance.
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11.
  • Holmberg, Johan, et al. (författare)
  • Activation of Neural and Pluripotent Stem Cell Signatures Correlates with Increased Malignancy in Human Glioma
  • 2011
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:3, s. e18454-
  • Tidskriftsartikel (refereegranskat)abstract
    • The presence of stem cell characteristics in glioma cells raises the possibility that mechanisms promoting the maintenance and self-renewal of tissue specific stem cells have a similar function in tumor cells. Here we characterized human gliomas of various malignancy grades for the expression of stem cell regulatory proteins. We show that cells in high grade glioma co-express an array of markers defining neural stem cells (NSCs) and that these proteins can fulfill similar functions in tumor cells as in NSCs. However, in contrast to NSCs glioma cells co-express neural proteins together with pluripotent stem cell markers, including the transcription factors Oct4, Sox2, Nanog and Klf4. In line with this finding, in high grade gliomas mesodermal-and endodermal-specific transcription factors were detected together with neural proteins, a combination of lineage markers not normally present in the central nervous system. Persistent presence of pluripotent stem cell traits could only be detected in solid tumors, and observations based on in vitro studies and xenograft transplantations in mice imply that this presence is dependent on the combined activity of intrinsic and extrinsic regulatory cues. Together these results demonstrate a general deregulated expression of neural and pluripotent stem cell traits in malignant human gliomas, and indicate that stem cell regulatory factors may provide significant targets for therapeutic strategies.
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12.
  • Holmberg, Kristina, et al. (författare)
  • Arts education and discourse analysis in Sweden : perspectives and contexts of application
  • 2011
  • Ingår i: Third New Zealand Discourse Conference, Engaging with Discourse, 5–7 December 2011. - : The Institute of Culture, Discourse & Communication (ICDC).
  • Konferensbidrag (refereegranskat)abstract
    • In the last decade different forms of discourse analysis have emerged in research on Arts education in Sweden. It includes macro- as well as micro oriented studies and embraces perspectives such as discursive psychology, critical discourse analysis, discourse theory and Foucault inspired analysis. The application is spread to a wide range of educational contexts from pre- and elementary school to higher education at universities as well as to schools of music and art. The purpose of this paper is two-folded: i) to give some examples on how discourse analysis have been used in Swedish research on Arts education and ii) discuss this in a meta-perspective focusing on similarities and differences according to empirical material and results. Data consists of four larger research projects completed during the last five years, all conducted by the authors. In a meta-perspective, all four studies enclosed, two kinds of approaches are shown: Word-level analysis, identified as rhetorical actions in group-conversations, and practice-oriented analysis, identified as rhetorical actions in classroom praxis. Both approaches aim to identify hegemony and antagonistic discourses, and also to problematize the subject agency and what possible subject positions they open up for. The relation discourse-subject also contributes to the analysis of the over-determined subject and ideological dilemmas. According to the results, the area of Arts education in Sweden seems to be a battlefield of different discoursers. For example, this is shown by different ideological dilemmas related to activities in the music classroom and in the questions of democracy and pupil influence that rises in the studies. Among teacher educators in arts education two prominent discourses are shown: The first is a relativization of the concept of quality, and the second is that lack of subject knowledge is articulated as a teacher quality. With Foucaultian discourse analysis, questions of power and control in arts education are handled. In line with this, democracy and knowledge formation are then put into focus, something that is also discussed in this presentation.
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13.
  • Holmberg, Kristina, et al. (författare)
  • Snacking on Knowledge and Feel Good : Challenging discourses on arts in education
  • 2016
  • Ingår i: European Journal of Philosophy in Arts Education. - 2002-4665. ; 1:1, s. 38-67
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this article is to re-think the results of four larger studies conducted by the authors during the last decade, all with a discourse analytical approach. The studies are empirical and concern the Swedish field of arts in education and deal with a comprehensive material consisting of interviews, observations and field notes. In the results of these studies three prominent discourses emerges. A Curriculum discourse, where content knowledge is connected to traditions, norms and values of educational institutions, a Feel-good discourse that deals with content knowledge where social and personal aspects are essential, and a Snacking on knowledge discourse where content knowledge is portrayed as something students are able to pick and choose according to their own preference. Ideas of late modern society and arts in education are then used as a basis to carry out a critical discussion about the emerging discourses. Also different teacher and student positions are problematized.
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14.
  • Holmberg, Lina, et al. (författare)
  • Validation of the Swedish Trauma Registry (SweTrau)
  • 2023
  • Ingår i: European Journal of Trauma and Emergency Surgery. - : Springer. - 1863-9933 .- 1863-9941. ; 49:4, s. 1627-1637
  • Tidskriftsartikel (refereegranskat)abstract
    • PurposeValidation of registries is important to ensure accuracy of data and registry-based research. This is often done by comparisons of the original registry data with other sources, e.g. another registry or a re-registration of data. Founded in 2011, the Swedish Trauma Registry (SweTrau) consists of variables based on international consensus (the Utstein Template of Trauma). This project aimed to perform the first validation of SweTrau.MethodsOn-site re-registration was performed on randomly selected trauma patients and compared to the registration in SweTrau. Accuracy (exact agreement), correctness (exact agreement plus data within acceptable range), comparability (similarity with other registries), data completeness (1-missing data) and case completeness (1-missing cases) were deemed as either good (≥85%), adequate (70–84%) or poor (< 70%). Correlation was determined as either excellent (≥0.8), strong (0.6–0.79), moderate (0.4–0.59) or weak (< 0.4).ResultsThe data in SweTrau had good accuracy (85.8%), correctness (89.7%) and data completeness (88.5%), as well as strong or excellent correlation (87.5%). Case completeness was 44.3%, however, for NISS > 15 case completeness was 100%. Median time to registration was 4.5 months, with 84.2% registered one year after the trauma. The comparability showed an accordance with the Utstein Template of Trauma of almost 90%.ConclusionsThe validity of SweTrau is good, with high accuracy, correctness, data completeness and correlation. The data are comparable to other trauma registries using the Utstein Template of Trauma; however, timeliness and case completeness are areas of improvement.
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15.
  • Holmberg, Monica, et al. (författare)
  • Localization of autosomal dominant cerebellar ataxia associated with retinal degeneration and anticipation to chromosome 3p12-p21.1
  • 1995
  • Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 4:8, s. 1441-1445
  • Tidskriftsartikel (refereegranskat)abstract
    • We present linkage analysis on a large Swedish five-generation family of 15 affected individuals with autosomal dominant cerebellar ataxia (ADCA) associated with retinal degeneration and anticipation, Common clinical signs in this family include ataxia, dysarthria and severely impaired vision with the phenotype ADCA type II, Different subtypes of ADCA have proven difficult to classify clinically due to extensive phenotypic variability within and between families. Genetic analysis of a number of ADCA type I families shows that heterogeneity exists also genetically, During the last few years several types of ADCA type I have been localized and to date six genetically distinct forms have been identified including SCA1 (6p), SCA2 (12q), SCA3 and Machado-Joseph disease (MJD) (14q), SCA4 (16q), and finally SCA5 (11), We performed a genome-wide search of the Swedish ADCA type II family using a total of 270 microsatellite markers, Positive lod scores were obtained with a number of microsatellite markers located on chromosome 3p12-p21.1. Three markers gave lod scores over 3 with a maximum lod score of 4.53 achieved with the marker D3S1600. The ADCA type II gene could be restricted to a region of 32 cM by the markers D3S1547 and D3S1274.
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16.
