| 1. |
- Andréasson, Sten, et al.
(författare)
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Phenotypes in three Swedish families with X-linked retinitis pigmentosa caused by different mutations in the RPGR gene
- 1997
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Ingår i: American Journal of Ophthalmology. - 1879-1891. ; 124:1, s. 95-102
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To assess the clinical phenotypes in three Swedish families with X-linked retinitis pigmentosa caused by different mutations in the RPGR gene. METHODS: Three families from different parts of Sweden, including nine patients with retinitis pigmentosa and six female carriers of X-linked retinitis pigmentosa, were examined clinically. Ophthalmologic examination included kinetic perimetry with a Goldmann perimeter using standardized objects I4e and V4e, dark adaptation final thresholds with a Goldmann-Weeker adaptometer, and full-field electroretinograms. RESULTS: The clinical findings in the patients demonstrated a severe form of retinitis pigmentosa with visual handicap early in life. Patients with a microdeletion of exons 8 through 10 of the RPGR gene had a more severe phenotype compared to the patients with single base-pair mutations in the introns 10 and 13 of the RPGR gene, resulting in splicing defects. Furthermore, heterozygous carriers in these families displayed a wide spectrum of clinical features, from minor symptoms to severe visual disability. CONCLUSION: These three families show a variable clinical phenotype resulting from different mutations in the RPGR gene. A microdeletion spanning at least parts of exons 8 through 10 seems to result in a severe phenotype compared to the splice defects. Heterozygous carriers of X-linked retinitis pigmentosa with these specific RPGR genotypes also show a variability of the phenotype; carriers with the microdeletion may be severely visually handicapped.
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| 2. |
- Ekström, Ulf, et al.
(författare)
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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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Ingår i: Ophthalmic Genetics. - : Swets & Zeitlinger Publishers. - 1744-5094 .- 1381-6810. ; 19:3, s. 149-156
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Tidskriftsartikel (refereegranskat)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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| 3. |
- Ekström, Ulf, et al.
(författare)
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Detection of alterations in all three exons of the peripherin/RDS gene in Swedish patients with retinitis pigmentosa using an efficient DGGE system
- 1998
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Ingår i: Molecular Pathology. - 1366-8714. ; 51:5, s. 287-291
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To develop a sensitive mutation screening procedure suitable for routine analysis of the peripherin/RDS gene, and to estimate the nature and prevalence of peripherin/RDS gene mutations in Swedish patients with autosomal dominant retinitis pigmentosa. METHODS: To make the method as sensitive as possible, as many as eight segments, covering the three exons and the flanking intron sequences of the peripherin/RDS gene, were analysed by denaturing gradient gel electrophoresis. A group of 38 Swedish patients with a clinical diagnosis of autosomal dominant retinitis pigmentosa were screened for mutations in the peripherin/RDS gene. RESULTS: Three point mutations were found in four of the patients and five polymorphisms were defined. One mutation in exon 1, R172W, has been described previously in other ethnic groups as causing a macular degeneration. Another mutation, in exon 2 and causing the substitution F211L, was found in two unrelated patients. A third mutation, resulting in the likely non-pathogenic substitution S289L, as well as a polymorphism not reported previously, was found in exon 3. CONCLUSIONS: The screening procedure described allows detection of mutations in all of the exons, including the polymorphic 5' and 3' ends of the gene, and is therefore suitable for routine screening of peripherin/RDS gene defects in patients with autosomal dominant retinitis pigmentosa. The frequency of mutations found in the Swedish patient group indicates that defects in the peripherin/RDS gene might be a more common cause of autosomal dominant retinitis pigmentosa than was thought previously.
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| 4. |
- Ekström, Ulf, et al.
(författare)
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Phenotypic expression of autosomal dominant retinitis pigmentosa in a Swedish family expressing a Phe-211-Leu variant of peripherin/RDS
- 1998
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Ingår i: Ophthalmic Genetics. - : Swets & Zeitlinger Publishers. - 1744-5094 .- 1381-6810. ; 19:1, s. 27-37
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To characterize the clinical phenotype, with emphasis on electrophysiology, of members of a Swedish family with autosomal dominant retinitis pigmentosa due to a novel mutation, F211L, in the peripherin/RDS gene. METHODS: Nine patients with autosomal dominant retinitis pigmentosa and two healthy family members underwent a full clinical evaluation including kinetic visual field testing, measurement of dark adaptation threshold, and full-field electroretinography. Blood samples were collected and DNA analysis was performed using denaturing gradient gel electrophoresis (DGGE). RESULTS: The grandfather, six of seven siblings from the middle generation, and two young boys carried the mutation F211L in the peripherin/RDS gene. The mutation segregated with the clinical presentation of disease. Fundus examination revealed mainly macular atrophy. All assessed parameters of retinal function (visual acuity, dark adaptation threshold, visual fields, and full-field electroretinograms) demonstrated a successive reduction with increasing age. Full-field electroretinograms showed a diminished rod response in all affected individuals and a reduction of the cone b-wave amplitudes with increasing age, indicating retinitis pigmentosa. In the affected family members, the disease seems to progress at a similar rate with increasing age. CONCLUSIONS: The peripherin/RDS gene mutation F211L is associated with a clinical phenotype and includes early loss of rod function and successive reduction of cone function with increasing age, but impressively well-preserved visual acuity and visual fields in young and middle-aged patients and moderately reduced vision in the old patient. Compared to previously described phenotypes segregating with mutations in the peripherin/RDS gene, the present family demonstrates a more benign clinical phenotype, which is concordant within the family.
