Autosomal dominant retinitis pigmentosa: A mutation in codon 178 of the rhodopsin gene in two families of celtic origin

Farrar, G. Jane; Kenna, Paul F.; Redmond, R M; Shiels, Denise; McWilliam, Peter; Humphries, Marian M.; Sharp, Elizabeth M.; Jordan, Siobhán A.; Kumar‐Singh, Rajendra; Humphries, Peter

doi:10.1016/0888-7543(91)90051-f

Cited by 27 publications

(6 citation statements)

References 6 publications

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“…Several RP genes, such as rhodopsin (MIM 180380), RP1 (MIM 603937), CRX (MIM 602225), and NRL (MIM 162080), are expressed primarily in the retina. [26][27][28][29][30] However, many other retinopathy-associated [31][32][33][34][35][36] Here, we identify a retinal-disease gene and suggest an additional cellular mechanism important for photoreceptor function and survival. KLHL7 transcripts are widely expressed and detected even in mature oocytes and embryonic stem cells.…”

Section: Discussionmentioning

confidence: 93%

Mutations in a BTB-Kelch Protein, KLHL7, Cause Autosomal-Dominant Retinitis Pigmentosa

Friedman

Ray

Waseem³

et al. 2009

The American Journal of Human Genetics

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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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Section: Discussionmentioning

confidence: 93%

Mutations in a BTB-Kelch Protein, KLHL7, Cause Autosomal-Dominant Retinitis Pigmentosa

Friedman

Ray

Waseem³

et al. 2009

The American Journal of Human Genetics

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“…RP has an inci-dence of 1 in 3000 to 1 in 5000 and may be inherited as an autosomal dominant (ad), autosomal recessive (ar), X-linked, or simplex/multiplex disease. 1 The identification of mutations in the rhodopsin gene [2][3][4][5] and genes encoding structural proteins, such as peripherin, 6,7 account for 20% to 30% of the adRP cases reported. 8 Defects in photoreceptor phosphodiesterase activity caused by mutations in the ␤ subunit of the rod cGMPphosphodiesterase (PDE6B) gene have been shown to underlie cases of arRP 9,10 accounting for ϳ1% to 2% of all cases of RP.…”

mentioning

confidence: 99%

Genotype–Phenotype Correlation of MousePde6bMutations

Hart

McKie

Morgan

et al. 2005

Invest. Ophthalmol. Vis. Sci.

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These data demonstrate a correlation between genotype and phenotype. Four of the mutants with severe genetic lesions have rapid onset of retinal degeneration, as determined by fundus examination. These mice were indistinguishable from Pde6b(rd1) mice, which are effectively blind by 3 weeks of age. In contrast, the milder genetic lesions show a slower progression of the disease and provide the community with models that more closely mimic human retinitis pigmentosa.

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“…The RHO Tyr178Cys mutation in Rho Tvrm334 mice is identical to a variant identified in human RP [ 90 – 92 ]. Based on expression studies of bovine opsin variants in cultured cells, this mutation results in retention of the opsin polypeptide in the endoplasmic reticulum, accompanied by a decreased yield of the protein and no detectable binding of 11- cis retinal [ 75 ], [ 76 ].…”

Section: Resultsmentioning

confidence: 99%

Mouse models of human ocular disease for translational research

et al. 2017

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Mouse models provide a valuable tool for exploring pathogenic mechanisms underlying inherited human disease. Here, we describe seven mouse models identified through the Translational Vision Research Models (TVRM) program, each carrying a new allele of a gene previously linked to retinal developmental and/or degenerative disease. The mutations include four alleles of three genes linked to human nonsyndromic ocular diseases (Aipl1tvrm119, Aipl1tvrm127, Rpgrip1tvrm111, RhoTvrm334) and three alleles of genes associated with human syndromic diseases that exhibit ocular phentoypes (Alms1tvrm102, Clcn2nmf289, Fkrptvrm53). Phenotypic characterization of each model is provided in the context of existing literature, in some cases refining our current understanding of specific disease attributes. These murine models, on fixed genetic backgrounds, are available for distribution upon request and may be useful for understanding the function of the gene in the retina, the pathological mechanisms induced by its disruption, and for testing experimental approaches to treat the corresponding human ocular diseases.

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Autosomal dominant retinitis pigmentosa: A mutation in codon 178 of the rhodopsin gene in two families of celtic origin

Cited by 27 publications

References 6 publications

Mutations in a BTB-Kelch Protein, KLHL7, Cause Autosomal-Dominant Retinitis Pigmentosa

Mutations in a BTB-Kelch Protein, KLHL7, Cause Autosomal-Dominant Retinitis Pigmentosa

Genotype–Phenotype Correlation of MousePde6bMutations

Mouse models of human ocular disease for translational research

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