| 1. |
- Burstedt, Marie, 1964-
(author)
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Bothnia dystrophy, a clinical, genetical and electrophysiological study
- 2003
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Doctoral thesis (other academic/artistic)abstract
- A high frequency of retinitis pigmentosa (RP) is found in Northern Sweden. In an inventory of autosomal recessive RP patients in Västerbotten County, a great number of cases with a unique phenotype was noticed, denoted Bothnia Dystrophy (BD). The aim of the study was to describe the phenotype, to determine the chromosomal location, and to identify the gene. Patients typically show night blindness from early childhood. Symptoms of defect macular function with a decrease of visual acuity can appear in early adulthood. The retinal fundus shows irregular white spots in a central, and parafoveal pattern along the arcades. Centrally areolar maculopathy develops and round circular atrophies are observed in the periphery. The disease was shown to be associated with a missense mutation in the RLBP1 gene resulting in an amino acid substitution (R234W) in the cellular retinaldehyde-binding protein (CRALBP). The R234W mutation was found in a homozygous state in 61 patients affected with BD. Ten patients were heterozygous for the R234W mutation, and presented a similar phenotype. No additional mutations in the coding sequence or exon-intron junctions were found. CRALBP is localised in retinal pigment epithelium (RPE), and Müller cells of the retina. In the RPE, CRALBP functions as a carrier protein for endogenous retinoids. Dark adaptometry and electrophysiologic testing showed an initial loss of rod function followed by a progressive reduction of the cone responses in older ages. A compromised rod function, dysfunction of the Müller cells, and indications of a disturbed function of the inner retina were found. With prolonged dark adaptation, a gradual increase in retinal sensitivity to light and an improvement of the ERG components occurred. The findings indicate a prolonged synthesis of photopigments, retardation of the visual process in the retinal pigment epithelium and a loss of retinal cells probably starting at a relative early age in BD. To evaluate the subjective visual function in BD patients, a battery of objective tests of visual function and composite score of the 25-item NEI-Visual Function Questionnaire (VFQ-25) were analyzed. We found that weighted distance logMAR visual acuity (WVA), had the strongest association with subjective visual function, and that there was a considerable loss of subjective and objective visual function with increasing age in BD patients. The prevalence of BD is as high as 1:3600 in Västerbotten County. The possibility that recycling of retinoids localized in the RPE might be impaired in BD might give future therapeutic possibilities. Due to the large and clinically well-characterized set of patients with this disease, they constitute a suitable study group.
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| 2. |
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| 3. |
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| 4. |
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| 5. |
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| 6. |
- Burstedt, Marie S, et al.
(author)
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Associations between specific measures of vision and vision-related quality of life in patients with bothnia dystrophy, a defined type of retinitis pigmentosa.
- 2005
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In: Retina. - : Lippincott, Williams & Wilkins. - 0275-004X .- 1539-2864. ; 25:3, s. 317-323
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Journal article (peer-reviewed)abstract
- PURPOSE: To assess the relationship between objective tests of visual function and vision-related quality of life in patients with Bothnia dystrophy (BD), a retinal dystrophy of retinitis pigmentosa type with progressive maculopathy. METHODS: Forty-nine patients were tested. Weighted distance logMAR visual acuity (WVA), weighted logMAR low contrast VA (WCS), and binocular visual field (VF) areas were calculated. Vision-related quality of life (VRQL) was assessed using the 25-item National Eye Institute-Visual Function Questionnaire (NEI-VFQ-25). Correlation statistics were used and adjusted analyses of the relationship between the composite score and the objective visual function tests were performed with multiple linear regression. RESULTS: VRQL was significantly correlated with age, WVA, WCS, and binocular VF areas (P < 0.001). Calculation of partial correlation coefficients showed age to be significantly correlated only with VF (V-4-e) area (P < 0.0001). Multiple linear regression analyses revealed age and WVA to be significantly associated with the NEI-VFQ-25 composite score (P < 0.02 and P = 0.001, respectively). WVA alone was the strongest predictor of self-reported experience of total visual function in BD patients (r 2= 0.69). CONCLUSIONS: A strong relationship between objective tests of visual function and patient perceived VRQL as assessed by a questionnaire was found. WVA was the strongest predictor and together with age explained almost 70% of the variability of the composite score of the questionnaire.
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| 7. |
- Burstedt, Marie S I, et al.
(author)
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Effects of prolonged dark adaptation in patients with retinitis pigmentosa of Bothnia type : an electrophysiological study.
- 2008
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In: Doc Ophthalmol. - 0012-4486. ; 116:3, s. 193-205
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Journal article (other academic/artistic)abstract
- Bothnia dystrophy (BD) is a variant of recessive retinitis punctata albescens (RPA), caused by the missense mutation R233W in cellular retinaldehyde-binding protein (CRALBP), which is localized in the retinal pigment epithelium (RPE) and Müller cells of the retina. The purpose of this study was, by examining the electrophysiological responses of the retina, to evaluate the capacity of recovery of the whole retinal area and different cell types induced by extremely prolonged dark adaptation (DA) in BD disease and to gain further understanding of the pathogenesis of BD. Six young patients underwent bilateral full-field ERGs after 24 h of DA in one eye and standard DA in the fellow eye. The results were also compared with the effect of prolonged DA (10 h), previously studied in the same patients. After extremely prolonged DA (24 h) the rod b-wave and the mixed rod-cone a-wave responses reached normal though delayed amplitudes. An increase, up to normal level, in the oscillatory response was found. There was no obvious recovery of the cone response. We conclude that in young BD patients during extremely prolonged DA there is a significant additional capacity of recovery of rod function and also significant gain of activity in the inner retinal layer. A continuous but slow regeneration of rod photopigment seems to occur at least up to 24 h. The visual process in the RPE is retarded and CRALBP acts in this process; also, the Müller cells of the retina seem to be involved. The findings also support an extremely slow synthesis of photopigments and irreversibly disturbed cone function early in BD.
