Missense mutation in the choroideremia gene

Donnelly, Peter; Menet, H.; Fouanon, C; Herbert, Odile; Moisan, J-P; Roux, Matthieu; Pascal, Olivier

doi:10.1093/hmg/3.6.1017

Cited by 16 publications

(9 citation statements)

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“…The possibility that these two families have a common ancestor was considered unlikely because, to their knowledge, their ancestors came from distant geographic regions. All mutations detected in this study, except for one nonsense mutation in exon 6 (Arg267stop), were different from those previously reported in European, Canadian and American CHM patients [12][13][14][15][16][17][18][19][20][21][22][23] . The deletions, the insertion, and the A to CC mutation of our patients produced a translational frameshift leading a stop codon in the downstream in each exon harboring the mutation.…”

Section: Discussioncontrasting

confidence: 93%

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Visual impairment and REP-1 gene mutations in Japanese choroideremia patients

Hayakawa

Fujiki

Hotta

et al. 1999

Ophthalmic Genetics

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Choroideremia (CHM), an X-linked recessive hereditary disease, is an intractable chorioretinal dystrophy. The rate of disease progression of CHM reportedly shows considerable variability. A number of mutations involving the gene that codes for Rab escort protein-1 (REP-1) have been detected in CHM patients. We have analyzed REP-1 gene mutations of Japanese CHM patients. The present study was designed to investigate the clinical variability and the genotype to phenotype relationship in 15 Japanese CHM patients referred to the Department of Ophthalmology of Juntendo University Hospital. The clinical investigation of visual acuity, visual field, color vision and refraction revealed inter-individual variability. Mutation analyses of the REP-1 gene revealed 10 types of mutations in 13 patients from 11 families, including an insertion, small deletions, nonsense mutations and an A to CC mutation. In 13 CHM patients with detectable REP-1 gene mutations, no relationship of genotype to phenotype was detected. At present, we consider the REP-1 genotype to be an unreliable prognostic factor for counseling of CHM patients. In two patients from one family, no mutations were detected in coding regions of the REP-1 gene. These patients may have intron mutations of the REP-1 gene, not detectable by the techniques employed in this study, or other causative genes. Both were observed to have somewhat slower disease progression than the other 13 patients. More advanced analyses are necessary to answer questions regarding the genotype-phenotype relationship in CHM patients.

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Section: Discussioncontrasting

confidence: 93%

“…The CHM gene encodes the A component of Rab geranylgeranyl transferase 10 (GGTase) now termed Rab escort protein-1 (REP-1) 11 . A number of mutations have been demonstrated in affected members of several CHM families [12][13][14][15][16][17][18][19][20][21][22][23] . We have already reported a REP-1 gene mutation in Japanese families 24,25 .…”

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confidence: 99%

Visual impairment and REP-1 gene mutations in Japanese choroideremia patients

Hayakawa

Fujiki

Hotta

et al. 1999

Ophthalmic Genetics

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“…We show that the SCRs do contain determinants for Ypt protein binding, but they are not sufficient for this function. Studies on the mutational spectrum of choroideremia patients have shown that choroideremia patients carry deletions of the whole reading frame or mutations leading to REP1 carboxy-terminal truncations Donnelly et al, 1994;van Bokhoven et al, 1994b). Here we show that carboxyterminal truncation of the Mrs6 protein affects RabGGTase activity because of the inability of the mutant protein to bind its substrates, the small G proteins.…”

Section: Introductionmentioning

confidence: 99%

Amino- and carboxy-terminal domains of the yeast Rab escort protein are both required for binding of Ypt small G proteins.

Bauer

Lorenzetti

Miączyńska

et al. 1996

MBoC

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“…Most described mutations of CHM are nonsense mutations, splice error mutations, or frameshift mutations, leading to premature stop codons that result in an abnormal protein or no expression from nonsense-mediated decay (3, 7, 9–11). Rare missense mutations have been described, resulting in presumably misfolded and nonfunctional proteins (8, 16). While no clear genotype/phenotype correlation exists (eg.…”

Section: Discussionmentioning

confidence: 99%

Clinical Characteristics of a Large Choroideremia Pedigree Carrying a Novel CHM Mutation

Huang¹,

Kim²,

Fawzi³

2012

Arch Ophthalmol

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Objective We describe a large family with a novel mutation in CHM. Clinical Relevance To demonstrate a novel CHM mutation that emphasizes severe posterior pole carrier phenotypes, age-related changes, and early choroideremia pathology. Methods Subjects were characterized using clinical examination, widefield fundus photography, widefield autofluorescence, and spectral domain optical coherence tomography. The CHM mutation was identified with the NIH-sponsored eyeGene™ program. Results A novel nonsense CHM mutation (T1194G), resulting in a premature stop (Y398X) and loss of the final one-third C-terminal portion of the protein, was identified. A large pedigree was generated from information provided by the twice-married proband. Seven males (ages 27–39) and seven females (ages 22–89) were evaluated. Affected males showed characteristic peripheral chorioretinal atrophy with islands of macular sparing. Female carriers exhibited a wide range of variability, from mild pigmentary alterations to significant chorioretinal atrophy with severe vision loss. Older women tended to have a more severe phenotype. Autofluorescence demonstrating subfoveal loss or absence of RPE correlated with vision loss in both sexes. Spectral domain optical coherence tomography demonstrated dynamic remodeling over time of the outer retina including focal thickening, drusen-like deposits, and disruption to photoreceptor inner segment/outer segment junctions in young female carriers. Conclusions CHM (T1194G) is a novel mutation manifesting a wide range of phenotypic variability in a single family, with a trend toward more severe phenotypes in older female carriers. Our findings emphasize the importance of considering X-linked diseases and carefully evaluating pedigrees with severe pathology in females.

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Missense mutation in the choroideremia gene

Cited by 16 publications

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Visual impairment and REP-1 gene mutations in Japanese choroideremia patients

Visual impairment and REP-1 gene mutations in Japanese choroideremia patients

Amino- and carboxy-terminal domains of the yeast Rab escort protein are both required for binding of Ypt small G proteins.

Clinical Characteristics of a Large Choroideremia Pedigree Carrying a Novel CHM Mutation

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