  • Johansson, Jenni, et al. (författare)
  • Expanded CAG repeats in Swedish Spinocerebellar ataxia type 7 (SCA7) patients : effect of repeat length on the clinical manifestation
  • 1998
  • Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 7:2, s. 171-176
  • Tidskriftsartikel (refereegranskat)abstract
    • Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disorder characterized by degeneration of the cerebellum, brainstem and retina. The gene responsible for SCA7, located on chromosome 3p, recently was cloned and shown to contain a CAG repeat in the coding region of the gene, that is expanded in SCA7 patients of French origin, We examined the SCA7 repeat region in four Swedish SCA7 families as well as in 57 healthy controls, All Swedish SCA7 patients exhibited expanded CAG repeats with a strong negative correlation between repeat size and age of onset, The repeat length in SCA7 patients ranged from 40 to >200 repeats, The largest expansion was observed in a juvenile case with an age of onset of 3 months, and represents the longest polyglutamine stretch ever reported, In patients with 59 repeats or more, visual impairment was the most common initial symptom observed, while ataxia predominates in patients with <59 repeats. Two of the Swedish SCA7 families analysed in this study were shown to be related genealogically, The other two SCA7 families could not be traced back to a common ancestor, All four families shared the same allele on the disease chromosome at a locus closely linked to SCA7, suggesting the possibility of a founder effect in the Swedish population.
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17.
  • Jonasson, Jenni, et al. (författare)
  • Evidence for a common Spinocerebellar ataxia type 7 (SCA7) founder mutation in Scandinavia
  • 2000
  • Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 8, s. 918-
  • Tidskriftsartikel (refereegranskat)abstract
    • Spinocerebellar ataxia type 7 (SCA7) is a neuro-degenerative disorder characterised by progressive cerebellar ataxia and macular degeneration. SCA7 is one of the least common genetically verified autosomal dominant cerebellar ataxias (ADCAs) in the world (4.5 to 11.6%), but in Sweden and Finland SCA7 is the most commonly identified form of ADCA. In an inventory of hereditary ataxias in Scandinavia (Sweden, Norway, Denmark and Finland) we identified 15 SCA7 families, eight in Sweden and seven in Finland, while no cases of SCA7 could be found in Norway or Denmark. We examined whether the relatively high frequency of SCA7 families in Sweden and Finland was the result of a common founder effect. Only two out of 15 families could be connected genealogically. However, an extensive haplotype analysis over a 10.2 cM region surrounding the SCAI gene locus showed that all 15 families studied shared a common haplotype over at least 1.9 cM. This strongly suggests that all Scandinavian SCA7 families originate from a common founder pre-mutation.
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18.
  • Jonasson, Jenni, et al. (författare)
  • Expression of ataxin-7 in CNS and non-CNS tissue of normal and SCA7 individuals
  • 2002
  • Ingår i: Acta Neuropathologica. - : Springer. - 0001-6322 .- 1432-0533. ; 104:1, s. 29-37
  • Tidskriftsartikel (refereegranskat)abstract
    • Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder primarily affecting the cerebellum, brain stem and retina. The disease is caused by an expanded polyglutamine tract in the protein ataxin-7. In this study we analyzed the expression pattern of ataxin-7 in CNS and non-CNS tissue from three SCA7 patients and age-matched controls. SCA7 is a rare autosomal dominant disorder, limiting the number of patients available for analysis. We therefore compiled data on ataxin-7 expression from all SCA7 patients (n=5) and controls (n=7) published to date, and compared with the results obtained in this study. Expression of ataxin-7 was found in neurons throughout the CNS and was highly abundant in Purkinje cells of the cerebellum, in regions of the hippocampus and in cerebral cortex. Ataxin-7 expression was not restricted to regions of pathology, and there were no apparent regional differences in ataxin-7 expression patterns between patients and controls. The subcellular distribution of ataxin-7 was primarily nuclear in all brain regions studied. In cerebellar Purkinje cells, however, differences in subcellular distribution of ataxin-7 were observed between patients and controls of different ages. Here we provide an increased understanding of the distribution of ataxin-7, and the possible implication of subcellular localization of this protein on disease pathology is discussed.
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19.
  • Jonasson, Jenni, 1971- (författare)
  • Genetic and Molecular analysis of the Spinocerebellar ataxia type 7 (SCA7) disease gene
  • 2000
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Spinocerebellar ataxia type 7 (SCA7) is a hereditary neurodegenerative disorder affecting the cerebellum, pons and retina. SCA7 patients present with gait ataxia and visual impairment as the main symptoms. Anticipation, commonly observed in SCA7 families, is a phenomenon where an earlier age at onset and a more severe progression of disease is seen in successive generations. In order to identify the gene responsible for SCA7, we performed linkage analysis on a Swedish SCA7 kindred. Evidence for linkage of the SCA7 disease locus to a 32 cM region on chromosome 3p12-21.1, between markers D3S1547 and D3S1274, was established. A number of neurodegenerative disorders associated with anticipation are caused by expanded (CAG)n repeats in their respective disease genes. In order to isolate the SCA7 disease gene we, therefore, screened a human infant brain stem cDNA library for CAG repeat containing clones, mapping to chromosome 3. Four candidate clones were isolated and analysed, but could all be excluded as the SCA7 disease gene. In 1997, the SCA7 disease gene was identified and, as expected, shown to harbour a CAG repeat, expanded in SCA7 patients. Analysis of the SCA7 CAG repeat region in Swedish SCA7 patients demonstrated that CAG repeat size was negatively correlated to age at onset of disease. Furthermore, patients with larger repeats presented with visual impairment, whereas patients with smaller repeats presented with ataxia as the initial symptom. SCA7 is the most common autosomal dominant cerebellar ataxia in Sweden and Finland, but rare in other populations. In order to investigate if the relatively high frequency of SCA7 in these countries is the result of a founder effect in the region, a haplotype analysis was performed on all SCA7 families available. All 7 families shared a common haplotype of at least 1.9 cM surrounding the SCA7 locus. In addition, strong linkage disequilibrium was demonstrated for marker D3S1287 closely linked to the SCA7 gene, suggesting a founder effect for the SCA7 mutation in Sweden and Finland. The function of the SCA7 protein, ataxin-7, is not known and it does not show significant homologies to any previously known proteins. In order to gain insight into the function of ataxin-7 we analysed the expression of ataxin-7 in brain and peripheral tissue from SCA7 patients and controls. In brain, expression was found to be mainly neuronal with a nuclear subcellular localisation. Ataxin-7 expression was found throughout the CNS, not restricted to sites of pathology. We also confirmed previously reported findings of neuronal intranuclear inclusions (NIls) in the brains of SCA7 patients. Based on our findings, we conclude that the cell type specific neurodegeneration in SCA7 is not due to differences in expression pattern in affected and non-affected tissue or the distribution pattern of aggregated protein.
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20.