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| 8. |
- Burstedt, Marie S I, et al.
(author)
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Retinal function in Bothnia dystrophy. An electrophysiological study.
- 2003
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In: Vision Research. - 0042-6989 .- 1878-5646. ; 43:24, s. 2559-2571
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Journal article (peer-reviewed)abstract
- Using prolonged dark adaptometry, standard dark adaptation (DA) and prolonged DA full-field electroretinograms (ERGs), we analysed the retinal function in patients with Bothnia dystrophy (BD), a variant of recessive retinitis punctata albescens (RPA). A compromised rod and cone function, a likely dysfunction of the Müller cells, and indications of disturbed neuronal function of the inner retina, were found. With prolonged DA, a gradual increase in retinal sensitivity to light and an improvement of the ERG components occurred. The findings indicate a prolonged synthesis of photopigments, retardation of the visual process in the retinal pigment epithelium (RPE), and a loss of retinal cells, probably starting at a relatively early age in BD.
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| 9. |
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| 10. |
- Dawidson, Ola, 1969, et al.
(author)
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Project Portfolio Management - a multiple case study of six Swedish companies
- 2005
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In: In proceedings of the 12th International Product Development Management Conference (EIASM) in Copenhagen, June 2005.
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Conference paper (other academic/artistic)abstract
- This paper presents the results from a multiple case study of Project Portfolio Management practices among six Swedish companies. Project portfolio management has gained much interest among practitioners in recent years, while earlier research has shown that using project portfolio management in practice is complex as it involves crucial decisions about the companys future. Such research has so far focused on the practices in US and UK companies and the present paper is to be seen as a complement.The results from the study show that all of the companies concerned have formal processes for evaluating and choosing projects for the portfolio. However, only half of them consider the project portfolio as a factor in their decisions. Two of the companies review the project portfolio regularly, and two use project portfolio management tools and methods. The decisions on the project portfolio composition are made on a cross-functional basis with people from different levels and organizational units involved.
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| 11. |
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| 13. |
- Ekström, Ulf, et al.
(author)
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A Swedish family with a mutation in the peripherin/RDS gene (Arg-172-Trp) associated with a progressive retinal degeneration
- 1998
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In: Ophthalmic Genetics. - : Swets & Zeitlinger Publishers. - 1744-5094 .- 1381-6810. ; 19:3, s. 149-156
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Journal article (peer-reviewed)abstract
- PURPOSE: To clinically characterize a Swedish family with autosomal dominant retinitis pigmentosa due to a mutation, Arg-172-Trp, in the peripherin/RDS gene. METHODS: Full clinical evaluation including kinetic visual field testing, measurement of dark-adaptation threshold, and full-field electroretinography in seven patients with autosomal dominant retinitis pigmentosa and three healthy family members. Denaturing gradient gel electrophoresis (DGGE) was used for mutation screening in seven patients and six healthy members of the family. RESULTS: Three of four siblings from the middle generation and four of the younger generation were heterozygous for the peripherin /RDS Arg-172-Trp mutation. The mutation segregated with the disease. Visual acuity decreased progressively with age and visual fields were moderately constricted in young patients, while central scotoma and constriction of the fields were detected in the family members above 50 years of age. The results from full-field electrography were comparable with a widespread retinal degeneration. CONCLUSIONS: Earlier, the peripherin/RDS Arg-172-Trp mutation was associated primarily with a macular degeneration phenotype. One previous study indicated that this mutation also can give rise to a degeneration of the more peripheral parts of the retina. In the present study, a widespread retinal degeneration is seen in the patients above 50 years of age, carrying the Arg-172-Trp mutation.
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| 14. |
- Goldsteins, Gundars, et al.
(author)
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Characterisation of two highly amyloidogenic mutants of transthyretin
- 1997
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In: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 36:18, s. 5346-5352
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Journal article (peer-reviewed)abstract
- The plasma protein transthyretin (TTR) has the potential to form amyloid under certain conditions. More than 50 different point mutations have been associated with amyloid formation that occurs only in adults. It is not known what structural changes are introduced into the structure of this otherwise stable molecule that results in its aggregation into insoluble amyloid fibrils. On the basis of calculations of the frequency of known mutations over the polypeptide, we have constructed two mutants in the D-strand of the polypeptide. These molecules, containing either a deletion or a substitution at amino acid positions 53−55, were unstable and spontaneously formed aggregates upon storage in TBS (pH 7.6). The precipitates were shown to be amyloid by staining with thioflavin T and Congo Red. Their ultrastructure was very similar to that of amyloid fibrils deposited in the vitreous body of patients with familial amyloidotic polyneuropathy type 1 with an amino acid replacement in position 30 (TTRmet30). Like amyloid isolated from the vitreous body of the eye, the amyloid precipitates generated from the TTR mutants exposed a trypsin cleavage site between amino acid residues 48 and 49, while plasma TTRmet30 isolated from amyloidosis patients as well as wild-type TTR only showed minor trypsin sensitivity. Our data indicate that the mutants we have constructed are similar to amyloid precursors or may share structural properties with intermediates on a pathway leading to amyloid deposits of plasma TTR.
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| 15. |
- Golovleva, Irina, et al.
