| 1. |
- Barg, Sebastian, et al.
(author)
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Delay between fusion pore opening and peptide release from large dense-core vesicles in neuroendocrine cells.
- 2002
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In: Neuron. - 0896-6273 .- 1097-4199. ; 33:2, s. 287-299
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Journal article (peer-reviewed)abstract
- Peptidergic neurotransmission is slow compared to that mediated by classical neurotransmitters. We have studied exocytotic membrane fusion and cargo release by simultaneous capacitance measurements and confocal imaging of single secretory vesicles in neuroendocrine cells. Depletion of the readily releasable pool (RRP) correlated with exocytosis of 10%-20% of the docked vesicles. Some remaining vesicles became releasable after recovery of RRP. Expansion of the fusion pore, seen as an increase in luminal pH, occurred after approximately 0.3 s, and peptide release was delayed by another 1-10 s. We conclude that (1) RRP refilling involves chemical modification of vesicles already in place, (2) the release of large neuropeptides via the fusion pore is negligible and only proceeds after complete fusion, and (3) sluggish peptidergic transmission reflects the time course of vesicle emptying.
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| 2. |
- Bengtsson, Daniel, 1975-, et al.
(author)
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Corticotroph Pituitary Carcinoma in a Patient With Lynch Syndrome (LS) and Pituitary Tumors in a Nationwide LS Cohort
- 2017
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In: Journal of Clinical Endocrinology and Metabolism. - : OXFORD UNIV PRESS INC. - 0021-972X .- 1945-7197. ; 102:11, s. 3928-3932
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Journal article (peer-reviewed)abstract
- Context: Lynch syndrome (LS) is a cancer-predisposing syndrome caused by germline mutations in genes involved in DNA mismatch repair (MMR). Patients are at high risk for several types of cancer, but pituitary tumors have not previously been reported. Case: A 51-year-old man with LS (MSH2 mutation) and a history of colon carcinoma presented with severe Cushing disease and a locally aggressive pituitary tumor. The tumor harbored a mutation consistent with the patients germline mutation and displayed defect MMR function. Sixteen months later, the tumor had developed into a carcinoma with widespread liver metastases. The patient prompted us to perform a nationwide study in LS. Nationwide Study: A diagnosis consistent with a pituitary tumor was sought for in the Swedish National Patient Registry. In 910 patients with LS, representing all known cases in Sweden, another two clinically relevant pituitary tumors were found: an invasive nonsecreting macroadenoma and a microprolactinoma (i.e., in total three tumors vs. one expected). Conclusion: Germline mutations in MMR genes may contribute to the development and/or the clinical course of pituitary tumors. Because tumors with MMR mutations are susceptible to treatment with immune checkpoint inhibitors, we suggest to actively ask for a family history of LS in the workup of patients with aggressive pituitary tumors.
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| 3. |
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| 4. |
- Carlsson, PO, et al.
(author)
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Unaltered pancreatic islet blood perfusion in islet amyloid polypeptide-deficient mice
- 2002
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In: European Journal of Endocrinology. - : Oxford University Press (OUP). - 1479-683X .- 0804-4643. ; 146:1, s. 107-112
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Journal article (peer-reviewed)abstract
- Objective: Several biological activities have been ascribed to islet amyloid polypeptide (IAPP). However, their physiological relevance remains unclear. Previous studies in rats with exogenous administration of IAPP suggest that the peptide may increase splanchnic vascular resistance and redistribute the blood flow within the pancreas to the islets. In this study, the use of IAPP-deficient mice allowed us to evaluate possible effects of the lack of IAPP on splanchnic blood perfusion and we could thereby circumvent the potentially pharmacological actions of exogenously administered IAPP Design: Regional splanchnic blood flow was measured after exogenous administration of IAPP and in IAPP-deficient mice. Methods: Blood flow values were determined using a non-radioactive microsphere technique in anesthetized animals. Results: No differences in whole pancreatic blood flow or islet blood flow could be detected in IAPP-deficient mice when compared with control mice; neither did IAPP deficiency affect the glucose-induced increase in islet blood flow. Duodenal, ileal and colonic blood flows were similar in IAPP-deficient and control mice. Exogenous administration of IAPP selectively increased islet blood flow in wild-type control mice. Conclusions: The present findings in the IAPP-deficient mice suggest that the vascular effects seen in the islets after exogenous administration of IAPP to normal mice reflect pharmacological, rather than physiological effects of the peptide. We conclude that the lack of endogenous IAPP within the splanchnic vascular system does not alter the blood perfusion of pancreatic islets or other splanchnic organs.