  • Jonsson, Frida, et al. (författare)
  • ATP-binding cassette subfamily A, member 4 intronic variants c.4773+3A > G and c.5461-10T > C cause Stargardt disease due to defective splicing
  • 2018
  • Ingår i: Acta Ophthalmologica. - : John Wiley & Sons. - 1755-375X .- 1755-3768. ; 96:7, s. 737-743
  • Tidskriftsartikel (refereegranskat)abstract
    • PurposeInherited retinal dystrophies (IRDs) represent a group of progressive conditions affecting the retina. There is a great genetic heterogeneity causing IRDs, and to date, more than 260 genes are associated with IRDs. Stargardt disease, type 1 (STGD1) or macular degeneration with flecks, STGD1 represents a disease with early onset, central visual impairment, frequent appearance of yellowish flecks and mutations in the ATP‐binding cassette subfamily A, member 4 (ABCA4) gene. A large number of intronic sequence variants in ABCA4 have been considered pathogenic although their functional effect was seldom demonstrated. In this study, we aimed to reveal how intronic variants present in patients with Stargardt from the same Swedish family affect splicing.MethodsThe splicing of the ABCA4 gene was studied in human embryonic kidney cells, HEK293T, and in human retinal pigment epithelium cells, ARPE‐19, using a minigene system containing variants c.4773+3A>G and c.5461‐10T>C.ResultsWe showed that both ABCA4 variants, c.4773+3A>G and c.5461‐10T>C, cause aberrant splicing of the ABCA4 minigene resulting in exon skipping. We also demonstrated that splicing of ABCA4 has different outcomes depending on transfected cell type.ConclusionTwo intronic variants c.4773+3A>G and c.5461‐10T>C, both predicted to affect splicing, are indeed disease‐causing mutations due to skipping of exons 33, 34, 39 and 40 of ABCA4 gene. The experimental proof that ABCA4 mutations in STGD patients affect protein function is crucial for their inclusion to future clinical trials; therefore, functional testing of all ABCA4 intronic variants associated with Stargardt disease by minigene technology is desirable.
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22.
  • Karlsson, Per, 1963, et al. (författare)
  • The role of the number of uninvolved lymph nodes in predicting locoregional recurrence in breast cancer.
  • 2007
  • Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 1527-7755. ; 25:15, s. 2019-26
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: To identify groups of early breast cancer patients with substantial risk (10-year risk > 20%) for locoregional failure (LRF) who might benefit from postmastectomy radiotherapy (RT). PATIENTS AND METHODS: Prognostic factors for LRF were evaluated among 6,660 patients (2,588 node-negative patients, 4,072 node-positive patients) in International Breast Cancer Study Group Trials I to IX treated with chemotherapy and/or endocrine therapy, and observed for a median of 14 years. In total, 1,251 LRFs were detected. All patients were treated with mastectomy without RT. RESULTS: No group with 10-year LRF risk exceeding 20% was found among patients with node-negative disease. Among patients with node-positive breast cancer, increasing numbers of uninvolved nodes were significantly associated with decreased risk of LRF, even after adjustment for other prognostic factors. The highest quartile of uninvolved nodes was compared with the lowest quartile. Among premenopausal patients, LRF risk was decreased by 35% (P = .0010); among postmenopausal patients, LRF risk was decreased by 46% (P < .0001). The 10-year cumulative incidence of LRF was 20% among patients with one to three involved lymph nodes and fewer than 10 uninvolved nodes. Age younger than 40 years and vessel invasion were also associated significantly with increased risk. Among patients with node-positive disease, overall survival was significantly greater in those with higher numbers of uninvolved nodes examined (P < .0001). CONCLUSION: Patients with one to three involved nodes and a low number of uninvolved nodes, vessel invasion, or young age have an increased risk of LRF and may be candidates for a similar treatment as those with at least four lymph node metastases.
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23.
  • Kurtsdotter, Idha, et al. (författare)
  • SOX5/6/21 prevent oncogene-driven transformation of brain stem cells
  • 2017
  • Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 77:18, s. 4985-4997
  • Tidskriftsartikel (refereegranskat)abstract
    • Molecular mechanisms preventing self-renewing brain stem cells from oncogenic transformation are poorly defined. We show that the expression levels of SOX5, SOX6, and SOX21 (SOX5/6/21) transcription factors increase in stem cells of the subventricular zone (SVZ) upon oncogenic stress, whereas their expression in human glioma decreases during malignant progression. Elevated levels of SOX5/6/21 promoted SVZ cells to exit the cell cycle, whereas genetic ablation of SOX5/6/21 dramatically increased the capacity of these cells to form glioma-like tumors in an oncogene-driven mouse brain tumor model. Loss-of-function experiments revealed that SOX5/6/21 prevent detrimental hyperproliferation of oncogene expressing SVZ cells by facilitating an antiproliferative expression profile. Consistently, restoring high levels of SOX5/6/21 in human primary glioblastoma cells enabled expression of CDK inhibitors and decreased p53 protein turnover, which blocked their tumorigenic capacity through cellular senescence and apoptosis. Altogether, these results provide evidence that SOX5/6/21 play a central role in driving a tumor suppressor response in brain stem cells upon oncogenic insult.
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24.
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25.
  • Larsson, Elin, et al. (författare)
  • Nerve growth factor R221W responsible for insensitivity to pain is defectively processed and accumulates as proNGF
  • 2009
  • Ingår i: Neurobiology of Disease. - San Diego : Academic P.. - 0969-9961 .- 1095-953X. ; 33:2, s. 221-228
  • Tidskriftsartikel (refereegranskat)abstract
    • We have previously identified a homozygous missense (R221W) mutation in the NGFB gene in patients with loss of deep pain perception. NGF is important not only for the survival of sensory neurons but also for the sympathetic neurons and cholinergic neurons of the basal forebrain; however, it is the sensory neurons that are mainly affected in patients with mutant NGFB. In this report, we describe the effects of the mutation on the function of NGF protein and the molecular mechanisms that may underlie the pain insensitivity phenotype in these patients. We show that the mutant NGF has lost its ability to mediate differentiation of PC12 cells into a neuron-like phenotype. We also show that the inability of PC12 cells to differentiate is due to a markedly reduced secretion of mature R221W NGF. The R221W NGF is found mainly as proNGF, in contrast to wild-type NGF which is predominantly in the mature form in both undifferentiated and differentiated PC12 cells. The reduction in numbers of sensory fibers observed in the patients is therefore probably due to loss of trophic support as a result of drastically reduced secretion of NGF from the target organs. Taken together, these data show a clear decrease in the availability of mutant mature NGF and also an accumulation of proNGF in both neuronal and non-neuronal cells. The differential loss of NGF-dependent neurons in these patients, mainly affecting sensory neurons, may depend on differences in the roles of mature NGF and proNGF in different cells and tissues.
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26.
  • Larsson, Elin, et al. (författare)
  • Purification and Characterization of the Nerve Growth Factor R221W mutant causing Insensitivity to Pain
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    •   We have previously identified a homozygous missense (R221W) mutation in the NGFβ gene which causes insensitivity to pain in patients. The mutation impairs the secretion of NGF and the majority of the protein accumulates as proNGF. NGF mediates its function by binding and activating the TrkA and p75 receptors and is important for the survival of the sensory and sympathetic neurons as well as the cholinergic neurons of the basal forebrain. However, the R221W mutation seems to discriminate between these types of neurons as it is the sensory neurons that are mainly affected in the patients. A second human NGFβ mutation causes a more severe form of pain insensitivity with additional anhidrosis and cognitive dysfunctions in affected patients which is also seen in patients with mutations in the gene encoding the TrkA receptor. Because R221W NGF cause a less severe phenotype we hypothesised that the mutation mainly affects the p75 interaction which is also strengthened by the fact that the substitution is located in a region known to interact with p75. In this report, we show that R221W NGF is able to bind and activate TrkA at a level comparable to wild-type NGF in cells stably expressing TrkA while the activation of the downstream target ERK1/2 is impaired in cells that co-express TrkA and p75. We also describe the effects of the mutation in terms of expression and purification properties from E.coli which indicate the likelihood that eukaryotic folding machinery is needed for correct folding of R221W NGF.
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27.