(author)
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Disease-causing mutations in the cellular retinaldehyde binding protein tighten and abolish ligand interactions
- 2003
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In: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 278:14, s. 12397-12402
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Journal article (peer-reviewed)abstract
- Mutations in the human cellular retinaldehyde binding protein (CRALBP) gene cause retinal pathology. To understand the molecular basis of impaired CRALBP function, we have characterized human recombinant CRALBP containing the disease causing mutations R233W or M225K. Protein structures were verified by amino acid analysis and mass spectrometry, retinoid binding properties were evaluated by UV-visible and fluorescence spectroscopy and substrate carrier functions were assayed for recombinant 11-cis-retinol dehydrogenase (rRDH5). The M225K mutant was less soluble than the R233W mutant and lacked retinoid binding capability and substrate carrier function. In contrast, the R233W mutant exhibited solubility comparable to wild type rCRALBP and bound stoichiometric amounts of 11-cis- and 9-cis-retinal with at least 2-fold higher affinity than wild type rCRALBP. Holo-R233W significantly decreased the apparent affinity of rRDH5 for 11-cis-retinoid relative to wild type rCRALBP. Analyses by heteronuclear single quantum correlation NMR demonstrated that the R233W protein exhibits a different conformation than wild type rCRALBP, including a different retinoid-binding pocket conformation. The R233W mutant also undergoes less extensive structural changes upon photoisomerization of bound ligand, suggesting a more constrained structure than that of the wild type protein. Overall, the results show that the M225K mutation abolishes and the R233W mutation tightens retinoid binding and both impair CRALBP function in the visual cycle as an 11-cis-retinol acceptor and as a substrate carrier.
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| 16. |
- Golovleva, Irina, et al.
(author)
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Mutation spectra in autosomal dominant and recessive retinitis pigmentosa in northern sweden.
- 2010
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In: Advances in Experimental Medicine and Biology. - New York, NY : Springer New York. - 0065-2598 .- 2214-8019. ; 664, s. 255-262
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Journal article (peer-reviewed)abstract
- Retinal degenerations represent a heterogeneous group of disorders affecting the function of the retina. The frequency of retinitis pigmentosa (RP) is 1/3500 worldwide, however, in northern Sweden it is 1/2000 due to limited migration and a 'founder' effect. In this study we identified genetic mechanisms underlying autosomal dominant and recessive RP present in northern Sweden. Several novel mutations unique for this region were found. In an autosomal recessive form of RP, Bothnia dystrophy caused by mutations in the RLBP1 gene, bi-allelic mutations R234W, M226K and compound heterozygosity, M226K+R234W was detected.In dominant form of RP mapped to 19q13.42 a 59 kb genomic deletion including the PRPF31 and three other genes was found.These data provide additional information on the molecular mechanisms of RP evolvement and in the future might be useful in development of therapeutic strategies. Identification of the disease-causing mutations allowed introducing molecular genetic testing of the patients and their families into the clinical practice.
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| 17. |
- Holmberg, Monica, et al.
(author)
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Localization of autosomal dominant cerebellar ataxia associated with retinal degeneration and anticipation to chromosome 3p12-p21.1
- 1995
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 4:8, s. 1441-1445
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Journal article (peer-reviewed)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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| 18. |
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| 19. |
- Johansson, Jenni, et al.
(author)
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Expanded CAG repeats in Swedish Spinocerebellar ataxia type 7 (SCA7) patients : effect of repeat length on the clinical manifestation
- 1998
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 7:2, s. 171-176
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Journal article (peer-reviewed)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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| 20. |
- Jonsson, Asa C, et al.
(author)
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Tinted contact lenses in Bothnia dystrophy.
- 2007
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In: Acta Ophthalmologica Scandinavica. - : Wiley. - 1395-3907 .- 1600-0420. ; 85:5, s. 534-539
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Journal article (peer-reviewed)abstract
- PURPOSE: To determine whether tinted contact lenses can improve visual function in patients with Bothnia dystrophy (BD), a genetically defined retinal dystrophy with prolonged dark adaptation. METHODS: Twelve patients with BD were fitted with the same type of soft contact lenses tinted dark brown. Visual acuity (VA), contrast vision, near vision and visual fields were tested before and 1 month after contact lens fitting. The patients completed a visual function questionnaire. The physical properties of the contact lenses were tested using spectrophotometry. RESULTS: The patients with the lowest VA described the most obvious improvement in visual function. This group of patients preferred darker contact lenses and continued wearing their contact lenses after the study ended. The patients with the best VA preferred lighter contact lenses and a few patients in this group discontinued contact lens wear upon completion of the study. CONCLUSIONS: Visual function in BD patients was improved by dark tinted contact lenses. The optimal colour for lenses varies, depending on the season and the individual. Other patient groups with retinal dystrophies associated with prolonged dark adaptation or dysfunction of the cone system, such as cone dystrophies or achromatopsia, may also benefit from this type of contact lens.
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| 21. |
- Jonsson, Frida, et al.
(author)
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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
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In: Acta Ophthalmologica. - : John Wiley & Sons. - 1755-375X .- 1755-3768. ; 96:7, s. 737-743
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Journal article (peer-reviewed)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. |
- Jonsson, Frida, et al.
(author)
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Genetic heterogeneity and clinical outcome in a Swedish family with retinal degeneration caused by mutations in CRB1 and ABCA4 genes
- 2014
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In: Retinal Degenerative Diseases. - New York, NY : Springer Berlin/Heidelberg. - 9781461432098 - 9781461432081 ; , s. 177-183
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Conference paper (peer-reviewed)abstract
- Genetic mechanisms underlying severe retinal dystrophy in a large Swedish family presenting two distinct phenotypes, Leber congenital amaurosis and Stargardt disease were investigated. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C>T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T>C in the ABCA4 gene and another was a compound heterozygous for c.5461-10T>C and a novel ABCA4 mutation c.4773+3 A>G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants.Our results provide evidence of genetic complexity causative of different clinical features present in the same family, which is an obvious challenge for ophthalmologists, molecular geneticists and genetic counsellors.