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| 5. |
- Christaller, Wilhelm A A, et al.
(author)
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L1 syndrome diagnosis complemented with functional analysis of L1CAM variants located to the two N-terminal Ig-like domains.
- 2016
-
In: Clinical Genetics. - : Wiley. - 0009-9163.
-
Journal article (peer-reviewed)abstract
- L1CAM gene mutations cause neurodevelopmental disorders collectively termed L1 syndrome. Insufficient information about L1CAM variants complicates clinical prognosis, genetic diagnosis and genetic counseling. We combined clinical data, in silico effect predictions and functional analysis of four L1CAM variants, p.I37N, p.D202Y, p.M172I and p.T38M, located to the two N-terminal Ig-like domains present in five families with symptoms of L1 syndrome. Software tools predicted destabilizing effects of p.I37N and p.D202Y but results for p.T38M and p.M172I were inconsistent. Cell surface expression of mutant proteins L1-T38M, L1-M172I and L1-D202Y was normal. Conversely, L1-I37N accumulated in the endoplasmic reticulum and showed temperature-sensitive protein maturation suggesting that p.I37N induces protein misfolding. L1CAM-mediated cell-cell aggregation was severely impaired by L1CAM variants p.I37N, p.M172I and p.D202Y but was preserved by the variant p.T38M. Our experimental data indicate that protein misfolding and accumulation in the endoplasmic reticulum affect function of the L1CAM variant p.I37N whereas the variants p.M172I and p.D202Y impair homophilic interaction at the cell surface.
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| 6. |
- Dacquin, R, et al.
(author)
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Amylin inhibits bone resorption while the calcitonin receptor controls bone formation in vivo
- 2004
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In: Journal of Cell Biology. - : Rockefeller University Press. - 0021-9525 .- 1540-8140. ; 164:4, s. 509-514
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Journal article (peer-reviewed)abstract
- Amylin is a member of the calcitonin family of hormones cosecreted with insulin by pancreatic beta cells. Cell culture assays suggest that amylin could affect bone formation and bone resorption, this latter function after its binding to the calcitonin receptor (CALCR). Here we show that Amylin inactivation leads to a low bone mass due to an increase in bone resorption, whereas bone formation is unaffected. In vitro, amylin inhibits fusion of mononucleated osteoclast precursors into multinucleated osteoclasts in an ERK1/2-dependent manner. Although Amylin +/- mice like Amylin-deficient mice display a low bone mass phenotype and increased bone resorption, Calcr +/- mice display a high bone mass due to an increase in bone formation. Moreover, compound heterozygote mice for Calcr and Amylin inactivation displayed bone abnormalities observed in both Calcr +/- and Amylin +/- mice, thereby ruling out that amylin uses CALCR to inhibit osteoclastogenesis in vivo. Thus, amylin is a physiological regulator of bone resorption that acts through an unidentified receptor.
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| 7. |
- Dalene Skarping, Karin, et al.