  • Larsson, Elin, 1978- (författare)
  • The use of monogenic disease to study basal and disease associated mechanisms with focus on NGF dependent pain insensitivity and ISCU myopathy
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Monogenic diseases make excellent models for the study of gene functions and basal cellular mechanisms in humans. The aim of this thesis was to elucidate how genetic mutations affect the basal cellular mechanisms in the monogenic diseases Nerve growth factor (NGF) dependent pain insensitivity and Iron-Sulphur cluster assembly protein U (ISCU) myopathy. NGF dependent pain insensitivity is a rare genetic disorder with clinical manifestations that include insensitivity to deep pain, development of Charcot joints, and impaired temperature sensation but with no effect on mental abilities. The disease is caused by a missense mutation in the NGFβ gene causing a drastic amino acid substitution (R221W) in a well-conserved region of the protein. NGF is secreted in limited amounts by its target tissues and is important for the development and maintenance of the cholinergic forebrain neurons as well as the sensory and sympathetic neurons. To reveal the underlying mechanisms of disease we performed functional studies of the mutant NGF protein. We could show that mutant NGF was unable to induce differentiation of PC12 cells as a consequence of impaired secretion. Furthermore, mutant NGF had different intracellular localisation compared to normal NGF and resided mostly in its unprocessed form proNGF. Mature NGF and proNGF have different binding properties to the receptors TrkA and p75. Individuals with mutations in TRKA are, aside from pain insensitive mentally affected; therefore it has been proposed that the R221W mutation mainly affects the interaction with p75. In agreement with this, we could show that R221W NGF was able to bind and activate TrkA whereas the interaction with p75 was impaired as compared to normal NGF. ISCU myopathy is a monogenic disease where the affected patients suffer from severe exercise intolerance resulting in muscle cramps and sometimes severe lactic acidosis. The disease is caused by a point mutation in the last intron of the Iron sulphur cluster assembly gene, ISCU, resulting in the inclusion of a part of the intron in the mRNA. ISCU functions as a scaffold protein in the assembly of iron-sulphur (Fe-S) clusters important for electron transport in Kreb’s cycle and the respiratory chain. We have shown that ISCU is vital in mammals since complete knock-down of Iscu in mice results in early embryonic death. The deletion of ISCU homologous in lower organisms has also been shown fatal. In spite this central role in energy metabolism the disease is restricted to the patient’s skeletal muscles while other energy demanding organs seem unaffected. To address this contradiction we examined if tissue-specific differences in the splicing of mutant ISCU could explain the muscle-specific phenotype. We could show that the splicing pattern did, indeed, differ with more incorrectly spliced ISCU in muscle compared to other tissues. This was accompanied by a decrease in Fe-S containing proteins in muscle, while no decrease was observed in other tissues. Alternative splicing is more common then previously thought and may depend upon interacting factors and/or differences in the surrounding milieu. To reveal plausible mechanisms involved in the tissue-specific splicing we identified nuclear factors that interacted with the region where the mutation was located. Five interacting factors were identified, out of which three affected the splicing of ISCU. PTBP1 was shown to repress the incorrect splicing while IGF2BP1 and RBM39 repressed the formation of normal transcript and could also counteract the effect of PTBP1. IGF2BP1 was the only factor that showed higher affinity to the mutant sequence making it a possible key factor in the incorrect splicing of the mutant ISCU gene. Together, these results offer important insights into the cellular mechanisms causing these diseases. We found impaired secretion and inaccurate sorting of NGF to be cellular mechanisms contributing to NGF dependent pain insensitivity while tissue-specific splicing of ISCU was found to be the event contributing to the phenotype of ISCU myopathy.
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28.
  • Minde, Jan, et al. (författare)
  • A novel NGFB point mutation : a phenotype study of heterozygous patients
  • 2009
  • Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group Ltd. - 0022-3050 .- 1468-330X. ; 80:2, s. 188-195
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: A family with neurological findings similar to hereditary sensory and autonomic neuropathy type V having a point mutation in the nerve growth factor beta (NGFB) gene was recently described. The homozygous genotype gives disabling symptoms. The purpose of the present study was to evaluate the symptoms in heterozygous patients. METHODS: 26 patients heterozygous for the NGFB mutation (12 men, mean age 50 (13-90) years) were examined clinically and answered a health status questionnaire, including the Michigan Neuropathy Screening Instrument (MNSI). 28 relatives (15 men, mean age 44 (15-86) years) without the mutation served as controls in the clinical examination part. 23 of the heterozygotes were examined neurophysiologically and six heterozygous patients underwent a sural nerve biopsy. RESULTS: The heterozygous phenotype ranged from eight patients with Charcot arthropathy starting in adult age and associated with variable symptoms of neuropathy but without complete insensitivity to pain, anhidrosis or mental retardation, to 10 symptom free patients. There was no difference in MNSI between the young heterozygous cases (<55 years old) and the controls. Six of 23 heterozygous patients had impaired cutaneous thermal perception and 11 of 23 had signs of carpal tunnel syndrome. Sural nerve biopsies showed a moderate reduction of both small myelinated (Adelta) and unmyelinated (C) fibres. No apparent correlation of small fibre reduction to symptoms was found. CONCLUSIONS: The NGFB mutation in its heterozygous form results in a milder disease than in homozygotes, with a variable clinical picture, ranging from asymptomatic cases to those with Charcot arthropathy appearing in adult age. Particularly age, but perhaps lifestyle factors also, may influence the development of clinical polyneuropathy.
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29.
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30.
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31.
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32.
  • Norberg, Anna, 1975- (författare)
  • Genetics of pain : studies of migraine and pain insensitivity
  • 2006
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Pain is a major public health issue throughout the world. Increased understanding of the different forms of pain and identification of susceptibility genes could contribute to improved treatments. The main aims of this thesis were to identify the underlying genetic causes of pain by studying two large families affected with migraine and pain insensitivity, respectively.Migraine is one of the most common neurovascular disorders, affecting over 12% of the western population. The genetic contribution to migraine is about 50% according to family and twin studies. To identify novel susceptibility loci for migraine, we performed a genome-wide screen in a large family with migraine from northern Sweden. Linkage analysis revealed significant evidence of linkage (LOD=5.41) on chromosome 6p12.2-p21.1. A predisposing haplotype spanning 10 Mb was inherited with migraine in all affected members of the pedigree. Further fine-mapping of multiple SNP markers restricted the disease critical region to 8.5 Mb. Nine candidate genes were sequenced, revealing no disease-associated polymorphisms in SLC29A1, CLIC5, PLA2G7, IL17, SLC25A27 and TNFRSF21, but rare novel polymorphisms segregating with the disease haplotype in EFHC1, RHAG and MEP1A. EFHC1 has recently been shown to be involved in epilepsy, which is interesting considering the link between migraine and epilepsy. However, association analysis of EFHC1 revealed no difference between patients and controls, suggesting that this gene is not a risk factor for migraine. The combination of the two polymorphisms in RHAG and MEP1A could, however, not be found in any control individuals, indicating that they might be involved in genetic predisposition to migraine in this family.Disorders with reduced pain sensitivity are very rare, since pain perception is essential for survival. A number of disorders have still been identified with pain insensitivity and peripheral nerve degeneration as major clinical signs, including the hereditary sensory and autonomic neuropathies (HSAN). In order to identify novel susceptibility genes for HSAN V, we performed a genome-wide screen in a large consanguineous pedigree from a small village in northern Sweden. A homozygous region identical-by-descent was identified on chromosome 1p11.2-p13.2 in the three most severely affected patients. Subsequent analysis of candidate genes revealed a missense mutation in a conserved region of the nerve growth factor beta (NGFB) gene, causing a drastic amino acid change (R211W) in the NGF protein. NGF is important for the development and maintenance of the sympathetic and sensory nervous system and is therefore likely to be involved in disease. Functional analysis revealed that mutant NGF failed to induce neurite outgrowth and cell differentiation in PC12 cells. Furthermore, almost no mutant NGF was secreted by COS-7 cells, indicating that the processing and/or secretion of the protein might be disrupted.In conclusion, these findings present a novel migraine locus on chromosome 6 and identification of two rare polymorphisms that might be risk factors for migraine. Furthermore, a mutation in NGFB was found to cause complete loss of deep pain perception, which represents a very interesting model system to study pain mechanisms.