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| 5. |
- Friedman, James S., et al.
(författare)
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Mutations in a BTB-Kelch Protein, KLHL7, Cause Autosomal-Dominant Retinitis Pigmentosa
- 2009
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 84:6, s. 792-800
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Tidskriftsartikel (refereegranskat)abstract
- Retinitis pigmentosa (RP) refers to a genetically heterogeneous group of progressive neurodegenerative diseases that result in dysfunction and/or death of rod and cone photoreceptors in the retina. So far, 18 genes have been identified for autosomal-dominant (ad) RP. Here, we describe an adRP locus (RP42) at chromosome 7p15 through linkage analysis in a six-generation Scandinavian family and identify a disease-causing mutation, c.449G -> A (p.S150N), in exon 6 of the KLHL7 gene. Mutation screening of KLHL7 in 502 retinopathy probands has revealed three different missense mutations in six independent families. KLHL7 is widely expressed, including expression in rod photoreceptors, and encodes a 75 kDa protein of the BTB-Kelch Subfamily within the BTB superfamily. BTB-Kelch proteins have been implicated in ubiquitination through Cullin E3 ligases. Notably, all three putative disease-causing KLHL7 mutations are within a conserved BACK domain; homology modeling suggests that mutant amino acid side chains can potentially fill the cleft between two helices, thereby affecting the ubiquitination complexes. Mutations in an identical region of another BTB-Kelch protein, gigaxonin, have previously been associated with giant axonal neuropathy. Our studies suggest an additional role of the ubiquitin-proteasome protein-degradation pathway in maintaining neuronal health and in disease.
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| 6. |
- Gränse, Lotta, et al.
(författare)
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Electrophysiologic findings in two young patients with Bothnia dystrophy and a mutation in the RLBP1 gene
- 2001
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Ingår i: Ophthalmic Genetics. - : Swets & Zeitlinger Publishers. - 1744-5094 .- 1381-6810. ; 22:2, s. 97-105
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To characterize the clinical phenotype, with emphasis on electrophysiology, of two children with suspected Bothnia dystrophy. Methods: Two unrelated affected patients, 10 and 11 years old, were studied. Ophthalmological examination included testing of visual acuity, fundus inspection and fundus photography, kinetic perimetry, full-field electroretinogram (ERG), and multifocal ERG. The presence of a mutation in exon 7 of the RLBP1 gene was investigated by DNA sequencing. Results: Both patients were homozygous for the Arg234Trp-causing mutation in the RLBP1 gene, but the resulting disease phenotype appeared to vary somewhat between them. Visual acuity was moderately reduced in one patient and normal in the other. Fundus inspection at this age revealed no pathology in either patient and there were no signs of retinitis punctata albescens, which has been described previously as a frequent clinical feature of Bothnia dystrophy. The result of kinetic perimetry was normal. The final rod threshold was moderately elevated. Full-field ERG demonstrated the uncommon combination of absent rod response and normal cone response after 40 minutes of dark adaptation. However, after prolonged dark adaptation (20-24 h), both the rod response and the dark adaptation threshold became normal. Multifocal ERG was performed in one of the patients (the one with normal visual acuity and normal fundus appearance) and showed a reduced cone response in the central region of the tested area. There was no improvement of the multifocal ERG result after 20-24 h of dark adaptation. Conclusion: Patients with mutations in the RLBP1 gene (Arg234Trp) may have a normal fundus appearance early in the disease course. Multifocal ERG can be used for the objective documentation of the disturbed macular function, especially when the patient's visual acuity and fundus appearance are normal. The rod response is absent in the electroretinogram; however, after prolonged dark adaptation (20-24 hours), the rods recover completely. The central cones do not seem to recover.
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| 7. |
- Hugosson, Therése, et al.
(författare)
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Phenotype associated with mutation in the recently identified autosomal dominant retinitis pigmentosa KLHL7 gene.