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| 23. |
- Jonsson, Frida, et al.
(author)
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Mutations in Collagen, Type XVII, Alpha 1 (COL17A1) Cause Epithelial Recurrent Erosion Dystrophy (ERED)
- 2015
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In: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 36:4, s. 463-473
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Journal article (peer-reviewed)abstract
- Corneal dystrophies are a clinically and genetically heterogeneous group of inherited disorders that bilaterally affect corneal transparency. They are defined according to the corneal layer affected and by their genetic cause. In this study, we identified a dominantly inherited epithelial recurrent erosion dystrophy (ERED)-like disease that is common in northern Sweden. Whole-exome sequencing resulted in the identification of a novel mutation, c.2816C>T, p.T939I, in the COL17A1 gene, which encodes collagen type XVII alpha 1. The variant segregated with disease in a genealogically expanded pedigree dating back 200 years. We also investigated a unique COL17A1 synonymous variant, c.3156C>T, identified in a previously reported unrelated dominant ERED-like family linked to a locus on chromosome 10q23-q24 encompassing COL17A1. We show that this variant introduces a cryptic donor site resulting in aberrant pre-mRNA splicing and is highly likely to be pathogenic. Bi-allelic COL17A1 mutations have previously been associated with a recessive skin disorder, junctional epidermolysis bullosa, with recurrent corneal erosions being reported in some cases. Our findings implicate presumed gain-of-function COL17A1 mutations causing dominantly inherited ERED and improve understanding of the underlying pathology.
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| 24. |
- Jonsson, Frida, et al.
(author)
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Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family
- 2013
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In: European Journal of Human Genetics. - : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 21:11, s. 1266-1271
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Journal article (peer-reviewed)abstract
- This study aimed to identify genetic mechanisms underlying severe retinal degeneration in one large family from northern Sweden, members of which presented with early-onset autosomal recessive retinitis pigmentosa and juvenile macular dystrophy. The clinical records of affected family members were analysed retrospectively and ophthalmological and electrophysiological examinations were performed in selected cases. Mutation screening was initially performed with microarrays, interrogating known mutations in the genes associated with recessive retinitis pigmentosa, Leber congenital amaurosis and Stargardt disease. Searching for homozygous regions with putative causative disease genes was done by high-density SNP-array genotyping, followed by segregation analysis of the family members. Two distinct phenotypes of retinal dystrophy, Leber congenital amaurosis and Stargardt disease were present in the family. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C>T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T>C in the ABCA4 gene and another was carrier of the same mutation and a novel ABCA4 mutation c.4773+3A>G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants, which were evaluated by bioinformatics tools. In conclusion, presence of different genetic mechanisms resulting in variable phenotype within the family is not rare and can challenge molecular geneticists, ophthalmologists and genetic counsellors.
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| 25. |
- Karlsson Potter, Hanna, et al.
(author)
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A systems analysis of biodiesel production from wheat straw using oleaginous yeast : process design, mass and energy balances
- 2016
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In: Biotechnology for Biofuels. - : Springer Science and Business Media LLC. - 1754-6834. ; 9:1, s. 1-13
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Journal article (peer-reviewed)abstract
- Background: Biodiesel is the main liquid biofuel in the EU and is currently mainly produced from vegetable oils. Alternative feedstocks are lignocellulosic materials, which provide several benefits compared with many existing feedstocks. This study examined a technical process and its mass and energy balances to gain a systems perspective of combined biodiesel (FAME) and biogas production from straw using oleaginous yeasts. Important process parameters with a determining impact on overall mass and energy balances were identified and evaluated. Results: In the base case, 41% of energy in the biomass was converted to energy products, primary fossil fuel use was 0.37 MJprim/MJ produced and 5.74 MJ fossil fuels could be replaced per kg straw dry matter. The electricity and heat produced from burning the lignin were sufficient for process demands except in scenarios where the yeast was dried for lipid extraction. Using the residual yeast cell mass for biogas production greatly increased the energy yield, with biogas contributing 38% of total energy products. Conclusions: In extraction methods without drying the yeast, increasing lipid yield and decreasing the residence time for lipid accumulation are important for the energy and mass balance. Changing the lipid extraction method from wet to dry makes the greatest change to the mass and energy balance. Bioreactor agitation and aeration for lipid accumulation and yeast propagation is energy demanding. Changes in sugar concentration in the hydrolysate and residence times for lipid accumulation greatly affect electricity demand, but have relatively small impacts on fossil energy use (NER) and energy yield (EE). The impact would probably be greater if externally produced electricity were used.
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| 26. |
- Karlsson Potter, Hanna, et al.