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33.
  • Nordin, Angelica, 1982- (författare)
  • Genetic and functional studies of hereditary myopathy with lactic acidosis
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Hereditary myopathy with lactic acidosis (HML, OMIM#255125) is an autosomal recessive disorder which originates from Västerbotten and Ångermanland in the Northern part of Sweden. HML is characterized by severe exercise intolerance which manifests with tachycardia, dyspnea, muscle pain, cramps, elevated lactate and pyruvate levels, weakness and myoglobinuria. The symptoms arise from malfunction of the energy metabolism in skeletal muscles with defects in several important enzymes involved in the TCA cycle and the electron transport chain. All affected proteins contain iron-sulfur (Fe-S) clusters, which led to the suggestion that the disease was caused by malfunctions in either the transportation, assembly or processing of Fe-S clusters. The aim of my thesis was to identify the disease causing gene of HML and to investigate the underlying disease-mechanisms. In paper I we identified a disease-critical region on chromosome 12; a region containing 16 genes. One of the genes coded for the Fe-S cluster assembly protein ISCU and an intronic base pair substitution (g.7044G>C) was identified in the last intron of this gene. The mutation gave rise to the insertion of intron sequence into the mRNA, leading to a protein containing 15 abberant amino acids and a premature stop. In paper II we investigated why a mutation in an evolutionary well conserved protein with a very important cellular role, which in addition is expressed in almost all tissues, gives rise to a muscle-restricted phenotype. Semi-quantitative RT-PCR analysis showed that the mutant transcript constituted almost 80% of total ISCU mRNA in muscle, while in both heart and liver the normal splice form was dominant. We could also show that, in mice, complete absence of Iscu protein was coupled with early embryonic death, further emphasizing the importance of the protein in all tissues. These data strongly suggested that tissue-specific splicing was the main mechanism responsible for the muscle-specific phenotype of HML. In paper III the splicing mechanisms that give rise to the mutant ISCU transcript was further investigated. We identified three proteins; PTBP1, IGF2BP1 and RBM39, that could bind to the region containing the mutation and could affect the splicing pattern of ISCU in an in vitro system. PTBP1 repressed the inclusion of the intronic sequence, while IGF2BP1 and RBM39 repressed the total ISCU mRNA level though the effect was more pronounced for the normal transcript. Moreover, IGF2BP1 and RBM39 were also able to reverse the effect of PTBP1. IGF2BP1, though not a splicing factor, had higher affinity for the mutant sequence. This suggested that the mutation enables IGF2BP1 binding, thereby preventing the PTBP1 induced repression seen in the normal case. In conclusion, we have determined the genetic cause of HML, identifying a base pair substitution in the last intron of the ISCU gene that gives rise to abnormally spliced transcript. The muscle-specific phenotype was also analyzed and tissue-specific splicing was identified as the main disease-mechanism. Furthermore, nuclear factors with ability to affect the splicing pattern of the mutant ISCU gene were identified. This work has thoroughly investigated the fundamental disease mechanisms, thus providing deeper understanding for this hereditary myopathy.
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34.
  • Nordin, Angelica, 1982-, et al. (författare)
  • The defective splicing caused by the ISCU intron mutation in patients with myopathy with lactic acidosis is repressed by PTBP1 but can be de-repressed by IGF2BP1
  • 2012
  • Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 33:3, s. 467-470
  • Tidskriftsartikel (refereegranskat)abstract
    • Hereditary myopathy with lactic acidosis (HML) is caused by an intron mutation in the iron-sulfur cluster assembly gene ISCU which leads to the activation of cryptic splice sites and the retention of part of intron 4. This incorrect splicing is more pronounced in muscle than in other tissues, resulting in a muscle-specific phenotype. In this study, we identified five nuclear factors that interact with the sequence harboring the mutation and analyzed their effect on the splicing of the ISCU gene. The identification revealed three splicing factors, SFRS14, RBM39 and PTBP1, and two additional RNA binding factors, matrin 3 (MATR3) and IGF2BP1. IGF2BP1 showed a preference for the mutant sequence, whereas the other factors showed similar affinity for both sequences. PTBP1 was found to repress the defective splicing of ISCU, resulting in a drastic loss of mutant transcripts. In contrast, IGF2BP1 and RBM39 shifted the splicing ratio toward the incorrect splice form.
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35.
  • Nordin, Angelica, 1982-, et al. (författare)
  • Tissue-specific splicing of ISCU results in a skeletal muscle phenotype in myopathy with lactic acidosis, while complete loss of ISCU results in early embryonic death in mice
  • 2011
  • Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 129:4, s. 371-378
  • Tidskriftsartikel (refereegranskat)abstract
    • Hereditary myopathy with lactic acidosis (HML) is caused by an intron mutation in the iron-sulphur cluster assembly gene (ISCU) leading to incorporation of intron sequence into the mRNA. This results in a deficiency of Fe-S cluster proteins, affecting the TCA cycle and the respiratory chain. The proteins involved in the Fe-S machinery are evolutionary conserved and shown to be fundamental in all organisms examined. ISCU is expressed at high levels in numerous tissues in mammals, including high metabolic tissues like the heart, suggesting that a drastic mutation in the ISCU gene would be damaging to all energy-demanding organs. In spite of this, the symptoms in patients with HML are restricted to skeletal muscle, and it has been proposed that splicing events may contribute to the muscle specificity. In this study we confirm that a striking difference in the splicing pattern of mutant ISCU exists between different tissues. The highest level of incorrectly spliced ISCU mRNA was found in skeletal muscle, while the normal splice form predominated in patient heart. The splicing differences were also reflected at a functional level, where loss of Fe-S cluster carrying enzymes and accumulation of iron were present in muscle, but absent in other tissues. We also show that complete loss of ISCU in mice results in early embryonic death. The mice data confirm a fundamental role for ISCU in mammals and further support tissue-specific splicing as the major mechanism limiting the phenotype to skeletal muscle in HML.
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36.
  • Norgren, Nina, et al. (författare)
  • A high-penetrance form of late-onset torsion dystonia maps to a novel locus (DYT21) on chromosome 2q14.3-q21.3
  • 2011
  • Ingår i: Neurogenetics. - Heidelberg : Springer Science and Business Media LLC. - 1364-6745 .- 1364-6753. ; 12:2, s. 137-143
  • Tidskriftsartikel (refereegranskat)abstract
    • The primary dystonias are a genetically heterogeneous group of disorders that can be subdivided in pure dystonias, dystonia-plus syndromes, and paroxymal dystonia. Four pure autosomal dominant dystonia loci have been mapped to date, DYT1, 6, 7, and 13, with varying penetrance. We report the mapping of a novel locus for a late-onset form of pure torsion dystonia in a family from northern Sweden. The disease is inherited in an autosomal dominant manner with a penetrance that may be as high as 90%. The torsion dystonia locus in this family was mapped to chromosome 2q14.3-q21.3 using an Illumina linkage panel. We also confirmed the linkage, using ten tightly linked microsatellite markers in the region, giving a maximum LOD score of 5.59 for marker D2S1260. The disease-critical region is 3.6-8.9 Mb depending on the disease status of one individual carrying a centromeric recombination. Mutational analysis was performed on 22 genes in the disease-critical region, including all known and hypothetical genes in the smaller, 3.6-Mb region, but no disease-specific mutations were identified. Copy number variation analysis of the region did not reveal any deletions or duplications. In order to increase the chances of finding the disease gene, fine-mapping may be necessary to decrease the region of interest. This report will hopefully result in the identification of additional dystonia families with linkage to the same locus, and thereby, refinement of the disease critical region.