(author)
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Attenuated huntingtin gene CAG nucleotide repeat size in individuals with Lynch syndrome
- 2024
-
In: Scientific Reports. - 2045-2322. ; 14:1
-
Journal article (peer-reviewed)abstract
- DNA mismatch repair (MMR) is thought to contribute to the onset and progression of Huntington disease (HD) by promoting somatic expansion of the pathogenic CAG nucleotide repeat in the huntingtin gene (HTT). Here we have studied constitutional HTT CAG repeat size in two cohorts of individuals with Lynch syndrome (LS) carrying heterozygous loss-of-function variants in the MMR genes MLH1 (n = 12/60; Lund cohort/Bochum cohort, respectively), MSH2 (n = 15/88), MSH6 (n = 21/23), and controls (n = 19/559). The sum of CAG repeats for both HTT alleles in each individual was calculated due to unknown segregation with the LS allele. In the larger Bochum cohort, the sum of CAG repeats was lower in the MLH1 subgroup compared to controls (MLH1 35.40 CAG repeats ± 3.6 vs. controls 36.89 CAG repeats ± 4.5; p = 0.014). All LS genetic subgroups in the Bochum cohort displayed lower frequencies of unstable HTT intermediate alleles and lower HTT somatic CAG repeat expansion index values compared to controls. Collectively, our results indicate that MMR gene haploinsufficiency could have a restraining impact on constitutional HTT CAG repeat size and support the notion that the MMR pathway is a driver of nucleotide repeat expansion diseases.
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| 8. |
- Fergelot, Patricia, et al.
(author)
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Phenotype and genotype in 52 patients with Rubinstein–Taybi syndrome caused by EP300 mutations
- 2016
-
In: American Journal of Medical Genetics. Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 170:12, s. 3069-3082
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Journal article (peer-reviewed)abstract
- Rubinstein–Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8–10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype–phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia.
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| 9. |
- Fredholm, BB, et al.
(author)
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Consequences of eliminating adenosine A(1) receptors in mice
- 2003
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In: Drug Development Research (Proceedings of the Seventh International Symposium on Adenosine and Adenine Nucleotides - Part 1). - : Wiley. - 1098-2299 .- 0272-4391. ; 58, s. 350-
-
Conference paper (peer-reviewed)abstract
- The second coding exon of the adenosine A, receptor gene was eliminated by homologous recombination. The phenotype of mice (mixed C57B6/129OlaHsd background) was studied, using siblings from matings of heterozygous mice. Among the offspring the ratio between+/+, +/-and -/-animals was 1:2:1. Over the first half-year-at least-growth and viability were the same in all genotypes. Binding of A(1) ligands was eliminated in-/-mice and halved in+/-mice. Blood pressure was increased in-/-mice and this was paralleled by an increase in plasma renin. Heart rate was unaffected, as was contractility. Furthermore, the response of the perfused heart to ischemia was similar in+/+and -/-hearts. However, remote preconditioning was eliminated in-/-mouse hearts. Tubuloglomerular feedback in the kidney was also lost in-/-mice. The analgesic response to a non-selective adenosing receptor agonist was lost in-/-mice, which also showed hyperalgesia in the tail-flick test. There was a slight hypoactivity in-/-mice, but responses to caffeine were essentially normal. The inhibition of excitatory neurotransmission in hippocampus by adenosine was lost in-/-mice and reduced in+/-mice. Responses to ATP were affected similarly. Hypoxic depression of synaptic transmission was essentially eliminated in hippocampus and hypoxic decrease in spinal respiratory neuron firing was markedly reduced. These results show that adenosine A, receptors play a physiologically important role in the kidney, spinal cord, and hippocampus and that they are critically important in the adaptive responses to hypoxia. (C) 2003 Wiley-Liss, Inc.
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| 10. |
- Gebre-Medhin, Samuel, et al.
(author)
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Recurrent Rearrangement of the PHF1 Gene in Ossifying Fibromyxoid Tumors.