(author)
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Greenhouse gas performance of biochemical biodiesel production from straw : Soil organic carbon changes and time-dependent climate impact
- 2017
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In: Biotechnology for Biofuels. - : Springer Science and Business Media LLC. - 1754-6834. ; 10:1
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Journal article (peer-reviewed)abstract
- Background: Use of bio-based diesel is increasing in Europe. It is currently produced from oilseed crops, but can also be generated from lignocellulosic biomass such as straw. However, removing straw affects soil organic carbon (SOC), with potential consequences for the climate impact of the biofuel. This study assessed the climate impacts and energy balance of biodiesel production from straw using oleaginous yeast, with subsequent biogas production from the residues, with particular emphasis on SOC changes over time. It also explored the impact of four different scenarios for returning the lignin fraction of the biomass to soil to mitigate SOC changes. Climate impact was assessed using two methods, global warming potential (GWP) and a time-dependent temperature model (ΔT s ) that describes changes in mean global surface temperature as a function of time or absolute temperature change potential (AGTP). Results: Straw-derived biodiesel reduced GWP by 33-80% compared with fossil fuels and primary fossil energy use for biodiesel production was 0.33-0.80 MJprim/MJ, depending on the scenario studied. Simulations using the time-dependent temperature model showed that a scenario where all straw fractions were converted to energy carriers and no lignin was returned to soil resulted in the highest avoided climate impact. The SOC changes due to straw removal had a large impact on the results, both when using GWP and the time-dependent temperature model. Conclusions: In a climate perspective, it is preferable to combust straw lignin to produce electricity rather than returning it to the soil if the excess electricity replaces natural gas electricity, according to results from both GWP and time-dependent temperature modelling. Using different methods to assess climate impact did not change the ranking between the scenarios, but the time-dependent temperature model provided information about system behaviour over time that can be important for evaluation of biofuel systems, particularly in relation to climate target deadlines.
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| 27. |
- Kawaji, Takahiro, et al.
(author)
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Transthyretin-related vitreous amyloidosis in different endemic areas.
- 2010
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In: Amyloid. - : Informa Healthcare. - 1350-6129 .- 1744-2818. ; 17:3-4, s. 105-108
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Journal article (peer-reviewed)abstract
- Background: to investigate the vitreous opacity in patients with familial amyloidotic polyneuropathy (FAP) in two major endemic areas, Japan and Sweden. Methods: we obtained clinical data for 90 patients with vitreous opacity that was associated with FAP amyloidogenic transthyretin (ATTR) Val30Met; 18 Japanese patients and 72 Swedish patients. We reviewed medical records at Kumamoto University Hospital in Japan and Umeå University Hospital in Sweden. We evaluated the characteristics of the patients, systemic and ocular histories, clinical findings and treatment. RESULTS: swedish patients were significantly older at the onset of vitreous opacity (mean age 67.8 years) than were Japanese patients (47.6 years). A similar age difference was found for the onset of polyneuropathy. In addition, Swedish patients without polyneuropathy were significantly older (74.1 years) at the onset of vitreous opacity than those with polyneuropathy (64.6 years). A significant difference in the occurrence of vitreous opacity as the only manifestation of FAP was seen for Swedish patients (35%) compared with Japanese patients (6%). CONCLUSIONS: swedish FAP ATTR Val30Met patients appeared to develop vitreous opacity later and more frequently compared with Japanese patients.
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| 28. |
- Köhn, Linda, 1979-, et al.
(author)
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Breakpoint characterization of a novel ~59 kb genomic deletion on 19q13.42 in autosomal dominant retinitis pigmentosa with reduced penetrance
- 2009
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In: European Journal of Human Genetics. - : Nature publishing group. - 1018-4813 .- 1476-5438. ; 17:5, s. 651-655
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Journal article (peer-reviewed)abstract
- The aim of this study was to identify and characterize the underlying molecular mechanisms in autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance in two Swedish families. An extended genealogical study and haplotype analysis indicated a common origin. Mutation identification was carried out by multiplex ligation-dependent probe amplification (MLPA) and sequencing. Clinical examinations of adRP families including electroretinography revealed obligate gene carriers without abnormalities, which indicated incomplete penetrance. Linkage analysis resulted in mapping of the disease locus to 19q13.42 (RP11). Sequence analyses did not reveal any mutations segregating with the disease in eight genes including PRPF31. Subsequent MLPA detected a large genomic deletion of 11 exons in the PRPF31 gene and, additionally, three genes upstream of the PRPF31. Breakpoints occurred in intron 11 of PRPF31 and in LOC441864, 'similar to osteoclast-associated receptor isoform 5.' An almost 59 kb deletion segregated with the disease in all affected individuals and was present in several asymptomatic family members but not in 20 simplex RP cases or 94 healthy controls tested by allele-specific PCR. A large genomic deletion resulting in almost entire loss of PRPF31 and three additional genes identified as the cause of adRP in two Swedish families provide an additional evidence that mechanism of the disease evolvement is haploinsufficiency. Identification of the deletion breakpoints allowed development of a simple tool for molecular testing of this genetic subtype of adRP.
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| 29. |
- Köhn, Linda, et al.
(author)
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Breakpoint characterization of a novel approximately 59 kb genomic deletion on 19q13.42 in autosomal-dominant retinitis pigmentosa with incomplete penetrance.
- 2009
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In: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 17:5, s. 651-655
-
Journal article (peer-reviewed)abstract
- The aim of this study was to identify and characterize the underlying molecular mechanisms in autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance in two Swedish families. An extended genealogical study and haplotype analysis indicated a common origin. Mutation identification was carried out by multiplex ligation-dependent probe amplification (MLPA) and sequencing. Clinical examinations of adRP families including electroretinography revealed obligate gene carriers without abnormalities, which indicated incomplete penetrance. Linkage analysis resulted in mapping of the disease locus to 19q13.42 (RP11). Sequence analyses did not reveal any mutations segregating with the disease in eight genes including PRPF31. Subsequent MLPA detected a large genomic deletion of 11 exons in the PRPF31 gene and, additionally, three genes upstream of the PRPF31. Breakpoints occurred in intron 11 of PRPF31 and in LOC441864, 'similar to osteoclast-associated receptor isoform 5.' An almost 59 kb deletion segregated with the disease in all affected individuals and was present in several asymptomatic family members but not in 20 simplex RP cases or 94 healthy controls tested by allele-specific PCR. A large genomic deletion resulting in almost entire loss of PRPF31 and three additional genes identified as the cause of adRP in two Swedish families provide an additional evidence that mechanism of the disease evolvement is haploinsufficiency. Identification of the deletion breakpoints allowed development of a simple tool for molecular testing of this genetic subtype of adRP.