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37.
  • Olsson, Angelica, 1982-, et al. (författare)
  • Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect
  • 2008
  • Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 17:11, s. 1666-1672
  • Tidskriftsartikel (refereegranskat)abstract
    • We describe the mapping and identification of the gene for hereditary myopathy with lactic acidosis (HML). HML is characterized by low physical performance, resulting in physical exertion that causes early exhaustion, dyspnoea and palpitations. Using an autosomal recessive mode of inheritance, we mapped the trait to chromosome 12q23.3-24.11, with a maximum lod score of 5.26. The 1.6-Mb disease-critical region contained one obvious candidate gene-ISCU-specifying a protein involved in iron-sulphur cluster assembly. IscU is produced in two isoforms; one cytosolic and one mitochondrial, coded for by different splice variants of the ISCU gene. Mutational analysis of all exon and intron sequences as well as 1000 bp of the promoter of the ISCU gene revealed one intron mutation that was specific for the disease haplotype. The mutation is located in a region with homology to the interferon-stimulated response element (ISRE), but we could not see any effect of the mutation on expression levels in vitro or in vivo. We did, however, observe a drastic difference in the splicing pattern between patients and controls. In controls the mRNA was, as expected, mainly in the mitochondrial form, while in the patients a larger mRNA transcript was predominant. Sequencing of the product revealed that the mutation activates cryptic splice sites in intron 5 resulting in aberrant mRNA containing 100 bp of the intron. To conclude, our data strongly suggest that an intron mutation in the ISCU gene, leading to incorrectly spliced mRNA, is the cause of myopathy with lactic acidosis in this family.
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38.
  • Pagani, Olivia, et al. (författare)
  • Is adjuvant chemotherapy of benefit for postmenopausal women who receive endocrine treatment for highly endocrine-responsive, node-positive breast cancer? International Breast Cancer Study Group Trials VII and 12-93.
  • 2009
  • Ingår i: Breast cancer research and treatment. - : Springer Science and Business Media LLC. - 1573-7217 .- 0167-6806. ; 116:3, s. 491-500
  • Tidskriftsartikel (refereegranskat)abstract
    • To compare the efficacy of chemoendocrine treatment with that of endocrine treatment (ET) alone for postmenopausal women with highly endocrine responsive breast cancer. In the International Breast Cancer Study Group (IBCSG) Trials VII and 12-93, postmenopausal women with node-positive, estrogen receptor (ER)-positive or ER-negative, operable breast cancer were randomized to receive either chemotherapy or endocrine therapy or combined chemoendocrine treatment. Results were analyzed overall in the cohort of 893 patients with endocrine-responsive disease, and according to prospectively defined categories of ER, age and nodal status. STEPP analyses assessed chemotherapy effect. The median follow-up was 13 years. Adding chemotherapy reduced the relative risk of a disease-free survival event by 19% (P = 0.02) compared with ET alone. STEPP analyses showed little effect of chemotherapy for tumors with high levels of ER expression (P = 0.07), or for the cohort with one positive node (P = 0.03). Chemotherapy significantly improves disease-free survival for postmenopausal women with endocrine-responsive breast cancer, but the magnitude of the effect is substantially attenuated if ER levels are high.
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39.
  • Pagani, Olivia, et al. (författare)
  • Patterns of recurrence of early breast cancer according to estrogen receptor status: a therapeutic target for a quarter of a century.
  • 2009
  • Ingår i: Breast cancer research and treatment. - : Springer Science and Business Media LLC. - 1573-7217 .- 0167-6806. ; 117:2, s. 319-24
  • Tidskriftsartikel (refereegranskat)abstract
    • The current therapeutic strategy in breast cancer is to identify a target, such as estrogen receptor (ER) status, for tailoring treatments. We investigated the patterns of recurrence with respect to ER status for patients treated in two randomized trials with 25 years' median follow-up. In the ER-negative subpopulations most breast cancer events occurred within the first 5-7 years after randomization, while in the ER-positive subpopulations breast cancer events were spread through 10 years. In the ER-positive subpopulation, 1 year endocrine treatment alone significantly prolonged disease-free survival (DFS) with no additional benefit observed by adding 1 year of chemotherapy. In the small ER-negative subpopulation chemo-endocrine therapy had a significantly better DFS than endocrine alone or no treatment. Despite small numbers of patients, "old-fashioned" treatments, and competing causes of treatment failure, the value of ER status as a target for response to adjuvant treatment is evident through prolonged follow-up.
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40.
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41.
  • Rawcliffe, Denise F. R., et al. (författare)
  • PTBP1 acts as a dominant repressor of the aberrant tissue-specific splicing of ISCU in hereditary myopathy with lactic acidosis
  • 2018
  • Ingår i: Molecular Genetics & Genomic Medicine. - : John Wiley & Sons. - 2324-9269. ; 6:6, s. 887-897
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Hereditary myopathy with lactic acidosis (HML) is an autosomal recessive disease caused by an intron mutation in the iron-sulfur cluster assembly (ISCU) gene. The mutation results in aberrant splicing, where part of the intron is retained in the final mRNA transcript, giving rise to a truncated nonfunctional ISCU protein. Using an ISCU mini-gene system, we have previously shown that PTBP1 can act as a repressor of the mis-splicing of ISCU, where overexpression of PTBP1 resulted in a decrease of the incorrect splicing. In this study, we wanted to, in more detail, analyze the role of PTBP1 in the regulation of endogenous ISCU mis-splicing.Methods: Overexpression and knockdown of PTBP1 was performed in myoblasts from two HML patients and a healthy control. Quantification of ISCU mis-splicing was done by qRTPCR. Biotinylated ISCU RNA, representing wildtype and mutant intron sequence, was used in a pull-down assay with nuclear extracts from myoblasts. Levels of PTBP1 in human cell lines and mice tissues were analyzed by qRTPCR and western blot.Results: PTBP1 overexpression in HML patient myoblasts resulted in a substantial decrease of ISCU mis-splicing while knockdown of PTBP1 resulted in a drastic increase. The effect could be observed in both patient and control myoblasts. We could also show that PTBP1 interacts with both the mutant and wild-type ISCU intron sequence, but with a higher affinity to the mutant sequence. Furthermore, low levels of PTBP1 among examined mouse tissues correlated with high levels of incorrect splicing of ISCU.Conclusion: Our results show that PTBP1 acts as a dominant repressor of ISCU mis-splicing. We also show an inverse correlation between the levels of PTBP1 and ISCU mis-splicing, suggesting that the high level of mis-splicing in the skeletal muscle is primarily due to the low levels of PTBP1.
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42.