- 2012
-
In: American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 181:3, s. 1069-1077
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Journal article (peer-reviewed)abstract
- Ossifying fibromyxoid tumor (OFMT) is a soft tissue tumor of unknown lineage. Although most cases are histologically and clinically benign, some show malignant morphological features and local recurrences are not uncommon; a few may even metastasize. In the present study, cytogenetic analysis identified different structural rearrangements of chromosome band 6p21 in tumor cells from three cases of OFMT, including one with typical, one with atypical, and one with malignant morphological features. Mapping of the 6p21 breakpoint by fluorescence in situ hybridization (FISH) indicated that the PHF1 gene was rearranged in all three cases. Further FISH, 5'-rapid amplification of cDNA ends, and RT-PCR analyses disclosed an EP400/PHF1 fusion transcript in one of the cases. Interphase FISH on tumor sections from 13 additional cases of OFMT showed rearrangement of the PHF1 locus in four of four typical, two of three atypical, and one of six malignant lesions. Thus, the PHF1 gene, previously shown to be the 3'-partner of fusion genes in endometrial stromal tumors, is also recurrently involved in the pathogenesis of OFMTs, irrespective of whether they are diagnosed as typical, atypical, or malignant lesions. The PHF1 protein interacts with the polycomb-repressive complex 2 (PRC2), which, in turn, regulates the expression of a variety of developmental genes. Thus, the results indicate that deregulation of PRC2 target genes is crucial for OFMT development.
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| 11. |
- Gebre-Medhin, Samuel, et al.
(author)
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Telomeric associations correlate with telomere length reduction and clonal chromosome aberrations in giant cell tumor of bone.
- 2009
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In: Cytogenetic and Genome Research. - : S. Karger AG. - 1424-859X .- 1424-8581. ; 124:2, s. 121-127
-
Journal article (peer-reviewed)abstract
- Giant cell tumor of bone (GCTB) is characterized cytogenetically by frequent telomeric associations (tas). To explore the mechanisms behind the formation of tas in GCTB and to investigate their karyotypic consequences, the frequencies of tas and clonal aberrations other than tas in 20 GCTBs were compared to telomere length and status, as assessed by quantitative PCR, fluorescence in situ hybridization (FISH), and expression levels of four genes involved in telomere maintenance. Based on the G-banding results, the tumors were divided into two groups, one with a high frequency of tas and one with a low frequency. Clonal aberrations were found to be restricted to the group with a high level of tas, and the same group showed a significantly larger reduction in telomere length in tumor cells compared to peripheral blood cells. Furthermore, 65 out of 66 tas analyzed by FISH were negative for telomeric sequences. The expression levels of TERT, TERF1, TERF2, and POT1 did not correlate with telomere length or the frequency of tas. Thus, the present findings provide strong support for the notion that decreased telomere length is a prerequisite for tas in GCTBs and that the clonal changes occurring in GCTBs are derived from tas.
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| 12. |
- Henriksson, Isabelle, et al.
(author)
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Hereditary colorectal cancer diagnostics in southern Sweden : retrospective evaluation and future considerations with emphasis on Lynch syndrome
- 2019
-
In: Journal of Community Genetics. - : Springer Science and Business Media LLC. - 1868-310X .- 1868-6001. ; 10:2, s. 259-266
-
Journal article (peer-reviewed)abstract
- Overlapping phenotypes between different hereditary colorectal cancer (CRC) syndromes together with a growing demand for cancer genetic testing and improved sequencing technology call for adjusted patient selection and adapted diagnostic routines. Here we present a retrospective evaluation of family history of cancer, laboratory diagnostic procedure, and outcome for 372 patients tested for Lynch syndrome (LS), i.e., the single most common hereditary cause of CRC. Based on number of affected family members and age at cancer diagnosis in families with genetically confirmed LS, we developed local patient selection criteria for a simplified one-step gene panel mutation screening strategy targeting also less common Mendelian CRC syndromes. Pros and cons of this strategy are discussed.
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| 13. |
- Karimi, Masoud, et al.