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| 30. |
- Köhn, Linda, 1979-, et al.
(author)
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Carrier of R14W in carbonic anhydrase IV presents Bothnia dystrophy phenotype caused by two allelic mutations in RLBP1
- 2008
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In: Investigative Ophthalmology and Visual Science. - : Association for Research in Vision and Ophthalmology. - 0146-0404 .- 1552-5783. ; 49:7, s. 3172-3177
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Journal article (peer-reviewed)abstract
- Purpose: Bothnia dystrophy (BD) is an autosomal recessive retinitis pigmentosa (arRP) associated with the c.700C>T mutation in the RLBP1 gene. Testing of patients with BD has revealed the c.700C>T mutation on one or both alleles. The purpose of this study was to elucidate the underlying genetic mechanisms along with a clinical evaluation of the heterozygous patients with BD.Methods: Patients with BD heterozygous for the RLBP1 c.700C>T were tested for 848 mutations by arrayed primer-extension technology. Further mutation detection was performed by PCR-restriction fragment length polymorphism (RFLP), sequencing, denaturing (d)HLPC and allelic discrimination. The ophthalmic examinations were performed in all c.700C>T heterozygotes.Results: The clinical findings in 10 BD heterozygotes were similar to those in the homozygotes. The presence of a second mutation, c.677T>A, corresponding to p.M226K was detected in all 10 cases. Segregation analysis showed that the mutations were allelic, and the patients were compound heterozygotes [c.677T>A]+[c.700C>T]. One of those patients was also a carrier of the c.40C>T corresponding to the p.R14W change in carbonic anhydrase IV (CAIV) associated with autosomal dominant RP, RP17. His mother, a carrier of the identical change was declared healthy after ophthalmic examination. This sequence variant was found in 6 of 143 tested blood donors.Conclusions: The high frequency of arRP in northern Sweden is due to two mutations in the RLBP1 gene: c.677T>A and c.700C>T. BD is caused by the loss of CRALBP function due to changed physical features and impaired activity of retinoid binding. The CAIV p.R14W sequence variant found in one of the patients with a BD phenotype is a benign polymorphism in a population of northern Sweden.
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| 31. |
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| 32. |
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| 33. |
- Köhn, Linda, 1979-, et al.
(author)
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Mutation in the PYK2-binding domain of PITPNM3 causes autosomal dominant cone dystrophy (CORD5) in two Swedish families
- 2007
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In: European Journal of Human Genetics. - : Nature publishing group. - 1018-4813 .- 1476-5438. ; 15:6, s. 664-671
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Journal article (peer-reviewed)abstract
- Autosomal dominant cone dystrophy (CORD5) (MIM 600977) is a rare disease predominantly affecting cone photoreceptors. Here we refine the CORD5 locus previously mapped to 17p13 from 27 to 14.3 cM and identified a missense mutation, Q626H in the phosphatidylinositol transfer (PIT) membrane-associated protein (PITPNM3) (MIM 608921) in two Swedish families. PITPNM3, known as a human homologue of the Drosophila retinal degeneration B (rdgB), lacks the N-terminal PIT domain needed for transport of phospholipids, renewal of photoreceptors membrane and providing the electroretinogram (ERG) response to light. In our study, the mutation causing CORD5 is located in the C-terminal region interacting with a member of nonreceptor protein tyrosine kinases, PYK2. Our finding on the first mutation in the human homologue of Drosophila rdgB indicates novel pathways and a potential important role of the PITPNM3 in mammalian phototransduction.
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| 34. |
- Köhn, Linda, et al.
(author)
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PITPNM3 is an uncommon cause of cone and cone-rod dystrophies.
- 2010
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In: Ophthalmic Genetics. - : Informa Healthcare. - 1381-6810 .- 1744-5094. ; 31:3, s. 139-140
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Journal article (peer-reviewed)abstract
- The first mutation in PITPNM3, a human homologue of the Drosophila retinal degeneration (rdgB not not) gene was reported in two large Swedish families with autosomal dominant cone dystrophy. To establish the global impact that PITPNM3 has on retinal degenerations we screened 163 patients from Denmark, Germany, the UK, and USA. Four sequence variants, two missence mutations and two intronic changes were identified in the screen. Thus, mutations in PITPNM3 do not appear to be a major cause of cone or cone-rod dystrophy.
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| 35. |
- Reinis, Ainars, et al.
(author)
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Ocular phenotype of CORD5, an autosomal dominant retinal dystrophy associated with PITPNM3 p.Q626H mutation
- 2013
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In: Acta Ophthalmologica. - : Wiley. - 1755-375X .- 1755-3768. ; 91:3, s. 259-266
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Journal article (peer-reviewed)abstract
- Purpose: To describe in detail the phenotype of CORD5 in two families segregating a mutation c.1878G > C (p.Q626H) in the PITPNM3 gene. Methods: The study included 35 individuals from two different families of Swedish origin, all heterozygous for a PITPNM3 p.Q626H mutation. All participants underwent ophthalmological examination including kinetic perimetry, and in selected cases adaptometry, colour vision tests and optical coherence tomography (OCT). Electrophysiological studies were also performed. In some cases, the data were obtained from medical records. Results: The majority of patients showed subnormal visual acuity and light sensitivity from childhood. Early signs of macular degeneration were also observed. There was a progressive decrease in visual acuity leading to legal blindness in early adulthood. Electrophysiological testing showed a progressive loss of photoreceptor function restricted mainly to the cones. OCT revealed decreased macular thickness with flattened and enlarged fovea. Conclusion: Our observations of the PITPNM3 p.Q626H mutation carriers confirm that CORD5 is a disease not to mix with other retinal degenerations mapped to 17p13. The results of our clinical evaluation so far indicate that CORD5 is characterized by predominant cone dysfunction without signs of general involvement of the retinal pigment epithelium. The rod system also seems to be unaffected. In this sense, CORD5 is different from other autosomal dominant CORDs where rod involvement is present to some degree in a late phase of the disease. Some intra-and inter-familial differences regarding the severity of the clinical picture were observed.