  • Rawcliffe, Denise F. R., et al. (författare)
  • The High Level of Aberrant Splicing of ISCU in Slow-Twitch Muscle May Involve the Splicing Factor SRSF3
  • 2016
  • Ingår i: PLOS ONE. - : Public library science. - 1932-6203. ; 11:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Hereditary myopathy with lactic acidosis (HML) is an autosomal recessive disease caused by an intronic one-base mutation in the iron-sulfur cluster assembly (ISCU) gene, resulting in aberrant splicing. The incorrectly spliced transcripts contain a 100 or 86 bp intron sequence encoding a non-functional ISCU protein, which leads to defects in several Fe-S containing proteins in the respiratory chain and the TCA cycle. The symptoms in HML are restricted to skeletal muscle, and it has been proposed that this effect is due to higher levels of incorrectly spliced ISCU in skeletal muscle compared with other energy-demanding tissues. In this study, we confirm that skeletal muscle contains the highest levels of incorrect ISCU splice variants compared with heart, brain, liver and kidney using a transgenic mouse model expressing human HML mutated ISCU. We also show that incorrect splicing occurs to a significantly higher extent in the slow-twitch soleus muscle compared with the gastrocnemius and quadriceps. The splicing factor serine/arginine-rich splicing factor 3 (SRSF3) was identified as a potential candidate for the slow fiber specific regulation of ISCU splicing since this factor was expressed at higher levels in the soleus compared to the gastrocnemius and quadriceps. We identified an interaction between SRSF3 and the ISCU transcript, and by overexpressing SRSF3 in human myoblasts we observed increased levels of incorrectly spliced ISCU, while knockdown of SRSF3 resulted in decreased levels. We therefore suggest that SRSF3 may participate in the regulation of the incorrect splicing of mutant ISCU and may, at least partially, explain the muscle-specific symptoms of HML.
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43.
  • Rawcliffe, Denise F. R., 1988- (författare)
  • The regulation of incorrect splicing of ISCU in hereditary myopathy with lactic acidosis
  • 2018
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Patients suffering from hereditary myopathy with lactic acidosis (HML) can be found in the northern Swedish counties of Ångermanland and Västerbotten. HML is a rare autosomal recessive disease where patients display a low tolerance to exercise at an early age. Exercise can trigger symptoms such as palpitations, tachycardia, muscle cramps and dyspnoea. Extensive exercise or strict diets can result in myoglobinuria and life-threatening levels of lactic acid. The disease is caused by a nonsense G > C mutation (c.418 + 328G < C) in the last intron of the iron-sulphur (FeS) cluster assembly gene (ISCU), resulting in nonsense-mediated decay (NMD) of the transcript due to incorrect splicing. The ISCU protein is involved in the assembly of FeS clusters, which are essential cofactors for a wide range of proteins. Patient muscles display decreased levels of several FeS cluster proteins: mitochondrial aconitase in the tricarboxylic acid (TCA) cycle and Complex I, II (succinate dehydrogenase [SDH]) and III in the electron transport chain (ETC). The incorrect splicing of ISCU occurs to the highest extent in HML patient skeletal muscle, restricting the loss of ISCU protein to muscles, thereby preventing a more severe phenotype.We found that the incorrect splicing occurs to the highest extent in slow-fibre muscle, which may be caused by the serine/arginine-rich splicing factor (SRSF3) as it is expressed at higher levels in slow-fibre muscle compared to other muscles, and since it is able to activate the incorrect splicing of ISCU. Following muscle, there is a gradual decrease of the incorrect splicing in heart, brain, liver and kidney, which is negatively correlated with the levels of the splicing inhibitor polypyrimidine-tract binding protein 1 (PTBP1). Overexpression of PTBP1 in HML patient myoblasts resulted in a drastic decrease in the incorrect splicing, while a PTBP1 knockdown had the opposite effect. Our results suggest that PTBP1 acts as a dominant inhibitor of the incorrect splicing and is likely the main cause for the tissue-specific splicing of ISCU in HML. We also identified RBM39 and MBNL1 as activators of the incorrect splicing of ISCU, which, together with the low levels of PTBP1, could explain the high levels of incorrect splicing in muscle.Since almost 95% of all human gene transcripts are alternatively spliced, it is not surprising that a wide range of diseases are caused by mutations that affect splicing. Further knowledge of the function of splicing, such as tissue-specific splicing, can provide vital information for the development of therapies for diseases caused by splicing.
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44.
  • Rudenstam, Carl-Magnus, 1930, et al. (författare)
  • Randomized trial comparing axillary clearance versus no axillary clearance in older patients with breast cancer: first results of International Breast Cancer Study Group Trial 10-93.
  • 2006
  • Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 1527-7755. ; 24:3, s. 337-44
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: Axillary clearance in early breast cancer aims to improve locoregional control and provide staging information but is associated with undesirable morbidity. We therefore investigated whether avoiding axillary surgery in older women would result in improved quality of life (QL) with similar disease-free survival (DFS) and overall survival (OS). PATIENTS AND METHODS: Between 1993 and 2002, women > or = 60 years old with clinically node-negative operable breast cancer in whom adjuvant tamoxifen was considered indicated regardless of pathologic nodal status were randomly assigned to primary surgery plus axillary clearance (Sx + Ax) followed by tamoxifen (Tam) versus Sx without Ax followed by Tam for 5 consecutive years. The primary end point was QL reported by the patient and by physician assessment. RESULTS: A total of 473 patients (234 to Sx + Ax, 239 to Sx) were randomly assigned. The median age was 74 years; 80% had estrogen receptor-positive disease. In both the patients' subjective assessment of their QL and the physicians' perception of the patients' QL, the largest adverse QL effects of Ax were observed from baseline to the first postoperative assessment, but the differences tended to disappear in 6 to 12 months. At a median follow-up of 6.6 years, results for Sx + Ax and Sx yielded similar DFS (6-year DFS, 67% v 66%; hazard ratio [HR] Sx + Ax/Sx, 1.06; 95% CI, 0.79 to 1.42; P = .69) and OS (6-year OS, 75% v 73%; HR Sx + Ax/Sx, 1.05; 95% CI, 0.76 to 1.46; P = .77). CONCLUSION: Avoiding axillary clearance for women > or = 60 years old who have clinically node-negative disease and receive Tam for endocrine-responsive disease yields similar efficacy with better early QL.
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45.
  • Sellgren, Mariana, 1958- (författare)
  • Den dubbla uppgiften : Tvåspråkiga elever i skolans mellanår arbetar med förklarande genre i SO
  • 2011
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • I denna licentiatuppsats undersöks det klassrumsarbete som sker i en flerspråkig elevgrupp i år 6 där SO-undervisningen är genrebaserad. Studien har fokus på elevernas deltagande i muntlig interaktion och skrivande av text när klassen arbetar med förklarande genre i geografi. I studien synliggörs mer av det som lärare i pågående arbete inte kan få del av d v s det som är bortom, eller mellan, lärarledda helklassamtal och färdigproducerade texter. Teoretiska utgångspunkter är sociokulturellt perspektiv, forskning om andraspråkinlärning och systemisk-funktionell lingvistik. En övergripande fråga är vilka språkliga resurser eleverna framförallt använder sig av i tal och skrift för att förklara. Data utgörs av lärobokstext, muntlig interaktion och klassrumsproducerade texter. Muntlig interaktion äger rum vid gemensam läsning och dekonstruktion av lärobokstext och gemensamt skrivande i helklass respektive smågrupp. Klassrumstexterna är av tre kategorier: skrivna i helklass under lärarledning, skrivna i smågrupp och individuellt. Materialet analyseras utifrån genre, realisering av kausalitet och semantiska ledfamiljer. Genreanalysen har fokus på struktur, analysen av kausala samband utgår från uppdelningen kongruenta och icke-kongruenta uttryckssätt och i analysen av semantiska fält studeras rörelser på olika abstraktionsnivå inom samma ledfamilj. Resultaten visar att eleverna i interaktivt smågruppsarbete har stort fokus på att förklara ämnesinnehåll som förutsättning för att appropriera språkliga resurser och för att skriva egen text. I gruppens muntliga interaktion rör sig eleverna mer i ett vardagligt/konkret språkligt register när de förklarar och diskuterar förlopp och skeenden för att sedan i den skrivna texten använda sig mer av ett mer abstrakt/tekniskt skolspråk. Det finns exempel på att eleverna ändrar språklig nivå på varandras yttranden genom att omformulera dem till ett mer abstrakt/tekniskt språkbruk. Det finns exempel på att en elevs yttrande upplevs för abstrakt/tekniskt och att kamraterna då efterfrågar en uppackning av ett alltför nominaliserat språkbruk, med följd att det förklaras konkret steg för steg. Samtliga skrivna texter i materialet är faktoriella förklaringar.