(author)
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A retrospective study of extracolonic, non-endometrial cancer in Swedish Lynch syndrome families
- 2018
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In: Hereditary Cancer in Clinical Practice. - : BMC. - 1731-2302 .- 1897-4287. ; 16
-
Journal article (peer-reviewed)abstract
- BackgroundLynch Syndrome is an autosomal dominant cancer syndrome caused by pathogenic germ-line variants in one of the DNA-mismatch-repair (MMR) genes MLH1, MSH2, MSH6 or PMS2. Carriers are predisposed to colorectal and endometrial cancer, but also other cancer types. The purpose of this retrospective study was to characterize the tumour spectrum of the Swedish Lynch syndrome families.MethodsData were obtained from genetically verified 235 Lynch families from five of the six health care regions in Sweden. The material was stratified for gender, primary cancer, age and mutated gene and the relative proportions of specific cancer types were compared to those in the general population.ResultsA total of 1053 family members had 1493 cancer diagnoses of which 1011 were colorectal or endometrial cancer. Individuals with pathogenic variants in MLH1 and MSH2 comprised 78% of the cohort. Among the 482 non-colorectal/non-endometrial cancer diagnoses, MSH2 carriers demonstrated a significantly increased proportion of urinary tract, gastric, small bowel, ovarian and non-melanoma skin cancer compared to the normal population. MLH1 carriers had an elevated proportion of gastrointestinal cancers (gastric, small bowel, pancreas), while MSH6 carriers had more ovarian cancer than expected. Gastric cancer was predominantly noted in older generations.ConclusionLynch syndrome confers an increased risk for multiple cancers other than colorectal and endometrial cancer. The proportions of other cancers vary between different MMR genes, with highest frequency in MSH2-carriers. Gender and age also affect the tumour spectrum, demonstrating the importance of additional environmental and constitutional parameters in determining the predisposition for different cancer types.
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| 14. |
- Karimi, Masoud, et al.
(author)
-
A retrospective study of extracolonic, non-endometrial cancer in Swedish Lynch syndrome families 11 Medical and Health Sciences 1112 Oncology and Carcinogenesis 11 Medical and Health Sciences 1117 Public Health and Health Services
- 2018
-
In: Hereditary Cancer in Clinical Practice. - : Springer Science and Business Media LLC. - 1731-2302 .- 1897-4287. ; 16:1
-
Journal article (peer-reviewed)abstract
- Background: Lynch Syndrome is an autosomal dominant cancer syndrome caused by pathogenic germ-line variants in one of the DNA-mismatch-repair (MMR) genes MLH1, MSH2, MSH6 or PMS2. Carriers are predisposed to colorectal and endometrial cancer, but also other cancer types. The purpose of this retrospective study was to characterize the tumour spectrum of the Swedish Lynch syndrome families. Methods: Data were obtained from genetically verified 235 Lynch families from five of the six health care regions in Sweden. The material was stratified for gender, primary cancer, age and mutated gene and the relative proportions of specific cancer types were compared to those in the general population. Results: A total of 1053 family members had 1493 cancer diagnoses of which 1011 were colorectal or endometrial cancer. Individuals with pathogenic variants in MLH1 and MSH2 comprised 78% of the cohort. Among the 482 non-colorectal/non-endometrial cancer diagnoses, MSH2 carriers demonstrated a significantly increased proportion of urinary tract, gastric, small bowel, ovarian and non-melanoma skin cancer compared to the normal population. MLH1 carriers had an elevated proportion of gastrointestinal cancers (gastric, small bowel, pancreas), while MSH6 carriers had more ovarian cancer than expected. Gastric cancer was predominantly noted in older generations. Conclusion: Lynch syndrome confers an increased risk for multiple cancers other than colorectal and endometrial cancer. The proportions of other cancers vary between different MMR genes, with highest frequency in MSH2-carriers. Gender and age also affect the tumour spectrum, demonstrating the importance of additional environmental and constitutional parameters in determining the predisposition for different cancer types.
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| 15. |
- Mulder, Hindrik, et al.