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| 36. |
- Sandgren, Johanna, 1979-
(author)
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Array-based Genomic and Epigenomic Studies in Healthy Individuals and Endocrine Tumours
- 2010
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Doctoral thesis (other academic/artistic)abstract
- The human genome is a dynamic structure, recently recognized to present with significant large-scale structural variation. DNA-copy number changes represent one common type of such variation and is found both between individuals and within the somatic cells of the same individual, especially in disease states like cancer. Apart from DNA-rearrangements, epigenomic changes are increasingly acknowledged as important events in the maintenance of genomic integrity. In this thesis, different array-based methods have been applied for global genomic and epigenomic profiling of both normal and cancer cells. In paper I, a genomic microarray was established and used to determine DNA-copy number variants (CNVs) in a cohort of 76 healthy individuals from three ethnic populations. We identified 315 CNV regions that in total encompassed ~3,5% of the genome. In paper II, the array was utilized to discover CNVs within several differentiated tissues from the same subject. Six variants were identified providing evidence for somatic mosaicism. In paper III and IV we studied pheochromocytomas and paragangliomas, rare endocrine tumours that most often present as benign and sporadic with unclear genetic/epigenetic cause. Genome-wide DNA-copy number analysis of 53 benign and malignant samples in paper III revealed numerous common and novel chromosomal regions of losses and gains. High frequencies of relatively small overlapping regions of deletions were detected on chromosome 1p arm, encompassing several candidate tumour suppressor genes. In paper IV, an epigenomic map for two histone modifications associated with silent (H3K27me3) or active (H3K4me3) gene transcription, was generated for one malignant pheochromocytoma. Integrated analysis of global histone methylation, copy number alterations and gene expression data aided in the identification of candidate tumour genes. In conclusion, the performed studies have contributed to gain knowledge of CNVs in healthy individuals, and identified regions and genes which are likely associated with the development and progression of pheochromocytoma/paraganglioma.
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| 37. |
- Sandgren, Johanna, et al.
(author)
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Recurrent genomic alterations in benign and malignant pheochromocytomas and paragangliomas revealed by whole-genome array comparative genomic hybridization analysis
- 2010
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In: Endocrine-Related Cancer. - 1351-0088 .- 1479-6821. ; 17:3, s. 561-579
-
Journal article (peer-reviewed)abstract
- Pheochromocytomas and abdominal paragangliomas are adrenal and extra-adrenal catecholamine-producing tumours. They arise due to heritable cancer syndromes, or more frequently occur sporadically due to an unknown genetic cause. The majority of cases are benign, but malignant tumours are observed. Previous comparative genomic hybridization (CGH) and loss of heterozygosity studies have shown frequent deletions of chromosome arms 1p, 3q and 22q in pheochromocytomas. We applied high-resolution whole-genome array CGH on 53 benign and malignant pheochromocytomas and paragangliomas to narrow down candidate regions as well as to identify chromosomal alterations more specific to malignant tumours. Minimal overlapping regions (MORs) were identified on 16 chromosomes, with the most frequent MORs of deletion (> or = 32%) occurring on chromosome arms 1p, 3q, 11p/q, 17p and 22q, while the chromosome arms 1q, 7p, 12q and 19p harboured the most common MORs of gain (> or = 14%). The most frequent MORs (61-75%) in the pheochromocytomas were identified at 1p, and the four regions of common losses encompassed 1p36, 1p32-31, 1p22-21 and 1p13. Tumours that did not show 1p loss generally demonstrated aberrations on chromosome 11. Gain of chromosomal material was significantly more frequent among the malignant cases. Moreover, gain at 19q, trisomy 12 and loss at 11q were positively associated with malignant pheochromocytomas, while 1q gain was commonly observed in the malignant paragangliomas. Our study revealed novel and narrow recurrent chromosomal regions of loss and gain at several autosomes, a prerequisite for identifying candidate tumour suppressor genes and oncogenes involved in the development of adrenal and extra-adrenal catecholamine-producing tumours.
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| 38. |
- Sandgren, Ola, et al.
(author)
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Ocular manifestations in liver transplant recipients with familial amyloid polyneuropathy.
- 2008
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In: Acta ophthalmologica. - : Wiley. - 1755-3768 .- 1755-375X. ; 86:5, s. 520-4
-
Journal article (peer-reviewed)abstract
- PURPOSE: To evaluate postoperative ocular involvement in Swedish liver transplant (LT) recipients with familial amyloid polyneuropathy (FAP). METHODS: Routine ophthalmological examinations were performed in 48 LT recipients, with particular attention given to amyloid deposition in the anterior segment and the vitreous body. Medical records were scrutinized for information regarding neurological impairment at the time of the LT. The diagnosis was secured in all cases by examining for amyloid deposits in biopsy specimens and positive genetic testing for amyloidogenic transthyretin (ATTR) Val30Met mutation. RESULTS: Six patients (12.5%) developed vitreous opacities within the post-LT observation period. The first opacities were seen 40 months after transplantation, 8 years after the onset of systemic disease. Four patients (8%) developed secondary glaucoma, the first of which was observed 18 months after the procedure and 6.5 years after the onset of disease. Sixteen patients (33%) developed deposits on the anterior surface of the lens. Scalloped pupillary margins were noted in 10 patients (21%). CONCLUSION: The prevalence of eye complications increases with time after LT and regular follow-up is necessary, especially to disclose the development of glaucoma--a complication with insidious symptoms of which patients are normally unaware.