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46.
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47.
  • Ström, Anna-Lena, et al. (författare)
  • A role for both wild-type and expanded ataxin-7 in transcriptional regulation
  • 2005
  • Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961 .- 1095-953X. ; 20:3, s. 646-655
  • Tidskriftsartikel (refereegranskat)abstract
    • Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease primarily affecting the brainstem, retina and Purkinje cells of the cerebellum. The disease is caused by a polyglutamine expansion in ataxin-7, a protein found in two complexes TFTC and STAGA, involved in transcriptional regulation. Transcriptional dysregulation has been implicated in the pathology of several polyglutamine diseases. In this paper, we analyzed the effect of both wild-type and expanded ataxin-7 on transcription driven by the co-activator CBP and the Purkinje cell expressed nuclear receptor RORα1. We could show that transcription mediated by both CBP and RORα1 was repressed by expanded ataxin-7. Interestingly, repression of transcription could also be observed with wild-type full-length ataxin-7, not only on CBP- and RORα1-mediated transcription, but also on basal transcription. The repression could be counteracted by inhibition of deacetylation, suggesting that ataxin-7 may act as a repressor of transcription by inhibiting the acetylation activity of TFTC and STAGA.
  •  
48.
  • Ström, Anna-Lena, et al. (författare)
  • Cloning and expression analysis of the murine homolg of the Spinocerebellar ataxia type 7 (SCA7) gene
  • 2002
  • Ingår i: Gene. - : Elsevier. ; 285:1-2, s. 91-99
  • Tidskriftsartikel (refereegranskat)abstract
    • Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease caused by the expansion of a polyglutamine tract in the protein ataxin-7, a protein of unknown function. In order to analyze the expression pattern of wild type ataxin-7 in detail, the murine SCA7 gene homolog was cloned and the expression pattern in mice analyzed. The SCA7 mouse and human gene exhibit a high degree of identity at both DNA (88.2%) and protein (88.7%) level. The CAG repeat region, known to be polymorphic in man, is conserved in mouse but contained only five repeats in all mouse strains analyzed. The arrestin homology domain and the nuclear localization signal found in human ataxin-7 is also conserved in the murine homolog. Expression of ataxin-7 was detected during mouse embryonic development and in all adult mouse tissues examined by northern and western blots. In brain, immunohistological staining revealed an ataxin-7 expression pattern similar to that in human, with ataxin-7 expression in cerebellum, several brainstem nuclei, cerebral cortex and hippocampus. Our data show high conservation of ataxin-7 both structurally and at the level of expression, suggesting a conserved role for the protein in mice and humans.
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49.
  • Ström, Anna-Lena, 1975- (författare)
  • Expression and functional analysis of the SCA7 disease protein ataxin-7
  • 2004
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease characterized by cerebellar ataxia and visual problems due to a progressive and selective loss of neurons within the cerebellum, brainstem and retina. The disease is caused by the expansion of a CAG repeat in the first coding exon of the SCA7 gene, resulting in an expanded polyglutamine domain in the N-terminal part of ataxin-7, a protein of unknown function.To expand our knowledge of the ataxin-7 protein and the mechanism by which mutant ataxin-7 causes disease, we have studied the expression and function of both the normal and the mutated ataxin-7 protein.Ataxin-7 expression was examination in brain and non-CNS tissues from SCA7 patients and age-matched controls. Expression was predominantly nuclear in neurons throughout the brain of both healthy and SCA7 individuals. We also observed aggregation of mutant ataxin-7 in the nuclei of neurons. No obvious difference in the expression level of ataxin-7 or the formation of aggregates could be observed between affected and non-affected brain regions in SCA7 patients. Based on these findings, we could conclude that the cell type specific neurodegeneration in SCA7 is not due to differences in expression levels or to the formation of ataxin-7 aggregates.To widen our studies on ataxin-7 expression, we isolated and characterized the mouse SCA7 gene homolog. Cloning of the mouse SCA7 gene revealed two SCA7 mRNA isoforms that were highly homologous to their human counterparts. Immunohistochemical analysis also revealed a conserved expression pattern of ataxin-7 in adult mouse brain. In addition, ataxin-7 expression was observed during embryonic development in brain as well as in several non-neuronal tissues such as heart, liver and lung.Besides SCA7, eight neurodegenerative disorders are known to be caused by expanded polyglutamine repeats, including SCA 1-3, 6 and 17, DRPLA, SBMA and Huntington’s disease. The polyglutamine disorders have many features in common and a common pathological disease mechanism involving transcriptional dysregulation has been proposed. To investigate the possible involvement of transcriptional dysregulation in SCA7 pathology, we analyzed the effects of both wild-type and expanded ataxin-7 on transcription driven by the co-activator CBP, the Purkinje cell-expressed nuclear receptor RORα1 or a basic TATA promoter. As previously shown for other polyglutamine disease proteins, expansion of the polyglutamine domain in ataxin-7 leads to reduced transcription. Surprisingly, strong repression of CBP-mediated, RORα1-mediated and basal transcription was also observed with wild-type ataxin-7, suggesting that the normal ataxin-7 protein may have a role in transcriptional regulation.
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50.
  • Ström, Anna-Lena, et al. (författare)
  • Identification and characterization of Spinocerebellar Ataxia Type 7 (SCA7) isoform SCA7b in mice
  • 2005
  • Ingår i: Biochimica et Biophysica Acta. - : Elsevier BV. - 0006-3002 .- 1878-2434. ; 1731:3, s. 149-153
  • Tidskriftsartikel (refereegranskat)abstract
    • Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease primarily affecting the cerebellum, brainstem and retina. The disease is caused by a polyglutamine expansion in ataxin-7, a protein with largely unknown function. To improve our knowledge of the expression and function of wild-type and expanded ataxin-7, we looked for alternative SCA7 transcripts in mice. We identified a murine SCA7 isoform (SCA7b) containing an uncharacterized exon homologous to the newly identified human exon 12b. Northern blot analysis revealed three exon 12b containing transcripts with molecular sizes of 7.5, 4.4 and 3.0 kb in mice. This contrasted with the situation in humans, where only one exon 12b-containing transcript was observed. Furthermore, Northern blot of the human 4.4 kb SCA7b isoform predominantly showed expression in the brain, while expression of both the murine 7.5-kb and the 4.4-kb transcripts were observed in several tissues including brain, heart, liver, kidney and testis. Quantitative real-time RT-PCR analysis revealed that in muscle and heart SCA7b is the predominant SCA7 isoform, while in brain equal levels of SCA7a and SCA7b was observed. Insertion of exon 12b into the murine SCA7 ORF resulted in a frame-shift that gave rise to an alternative ataxin-7 protein (ataxin-7b). The novel 58-amino acid C-terminus in ataxin-7b directed the protein to a more cytoplasmic location.
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