(author)
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Pituitary adenylate cyclase-activating polypeptide and islet amyloid polypeptide in primary sensory neurons : Functional implications from plasticity in expression on nerve injury and inflammation
- 1999
-
In: Molecular Neurobiology. - 0893-7648. ; 19:3, s. 229-253
-
Research review (peer-reviewed)abstract
- Primary sensory neurons serve a dual role as afferent neurons, conveying sensory information from the periphery to the central nervous system, and as efferent effectors mediating, e.g., neurogenic inflammation. Neuropeptides are crucial for both these mechanisms in primary sensory neurons. In afferent functions, they act as messengers and modulators in addition to a principal transmitter; by release from peripheral terminals, they induce an efferent response, 'neurogenic inflammation,' which comprises vasodilatation, plasma extravasation, and recruitment of immune cells. In this article, we introduce two novel members of the sensory neuropeptide family: pituitary adenylate cyclase-activating polypeptide (PACAP) and islet amyloid polypeptide (IAPP). Whereas PACAP, a vasoactive intestinal polypeptide-resembling peptide, predominantly occurs in neuronal elements, IAPP, which is structurally related to calcitonin gene-related peptide, is most widely known as a pancreatic β-cell peptide; as such, it has been recognized as a constituent of amyloid deposits in type 2 diabetes. In primary sensory neurons, under normal conditions, both peptides are predominantly expressed in small-sized nerve cell bodies, suggesting a role in nociception. On axotomy, the expression of PACAP is rapidly induced, whereas that of IAPP is reduced. Such a regulation of PACAP suggests that it serves a protective role during nerve injury, but that of IAPP may indicate that it is an excitatory messenger under normal conditions. In contrast, in localized adjuvant-induced inflammation, expression of both peptides is rapidly induced. For IAPP, studies in IAPP-deficient mice support the notion that IAPP is a pronociceptive peptide, because these mutant mice display a reduced nociceptive response when challenged with formalin.
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| 16. |
- Olkinuora, A., et al.
(author)
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Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition
- 2019
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In: Genetics in Medicine. - : Elsevier BV. - 1098-3600. ; 21:8, s. 1868-1873
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Journal article (peer-reviewed)abstract
- Purpose: Some 10% of familial adenomatous polyposis (FAP) and 80% of attenuated polyposis (AFAP) cases remain molecularly unexplained. We scrutinized such cases by exome-wide and targeted methods to search for novel susceptibility genes. Methods: Exome sequencing was conducted on 40 unexplained (mainly sporadic) cases with FAP or AFAP from Finland. The DNA mismatch repair (MMR) gene MLH3 (MutL Homolog 3) was pinpointed and prompted a subsequent screen of similar to 1000 Swedish patients referred to clinical panel sequencing for colon tumor susceptibility. Results: Three homozygous carriers of a truncating variant in MLH3, c.3563C>G, p.Ser1188Ter, were identified among the index cases from the Finnish series. An additional biallelic carrier of the same variant was present in the Swedish series. All four patients shared a 0.8-Mb core haplotype around MLH3, suggesting a founder variant. Colorectal polyps from variant carriers showed no instability at mono-, di-, tri-, or tetranucleotide repeats, in agreement with previous findings of a minor role of MLH3 in MMR. Multiple loci were affected by loss of heterozygosity, suggesting chromosomal instability. Conclusion: Our results show that a biallelic nonsense variant of MLH3 underlies a novel syndrome with susceptibility to classical or attenuated adenomatous polyposis and possibly extracolonic tumors, including breast cancer.
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| 17. |
- Olsson, Madelene, et al.
(author)
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Food intake and meal pattern in IAPP knockout mice with and without infusion of exogenous IAPP
- 2012
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In: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 1502-7708 .- 0036-5521. ; 47:2, s. 191-196
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Journal article (peer-reviewed)abstract
- Objective. The current study used islet amyloid polypeptide (IAPP) knockout mice (KO mice) to investigate the physiological role of IAPP in the regulation of food intake (FI). Material and methods. FI and body weight were measured in KO and wild-type (WT) mice for 27 weeks. In an additional short-term experiment, IAPP (25 pmol . kg(-1)min(-1)) was infused subcutaneously for 3 days in KO and WT mice, and FI, meal pattern, and body weight were analyzed. Results. In the long-term experiment, no significant differences in body weight were seen between WT and KO mice at any point. FI, meal number, and meal size did not differ significantly between the groups in any of the five selected weeks that were studied. In the short-term experiment, FI decreased significantly during IAPP infusion in both WT and KO groups. FI was significantly lower in the KO mice compared with WT on days 1 and 2 (p < 0.05 and p < 0.01, respectively). Conclusions. The data showing no differences in FI and body weight were seen between KO and WT mice, indicating that FI can be controlled in the absence of IAPP. The more marked anorectic effect seen in the KO mice during IAPP infusion suggests that IAPP receptors and/or IAPP post-receptor signaling pathways are up-regulated in mice lacking endogenous IAPP.