- 2010
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Ingår i: Archives of Ophthalmology. - : American Medical Association (AMA). - 0003-9950. ; 128:6, s. 772-778
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To characterize the clinical phenotype, with an emphasis on electrophysiologic findings, in a family with autosomal dominant retinitis pigmentosa caused by mutation in the recently identified KLHL7 gene. METHODS: Eleven patients from a single family were selected from the Swedish retinitis pigmentosa register. Four patients had been examined 13 to 17 years earlier and underwent further ophthalmologic examination, including visual acuity, fundus inspection, Goldmann perimetry, full-field electroretinography (ERG), multifocal ERG, and optical coherence tomography. KLHL7 mutation was identified by sequence analysis. RESULTS: In most examined family members, the fundus showed minor abnormalities. Full-field ERG demonstrated reduced cone and rod function, but rod responses were preserved in some patients late in life. Follow-up (T) in 7 family members. CONCLUSIONS: Observed in 2 Scandinavian families to date, KLHL7 mutation has recently been associated with autosomal dominant retinitis pigmentosa. Clinical examination with long-term follow-up verified a phenotype with a varying degree of retinal photoreceptor dysfunction and, in some family members, with late onset and preserved rod function until late in life. Clinical Relevance Patients with minor retinal abnormalities and normal ERG findings early in life can harbor an autosomal dominant form of retinitis pigmentosa with a varying degree of visual impediment. Some patients with late onset may retain night vision for many years.
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| 8. |
- Jacobson, S G, et al.
(författare)
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Digenic inheritance of a ROM1 gene mutation with a peripherin/RDS or rhodopsin mutation in families with retinitis pigmentosa
- 1999
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Ingår i: Digital Journal of Ophthalmology. - 1542-8958. ; 5:6
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Tidskriftsartikel (refereegranskat)abstract
- Two families with retinitis pigmentosa showed inheritance of an Arg-16-His ROM1 gene mutation with either an Arg-13-Trp RDS mutation or an Arg-135-Trp RHO mutation. The phenotypes of double and single heterozygotes were determined to examine the hypothesis that digenic inheritance may increase disease expression. In the family with ROM1 and RDS mutations, single heterozygotes were normal but one double heterozygote showed severe RP. Two other double heterozygotes, however, were normal by clinical and retinal function tests. In the family with ROM1 and RHO mutations, single heterozygotes with the RHO mutation all manifested RP, while a single heterozygote for the ROM1 mutation was normal. Disease severity was comparable in double heterozygotes and single heterozygotes HAVING the RHO mutation. We conclude that the Arg-16-His ROM1 gene mutation is non-pathogenic in the single heterozygous state, and there is no consistent evidence of digenic augmentation of pathogenicity in double heterozygotes carrying the Arg-16-His ROM1 mutation with either the benign Arg-13-Trp RDS mutation or the disease-causing Arg-135-Trp RHO mutation.
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| 9. |
- Ponjavic, Vesna, et al.
(författare)
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A mild phenotype of autosomal dominant retinitis pigmentosa is associated with the rhodopsin mutation Pro-267–Leu
- 1997
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Ingår i: Ophthalmic Genetics. - 1744-5094. ; 18:2, s. 63-70
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Tidskriftsartikel (refereegranskat)abstract
- By screening blood samples from patients with autosomal dominant retinitis pigmentosa, we found in one of the families a rhodopsin mutation (Pro-267-Leu), which segregates with the disease in two affected and five unaffected family members. Here, we present the results of the clinical evaluation of the family, including full-field electroretinography from the two affected family members. A 25-year-old family member with the mutation had an almost normal electrophysiological retinal response. The patient's father, who was also heterozygous for the mutation and had mild subjective symptoms of retinitis pigmentosa, demonstrated a substantially preserved retinal function. Our results suggest that the Pro-267-Leu rhodopsin mutation is associated with a very mild phenotype of retinitis pigmentosa. Young patients with the disease may have minimal pathological changes in the electroretinogram and some patients with few symptoms may be affected without acquiring a diagnosis of eye disease.
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| 10. |
- Ponjavic, Vesna, et al.
(författare)
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Autosomal dominant retinitis pigmentosa with a rhodopsin mutation (Arg-135–Trp): Disease phenotype in a Swedish family
- 1997
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Ingår i: Acta Ophthalmologica Scandinavica. - 1395-3907. ; 75:2, s. 218-223
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Tidskriftsartikel (refereegranskat)abstract
- We here present the clinical phenotype in 6 patients from a family with autosomal dominant retinitis pigmentosa found to carry a point mutation in the rhodopsin gene (arginine-135-tryptophan). The mutation is the second found by mutation screening of DNA from 20 Swedish families with dominant retinitis pigmentosa. With full-field electroretinography we could document a severe form of retinitis pigmentosa in patients belonging to the family, similar to the phenotype associated with the previously reported mutation (arginine-135-leucine). Our results indicate that different point mutations in the same region of the rhodopsin gene, resulting in amino acids with similar properties (both hydrophobic), may cause a similar clinical phenotype. Further, point mutations in this specific region seem to cause an agressive form of retinitis pigmentosa.
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