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Case Reports
. 2008 Feb 4:14:262-7.

Molecular analysis of ABCA4 and CRB1 genes in a Spanish family segregating both Stargardt disease and autosomal recessive retinitis pigmentosa

Rosa Riveiro-Alvarez  1 , Elena Vallespin, Robert Wilke, Blanca Garcia-Sandoval, Diego Cantalapiedra, Jana Aguirre-Lamban, Almudena Avila-Fernandez, Ascension Gimenez, Maria-Jose Trujillo-Tiebas, Carmen Ayuso
Affiliations
Case Reports

Molecular analysis of ABCA4 and CRB1 genes in a Spanish family segregating both Stargardt disease and autosomal recessive retinitis pigmentosa

Rosa Riveiro-Alvarez et al. Mol Vis. .

Abstract

Purpose: Stargardt disease (STGD), characterized by central visual impairment, is the most common juvenile macular dystrophy. All recessively inherited cases are thought to be due to mutations in the ABCA4 gene. Early-onset autosomal recessive retinitis pigmentosa (arRP) is a severe retinal degeneration that presents before the patient is ten years old. It has been associated with mutations in different genes, including CRB1. The aim of this study was to determine the genetic causes for two different retinal dystrophies, STGD and early-onset arRP, both segregating in one Spanish family.

Methods: Mutational analyses were performed using the ABCR400 and Leber congenital amaurosis (LCA) genotyping microarrays. Additional scanning for mutations was conducted by denaturing high performance liquid chromatography (dHPLC); results were confirmed by direct sequencing.

Results: A patient, who exhibited a STGD phenotype, was found to be homozygous for the p.Asn1805Asp (c.5413A>G) mutation in ABCA4. However, his affected sister, who had the arRP phenotype, was found to be heterozygous for this allele; no other sequence change could be found in ABCA4. Analysis using the LCA chip revealed the p.Cys948Tyr mutation in CRB1 in heterozygous state. A second mutation (p.Trp822ter) was found in the CRB1 gene in the affected female by denaturing high performance liquid chromatography (dHPLC) and direct sequencing.

Conclusions: Two distinct retinal dystrophies with mutations affecting two different genes cosegregated in this family. The presence of two different phenotypes associated with mutations in two distinct genes in one single family must be considered especially when dealing with retinal dystrophies which bear high carrier frequencies in general population.

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Figures

Figure 1
Figure 1
Pedigrees from a Spanish family cosegregating Stargardt disease and early-onset retinitis pigmentosa. A: Haplotype analysis showing microsatellite markers flanking the ABCA4 gene (TEL-D1S435-D1S2804-ABCA4-D1S236-CEN) confirmed the Stargardt disease phenotype in II:1. His affected sister (II:4) was found to be a carrier of one disease-associated allele. B: Haplotype analysis with markers flanking the CRB1 gene (TEL-D1S1660-CRB1- D1S2757- D1S2816-D1S408-CEN) showed cosegregation of the disease. Three brothers (II:1, II:2, II:3) were found to be carriers of the p.Cys948Tyr allele.
Figure 2
Figure 2
Funduscopic photograph of a patient with Stargardt disease. Funduscopy revealed a maculopathy with retinal pigment epithelium atrophy and hyperpigmentation and few central yellowish flecks. A slight temporal papillary pallor was present and retinal vessels showed no constriction.
Figure 3
Figure 3
Funduscopic photograph of a patient with autosomal recessive retinitis pigmentosa. Funduscopy showed pigment spots homogeneously scattered through the retina with preservation of the paraarteriolar retinal pigmentary epithelium.
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