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| 18. |
- Rohlin, Anna, et al.
(author)
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Expanding the genotype–phenotype spectrum in hereditary colorectal cancer by gene panel testing
- 2017
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In: Familial Cancer. - : Springer Science and Business Media LLC. - 1389-9600 .- 1573-7292. ; 16:2, s. 195-203
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Journal article (peer-reviewed)abstract
- Hereditary syndromes causing colorectal cancer include both polyposis and non-polyposis syndromes. Overlapping phenotypes between the syndromes have been recognized and this make targeted molecular testing for single genes less favorable, instead there is a gaining interest for multi-gene panel-based approaches detecting both SNVs, indels and CNVs in the same assay. We applied a panel including 19 CRC susceptibility genes to 91 individuals of six phenotypic subgroups. Targeted NGS-based sequencing of the whole gene regions including introns of the 19 genes was used. The individuals had a family history of CRC or had a phenotype consistent with a known CRC syndrome. The purpose of the study was to demonstrate the diagnostic difficulties linked to genotype-phenotype diversity and the benefits of using a gene panel. Pathogenicity classification was carried out on 46 detected variants. In total we detected sixteen pathogenic or likely pathogenic variants and 30 variants of unknown clinical significance. Four of the pathogenic or likely pathogenic variants were found in BMPR1A in patients with unexplained familial adenomatous polyposis or atypical adenomatous polyposis, which extends the genotype-phenotype spectrum for this gene. Nine patients had more than one variant remaining after the filtration, including three with truncating mutations in BMPR1A, PMS2 and AXIN2. CNVs were found in three patients, in upstream regions of SMAD4, MSH3 and CTNNB1, and one additional individual harbored a 24.2 kb duplication in CDH1 intron1.
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| 19. |
- Svensson, Sara, et al.
(author)
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Merged testing for colorectal cancer syndromes and re-evaluation of genetic variants improve diagnostic yield: Results from a nationwide prospective cohort
- 2022
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In: Genes Chromosomes & Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 61:10, s. 585-591
-
Journal article (peer-reviewed)abstract
- Approximately 5% of patients with colorectal cancer (CRC) have a Mendelian predisposition for the disease. Identification of the disease-causing genetic variant enables carrier testing and tailored cancer prevention within affected families. To determine the panorama and genetic variation of Mendelian CRC syndromes among referrals at the cancer genetics clinics in Sweden, 850 patients clinically selected for CRC genetic investigation were included in a prospective study that tested for all major hereditary polyposis and nonpolyposis CRC conditions. Genetically defined syndromes were diagnosed in 11% of the patients. Lynch syndrome was predominant (n = 73) followed by familial adenomatous polyposis (n = 12) and MUTYH-associated polyposis (n = 8); the latter of which two patients presented with CRC before polyposis was evident. One patient with a history of adolescent-onset CRC and polyposis had biallelic disease-causing variants diagnostic for constitutional mismatch repair deficiency syndrome. Post-study review of detected variants of unknown clinical significance (n = 129) resulted in the reclassification of variants as likely benign (n = 59) or as diagnostic for Lynch syndrome (n = 2). Our results reveal the panorama of Mendelian CRC syndromes at the cancer genetics clinics in Sweden and show that unified testing for polyposis and nonpolyposis CRC conditions as well as regular reexamination of sequence data improve the diagnostic yield.
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| 20. |
- von Salomé, Jenny, et al.
