ABCA4 gene analysis in patients with autosomal recessive cone and cone rod dystrophies

Abstract

The ATP-binding cassette (ABC) transporters constitute a family of large membrane proteins, which transport a variety of substrates across membranes. The ABCA4 protein is expressed in photoreceptors and possibly functions as a transporter for N-retinylidene-phosphatidylethanolamine (N-retinylidene-PE), the Schiff base adduct of all-trans-retinal with PE. Mutations in the ABCA4 gene have been initially associated with autosomal recessive Stargardt disease. Subsequent studies have shown that mutations in ABCA4 can also cause a variety of other retinal dystrophies including cone rod dystrophy and retinitis pigmentosa. To determine the prevalence and mutation spectrum of ABCA4 gene mutations in non-Stargardt phenotypes, we have screened 64 unrelated patients with autosomal recessive cone (arCD) and cone rod dystrophy (arCRD) applying the Asper Ophthalmics ABCR400 microarray followed by DNA sequencing of all coding exons of the ABCA4 gene in subjects with single heterozygous mutations. Disease-associated ABCA4 alleles were identified in 20 of 64 patients with arCD or arCRD. In four of 64 patients (6%) only one mutant ABCA4 allele was detected and in 16 patients (25%), mutations on both ABCA4 alleles were identified. Based on these data we estimate a prevalence of 31% for ABCA4 mutations in arCD and arCRD, supporting the concept that the ABCA4 gene is a major locus for various types of degenerative retinal diseases with abnormalities in cone or both cone and rod function.

Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family

“…The c.5461-10T4C variant was found to be the most prevalent allele among patients with autosomal recessive cone and cone-rod dystrophy (8 of 64 patients). 34 In another study, the variant was found in 27 of 518 STGD1 patients compared with 1 of 316 clinically matched control individuals. 33 It is to be noticed that another affected member (VI:10) in the same family was homozygous for the c.5461-10T4C mutation.…”

VII-2 : ELECTROPHYSIOLOGIE PEDIATRIQUE : EXEMPLES Première partie

“…Cependant, les résultats du bilan électrophysiologique pratiqué ne permettent pas de trancher absolument entre une dystrophie des cônes et une maladie de Stargardt, tant ces pathologies ont de points communs (Kitiratschky, Grau, Bernd, Zrenner, Jagle, Renner, Kellner, Rudolph, Jacobson, Cideciyan, Schaich, Kohl & Wissinger, 2008), (Shastry, 2008).…”

“…Ce résultat ne permet pas non plus d'étiqueter de façon absolue la pathologie en cours ; en effet, il a été montré que la dystrophie des cônes ou la cone-rod dystrophy présentaient dans 30% des cas, des mutations du gène ABCA4 (Kitiratschky et al, 2008)… L'évolution tranchera… L'évolution fonctionnelle déterminera si l'épithélium pigmentaire et les bâtonnets sont secondairement davantage impliqués (voir exemple de l'évolution d'une maladie de Stargardt au chapitre VI-1) ou si le dysfonctionnement constaté reste limité aux cônes maculaires.…”

Vi-2 : Apport De l'ÉLECTROPHYSIOLOGIE Chez l'ADULTE : Exemples

“…Une mutation du gène ABCA4 n'est pas pathognomonique de la maladie de Stargardt et se retrouve dans des pathologies avec atteinte maculaire comme la dystrophie des cônes ou les cone-rod dystrophies [Kitiratschky et al, 2008]. Les erreurs ou errances de diagnostic sont donc compréhensibles.…”