| 1. |
- 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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| 2. |
- Fujita, Ricardo, et al.
(författare)
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Analysis of the RPGR gene in 11 pedigrees with the retinitis pigmentosa type 3 genotype: Paucity of mutations in the coding region, but splice defects in two families
- 1997
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 61:3, s. 571-580
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Tidskriftsartikel (refereegranskat)abstract
- X-linked retinitis pigmentosa (XLRP) is a severe form of inherited progressive retinal degeneration. The RP3 (retinitis pigmentosa type 3) locus at Xp21.1 is believed to account for the disease in the majority of XLRP families. Linkage analysis and identification of patients with chromosomal deletion have refined the location of the RP3 locus and recently have led to the cloning of the RPGR (retinitis pigmentosa GTPase regulator) gene, which has been shown to be mutated in 10%15% of XLRP patients. In order to systematically characterize the RPGR mutations, we identified 11 retinitis pig-mentosa type III (RP3) families by haplotype analysis. Sequence analysis of the PCR-amplified genomic DNA from patients representing these RP3 families did not reveal any causative mutation in RPGR exons 219, spanning > 98% of the coding region. In patients from two families, we identified transition mutations in the intron region near splice sites (IVS10/3 and IVS13-8). RNA analysis showed that both splice-site mutations resulted in the generation of aberrant RPGR transcripts. Our results support the hypothesis that mutations in the reported RPGR gene are not a common defect in the RP3 subtype of XLRP and that a majority of causative mutations may reside either in as yet unidentified RPGR exons or in another nearby gene at Xp21.1.
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| 3. |
- 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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