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| 39. |
- Sandgren, Veronica, et al.
(author)
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Design and synthesis of novel macrocyclic BACE-1 inhibitors
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Other publication (other academic/artistic)abstract
- A series of arylketo-containing P1-P3 linked macrocyclic inhibitors was designed and synthesized and compared with a previously known and extensively used corresponding P2 isophthalamide moiety with the aim to improve on permeability whilst retaining the enzyme and cell-based potencies. Several inhibitors displayed a substantial increase in Caco-2 cell-based permeability and notably also with retained potencies, showing that this approach might lead to centrally active BACE-1 inhibitors.
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| 40. |
- Sandgren, Veronica, et al.
(author)
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Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core : Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes
- 2012
-
In: Bioorganic & Medicinal Chemistry. - : Elsevier. - 0968-0896 .- 1464-3391. ; 29:14, s. 4377-4389
-
Journal article (peer-reviewed)abstract
- A series of P1-P3 linked macrocyclic BACE-1 inhibitors containing a hydroxyethylamine (HEA) isostere scaffold has been synthesized. All inhibitors comprise a toluene or N-phenylmethanesulfonamide P2 moiety. Excellent BACE-1 potencies, both in enzymatic and cell-based assays, were observed in this series of target compounds, with the best candidates displaying cell-based IC50 values in the low nanomolar range. As an attempt to improve potency, a phenyl substituent aiming at the S3 subpocket was introduced in the macrocyclic ring. X-ray analyses were performed on selected compounds, and enzyme-inhibitor interactions are discussed.
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| 41. |
- Sandström, Herbert, et al.
(author)
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Angioid streaks are part of a familial syndrome of dyserythropoietic anaemia (CDA III)
- 1997
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In: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 98:4, s. 845-849
-
Journal article (peer-reviewed)abstract
- Congenital dyserythropoietic anaemia type III (CDA III) is a rare disease inherited in an autosomal dominant way and characterized by mild to moderate haemolytic anaemia. Most patients are adapted to their disease and have no or few complaints. Bone marrow examination shows a characteristic picture with erythroid hyperplasia and multinucleate erythroblasts. 20% of patients in a Swedish family affected with the CDA III condition have monoclonal gammopathy or multiple myeloma. By linkage and recombination analysis in the same family, the gene linked to the CDA III condition (CDAN3) has been located to chromosome 15q22. In this paper we report the observation of visual disturbances with macular degeneration and angioid streaks in six patients with CDA III and discuss the apparent association between CDA III, angioid streaks and monoclonal gammopathy. We suggest that this triad forms a previously unreported syndrome.
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| 42. |
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| 43. |
- Westin, Ida Maria, 1982-
(author)
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Genetics, epigenetics and functional mechanisms in inherited corneal and retinal dystrophies
- 2022
-
Doctoral thesis (other academic/artistic)abstract
- Inherited eye disorders (IED) are groups of genetically and clinically heterogenous conditions affecting different tissues in the eye. IED are most often progressive with reduced vision or legal blindness as outcome. This thesis is focused on investigating the underlying mechanisms in Fuchs’ endothelial corneal dystrophy (FECD) and two retinal dystrophies, Stargardt disease (STGD1) and autosomal recessive Retinitis pigmentosa (arRP, RP25).In FECD, we studied the association between FECD and the (CTG)n repeat expansion at the CTG18.1 locus in the TCF4 gene, in patients from northern Sweden. By using STR-PCR and TP-PCR, we found that 90% of FECD patients carry an expanded CTG18.1 allele, establishing the highest prevalence among FECD patients world-wide. With droplet digital PCR, we showed that transcripts spanning over the CTG18.1 have lower fractions in human corneal endothelium (CE) compared to skin, brain, muscle, and white blood cells. With Illumina Methylation arrays (850K), we detected a decreased global methylation in the CE at advanced age, that could possibly contribute to the late onset of FECD. We also found distinct differences in methylation between FECD patients and controls, that led us to two coagulation factors, found to be over-expressed in the CE from FECD patients.For the two retinal dystrophies, STGD1 and RP25, we investigated the functional effect of four genetic variants residing adjacent to or in splice consensus sequence of the ABCA4 gene (STDG1) and the EYS gene (RP25). With an in vitro mini-gene splicing assay we showed that all four genetic variants caused exon skipping in Retinal Pigment Epithelial cell line (ARPE-19) and Human Embryonic kidney cell line (HEK293T). Our results functionally proved these variants to be pathogenic and causative of STGD1 and RP25.In RP25, we also investigated the prevalence of pathogenic EYS variants in a cohort of patients from northern Sweden. DNA from 81 patients with a clinical diagnosis of RP were interrogated with a "cascade-targeted mutation analysis" approach, where NGS, MLPA and Sanger sequencing was used to find common EYS variants in this acknowledged genetically homogenous population. EYS mutations were present in at least 16% of all arRP patients and the most recurrent mutation in the study was an 8-bp deletion, previously found in the Finnish population.In conclusion, this thesis provides knowledge on disease causative mechanisms in IED and contributes with valuable information for future genetic counselling and genetic testing for affected families.
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