(author)
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Genetic anticipation in Swedish Lynch syndrome families
- 2017
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In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 13:10
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Journal article (peer-reviewed)abstract
- Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS) caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an increased risk of early onset colon and endometrial cancer, but also other tumors that generally have an earlier onset compared to the general population. However, age at first primary cancer varies within families and genetic anticipation, i.e. decreasing age at onset in successive generations, has been suggested in LS. Anticipation is a well-known phenomenon in e.g neurodegenerative diseases and several reports have studied anticipation in heritable cancer. The purpose of this study is to determine whether anticipation can be shown in a large cohort of Swedish LS families referred to the regional departments of clinical genetics in Lund, Stockholm, Linköping, Uppsala and Umeå between the years 1990–2013. We analyzed a homogenous group of mutation carriers, utilizing information from both affected and non-affected family members. In total, 239 families with a mismatch repair gene mutation (96 MLH1 families, 90 MSH2 families including one family with an EPCAM–MSH2 deletion, 39 MSH6 families, 12 PMS2 families, and 2 MLH1+PMS2 families) comprising 1028 at-risk carriers were identified among the Swedish LS families, of which 1003 mutation carriers had available follow-up information and could be included in the study. Using a normal random effects model (NREM) we estimate a 2.1 year decrease in age of diagnosis per generation. An alternative analysis using a mixed-effects Cox proportional hazards model (COX-R) estimates a hazard ratio of exp(0.171), or about 1.19, for age of diagnosis between consecutive generations. LS-associated gene-specific anticipation effects are evident for MSH2 (2.6 years/generation for NREM and hazard ratio of 1.33 for COX-R) and PMS2 (7.3 years/generation and hazard ratio of 1.86). The estimated anticipation effects for MLH1 and MSH6 are smaller.
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| 21. |
- Wang, Shu, et al.
(author)
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Targeted disruption of the mouse phospholipase C β3 gene results in early embryonic lethality
- 1998
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In: FEBS Letters. - 0014-5793 .- 1873-3468. ; 441:2, s. 261-265
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Journal article (other academic/artistic)abstract
- In order to investigate the biological function of phosphatidylinositol-specific phospholipase C (PLC) we generated mutant mice by gene targeting. Homozygous inactivation of PLCbeta3 is lethal at embryonic day 2.5. These mutants show poor embryonic organization as well as reduced numbers of cells. Identical phenotypes were recorded in homozygous mutants generated from two independently targeted embryonic stem cell clones. Heterozygous mutant mice, however, are viable and fertile for at least two generations. We also showed that mouse PLCbeta3 is expressed in unfertilized eggs, 3-cell and egg cylinder stages of embryos. In conclusion, these results indicate that PLCbeta3 expression is essential for early mouse embryonic development.
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| 22. |
- Westermark, Gunilla, 1958-, et al.
(author)
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Pro islet amyloid polypeptide (ProIAPP) immunoreactivity in the islets of langerhans
- 2000
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In: Upsala Journal of Medical Sciences. - 0300-9734 .- 2000-1967. ; 105:2, s. 97-106
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Journal article (peer-reviewed)abstract
- Islet amyloid is typically found in type 2 diabetes mellitus and is believed to participate in the beta cell deterioration. The islet amyloid fibril consists of the 37-amino-acid islet amyloid polypeptide (IAPP) but its pathogenesis is only partly understood. We developed several different rabbit antisera against the flanking peptides of the IAPP precursor (proIAPP) and the proIAPP processing sites in order to study the possible occurrence of unprocessed proIAPP or parts thereof in islet amyloid. We applied these antisera in an immunohistochemical study on islet amyloid deposits present in a newly generated mouse strain that over-expresses human IAPP but is devoid of mouse IAPP. Male mice of this strain develop severe islet amyloidosis when given a high fat diet. Generally, the antisera showed no immunoreactivity with the amyloid. However, in scattered single beta cells, where amyloid could be seen intracellularly, immunoreactivity with one or more of the antisera colocalized with the amyloid. Although virtually all amyloid in human islets of Langerhans is found extracellularly, we propose that the initial amyloid formation occurs intracellularly, perhaps by not fully processed or folded (pro)IAPP. This amyloid, which may develop rapidly under certain circumstances, probably leads to cell death. If not degraded these amyloid spots may then act as nidus for further amyloid formation from fully processed IAPP, secreted from surrounding beta cells.
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