Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies

Rozet, Jean–Michel; Gerber, Sylvie; Souied, Eric H.; Perrault, Isabelle; Châtelin, Sophie; Ghazi, Imad; Leowski, Corinne; Dufier, Jean‐Louis; Münnich, Arnold; Kaplan, Josseline

doi:10.1038/sj.ejhg.5200221

Cited by 137 publications

(83 citation statements)

References 12 publications

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“…The phenotype of this woman associated with compound heterozygosity for the p.G1961E and p.G1202R mutations is less severe than the association of one of them with the c.5460 þ 1G4A splice-site mutation. These findings are consistent with the previously reported ABCA4 genotypephenotype correlations, on one hand, 15,20,21 and with the report of families segregating different phenotypes associated with different ABCA4 mutations, on the other hand. 6,16,22 -25 This study emphasizes the homozygosity pitfals in highly inbred families when the heterozygote carrier frequency is known to be much higher than the mean frequency of heterozygote individuals in the general population.…”

Section: Discussionsupporting

confidence: 82%

Three different ABCA4 mutations in the same large family with several consanguineous loops affected with autosomal recessive cone–rod dystrophy

et al. 2006

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A large multiplex family presumably affected with autosomal recessive cone-rod dystrophy (CRD) was ascertained from Israel. In this family of Christian Arab ancestry with six consanguineous loops, linkage analysis failed to identify homozygosity in all six nuclear families at any of the three arCORD loci hitherto reported. However, homozygosity was found at the CORD3 locus for two nuclear families and the segregation of three distinct haplotypes at this locus in the whole pedigree suggested the alteration of the ABCA4 gene. This hypothesis was confirmed by the identification of three distinct mutations. Subsequently, with regard to the wide spectrum of autosomal recessive retinal dystrophies related to ABCA4 mutations, the natural history of the disease was revisited in all patients. Although the diagnosis of CRD was confirmed in 8/9 patients, the last one, aged of 34, displayed typical signs of Stargardt disease without extension to the peripheral retina. The results of this study emphasize the pitfalls of homozygosity mapping in highly inbred families when the heterozygote carrier frequency is particularly high in the general population.

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Section: Discussionsupporting

confidence: 82%

Three different ABCA4 mutations in the same large family with several consanguineous loops affected with autosomal recessive cone–rod dystrophy

et al. 2006

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“…7 Mutations in the ATP-binding cassette subfamily A group 4 (ABCA4) gene give rise to the recessive form of STGD, but are also associated with other retinal degenerative disorders such as cone-rod dystrophy (CRD) and autosomal recessive retinitis pigmentosa (arRP), 2,8,9 thereby characterising these dystrophies as ABCA4-associated retinopathies (AARs). 3,[10][11][12] It is proposed that malfunctioning ABCA4 protein prevents complete removal of retinoid products from the outer segment disc membrane of photoreceptors, resulting in the accumulation of downstream derivatives such as di-retinoid-ethanolamine in the retinal pigment epithelium (RPE). Such products can trigger RPE dysfunction through various mechanisms, consequently leading to degeneration of photoreceptors and ultimately vision loss.…”

Section: Introductionmentioning

confidence: 99%

Stargardt Disease: towards developing a model to predict phenotype

et al. 2013

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Stargardt disease is an ABCA4-associated retinopathy, which generally follows an autosomal recessive inheritance pattern and is a frequent cause of macular degeneration in childhood. ABCA4 displays significant allelic heterogeneity whereby different mutations can cause retinal diseases with varying severity and age of onset. A genotype-phenotype model has been proposed linking ABCA4 mutations, purported ABCA4 functional protein activity and severity of disease, as measured by degree of visual loss and the age of onset. It has, however, been difficult to verify this model statistically in observational studies, as the number of individuals sharing any particular mutation combination is typically low. Seven founder mutations have been identified in a large number of Caucasian Afrikaner patients in South Africa, making it possible to test the genotype-phenotype model. A generalised linear model was developed to predict and assess the relative pathogenic contribution of the seven mutations to the age of onset of Stargardt disease. It is shown that the pathogenicity of an individual mutation can differ significantly depending on the genetic context in which it occurs. The results reported here may be used to identify suitable candidates for inclusion in clinical trials, as well as guide the genetic counselling of affected individuals and families.

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“…A novel PROM1 variant that is predicted to be damaging through PolyPhen-2 was identified in P14. Five patients (P1, P7, P13, P21, P22) had single ABCA4 mutant alleles, which are considered to be disease-causing (p.L1970F 35 ; p.W439X 36 ; p.F873L 37 ; IVS38-10 T>C and p.V552I 38 ). The PRD patients who were heterozygous for ABCA4 mutations did not show fundus features that would be considered typical of Stargardt disease such as yellow-white irregular flecks in the posterior pole.…”

Section: Clinical and Molecular Characteristics Of The Pericentral Rdmentioning

confidence: 99%

Molecular Heterogeneity Within the Clinical Diagnosis of Pericentral Retinal Degeneration

Matsui

Cideciyan

Schwartz

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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METHODS. Patients were screened for an annular ring scotoma ranging from 38 to 408 (n ¼ 28, ages 24-71) with kinetic perimetry. All patients had pigmentary retinopathy in the region of the dysfunction. Further studies included cross-sectional and en face imaging, static chromatic perimetry, and electroretinography. Molecular screening was performed.RESULTS. Genotypes of 14 of 28 PRD patients were identified: There were mutations in eight different genes previously associated with autosomal dominant or autosomal recessive RDs. Kinetic fields monitored in some patients over years to more than a decade could be stable or show increased extent of the scotoma. Electroretinograms were recordable but with different severities of dysfunction. Patterns of photoreceptor outer nuclear layer (ONL) loss corresponded to the distribution of visual dysfunction. Outer nuclear layer thickness topography and en face imaging indicated that the greatest disease expression was in the area of known highest rod photoreceptor density.CONCLUSIONS. Molecular heterogeneity was a feature of the PRD phenotype. Many of the molecular causes were also associated with other phenotypes, such as maculopathies, typical retinitis pigmentosa (RP) and cone-rod dystrophy. The pericentral pattern of retinal degeneration is thus confirmed to be an uncommon phenotype of many different genotypes rather than a distinct disease entity.

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Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies

Cited by 137 publications

References 12 publications

Three different ABCA4 mutations in the same large family with several consanguineous loops affected with autosomal recessive cone–rod dystrophy

Three different ABCA4 mutations in the same large family with several consanguineous loops affected with autosomal recessive cone–rod dystrophy

Stargardt Disease: towards developing a model to predict phenotype

Molecular Heterogeneity Within the Clinical Diagnosis of Pericentral Retinal Degeneration

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