ABCMdb

ABCA4 p.Gly991*

ClinVar:

c.2971G>T , p.Gly991* ? , not provided
c.2971G>C , p.Gly991Arg ? , not provided

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Publications
[hide] Association of a homozygous nonsense mutation in t... Ophthalmic Res. 2004 Mar-Apr;36(2):82-8. Simonelli F, Testa F, Zernant J, Nesti A, Rossi S, Rinaldi E, Allikmets R
Association of a homozygous nonsense mutation in the ABCA4 (ABCR) gene with cone-rod dystrophy phenotype in an Italian family.
Ophthalmic Res. 2004 Mar-Apr;36(2):82-8., [PMID:15017103]

Abstract [show]
Genetic variation in the ABCA4 (ABCR) gene has been associated with several distinct retinal phenotypes, including Stargardt disease/fundus flavimaculatus (STGD/FFM), cone-rod dystrophy (CRD), retinitis pigmentosa (RP) and age-related macular degeneration. The current model of genotype/phenotype association suggests that patients harboring deleterious mutations in both ABCR alleles would develop RP-like retinal pathology. Here we describe ABCA4-associated phenotypes, including a proband with a homozygous nonsense mutation in a family from Southern Italy. The proband had been originally diagnosed with STGD. Ophthalmologic examination included kinetic perimetry, electrophysiological studies and fluorescein angiography. DNA of the affected individual and family members was analyzed for variants in all 50 exons of the ABCA4 gene by screening on the ABCR400 microarray. A homozygous nonsense mutation 2971G>T (G991X) was detected in a patient initially diagnosed with STGD based on funduscopic evidence, including bull's eye depigmentation of the fovea and flecks at the posterior pole extending to the mid-peripheral retina. Since this novel nucleotide substitution results in a truncated, nonfunctional, ABCA4 protein, the patient was examined in-depth for the severity of the disease phenotype. Indeed, subsequent electrophysiological studies determined severely reduced cone amplitude as compared to the rod amplitude, suggesting the diagnosis of CRD. ABCR400 microarray is an efficient tool for determining causal genetic variation, including new mutations. A homozygous protein-truncating mutation in ABCA4 can cause a phenotype ranging from STGD to CRD as diagnosed at an early stage of the disease. Only a combination of comprehensive genotype/phenotype correlation studies will determine the proper diagnosis and prognosis of ABCA4-associated pathology.

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No. Sentence Comment
7 A homozygous nonsense mutation 2971G1T (G991X) was detected in a patient initially diagnosed with STGD based on funduscopic evidence, including bull`s eye depigmentation of the fovea and flecks at the posterior pole extending to the mid-peripheral retina. Login to comment
46 This novel nucleotide substitution results in a G991X nonsense mutation and, therefore, in a truncated, nonfunctional, ABCA4 protein. Login to comment
58 were, as expected, heterozygous for the G991X mutation, while both siblings lacked it altogether, presenting homozygous wild-type alleles. Login to comment
75 Study subjects 1134 and 1135, the brother and the sister of patient 1133, aged 18 and 20 years, respectively, showed normal visual acuity and normal fundus appearance, correlating with their normal genotype lacking the G991X mutation. Login to comment
76 Discussion This study describes segregation of a novel homozygous nonsense ('severe`) mutation, G991X, in the ABCA4 gene in an Italian family with a clinical phenotype of CRD. Login to comment
90 The proband of the family described in this study was homozygous for a G991X mutation, which terminates the protein at exon 20, rendering a 'knockout` for the ABCA4 gene. Login to comment

[hide] Genotyping microarray (gene chip) for the ABCR (AB... Hum Mutat. 2003 Nov;22(5):395-403. Jaakson K, Zernant J, Kulm M, Hutchinson A, Tonisson N, Glavac D, Ravnik-Glavac M, Hawlina M, Meltzer MR, Caruso RC, Testa F, Maugeri A, Hoyng CB, Gouras P, Simonelli F, Lewis RA, Lupski JR, Cremers FP, Allikmets R
Genotyping microarray (gene chip) for the ABCR (ABCA4) gene.
Hum Mutat. 2003 Nov;22(5):395-403., [PMID:14517951]

Abstract [show]
Genetic variation in the ABCR (ABCA4) gene has been associated with five distinct retinal phenotypes, including Stargardt disease/fundus flavimaculatus (STGD/FFM), cone-rod dystrophy (CRD), and age-related macular degeneration (AMD). Comparative genetic analyses of ABCR variation and diagnostics have been complicated by substantial allelic heterogeneity and by differences in screening methods. To overcome these limitations, we designed a genotyping microarray (gene chip) for ABCR that includes all approximately 400 disease-associated and other variants currently described, enabling simultaneous detection of all known ABCR variants. The ABCR genotyping microarray (the ABCR400 chip) was constructed by the arrayed primer extension (APEX) technology. Each sequence change in ABCR was included on the chip by synthesis and application of sequence-specific oligonucleotides. We validated the chip by screening 136 confirmed STGD patients and 96 healthy controls, each of whom we had analyzed previously by single strand conformation polymorphism (SSCP) technology and/or heteroduplex analysis. The microarray was >98% effective in determining the existing genetic variation and was comparable to direct sequencing in that it yielded many sequence changes undetected by SSCP. In STGD patient cohorts, the efficiency of the array to detect disease-associated alleles was between 54% and 78%, depending on the ethnic composition and degree of clinical and molecular characterization of a cohort. In addition, chip analysis suggested a high carrier frequency (up to 1:10) of ABCR variants in the general population. The ABCR genotyping microarray is a robust, cost-effective, and comprehensive screening tool for variation in one gene in which mutations are responsible for a substantial fraction of retinal disease. The ABCR chip is a prototype for the next generation of screening and diagnostic tools in ophthalmic genetics, bridging clinical and scientific research.

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No. Sentence Comment
194 In the Italian cohort we detected two new variants, one of which was a homozygous 2971G>T (G991X) nonsense mutation in one STGD patient. Login to comment