Novel mutations in of the ABCR gene in italian patients with Stargardt disease

Abstract

Purpose: Stargardt disease (STGD) is the most prevalent juvenile macular dystrophy, and it has been associated with mutations in the ABCR gene, encoding a photoreceptor-specific transport protein. In this study, we determined the mutation spectrum in the ABCR gene in a group of Italian STGD patients. Methods: The DNA samples of 71 Italian patients (from 62 independent pedigrees), affected with autosomal recessive STGD, were analysed for mutations in all 50 exons of the ABCR gene by the DHPLC approach (with optimization of the DHPLC conditions for mutation analysis) and direct sequencing techniques. Results: In our group of STGD patients, 71 mutations were identified in 68 patients with a detection rate of 95.7%. Forty-three mutations had been already reported in the literature, whereas 28 mutations had not been previously described and were not detected in 150 unaffected control individuals of Italian origin. Missense mutations represented the most frequent finding (59.2%); G1961E was the most common mutation and it was associated with phenotypes in various degrees of severity. Conclusions: Some novel mutations in the ABCR gene were reported in a group of Italian STGD patients confirming the extensive allelic heterogeneity of this geneFprobably related to the vast number of exons that favours rearrangements in the DNA sequence.

Retinal Phenotypes in Patients Homozygous for the G1961E Mutation in theABCA4Gene

“…41 It is predicted to give rise to an amino acid change that lies outside the functional domain of the ABCA4 protein, it never occurs without G1961E, and, therefore, its pathogenicity has not been confirmed. The N96K missense change, which previously has been reported as a disease causing mutation in the ABCA4 gene, 42,43 was detected 4 times in this cohort, that is twice in 2 siblings heterozygous for this mutation (patients 8-1 and 8-2), and once in a double homozygous patient (patient 9). In all 3 cases, this additional mutation yielded a severe disease phenotype with extensive retinal atrophy, primarily affecting the macular region.…”

“…These genetic findings in our patients of Italian origin are in keeping with recent reports of this mutation in Italian populations with STGD1. 43 The H1838D mutation has been reported previously in patient 7-1. 31 This variant clearly has a profoundly deleterious effect on ABCA4 protein function, at least when present in conjunction with the G1961E in homozygosity, giving rise to a severe, early-onset and complex phenotype in both siblings from a consanguineous family of Jordanian descent.…”

Expanding the Mutation Spectrum in ABCA4: Sixty Novel Disease Causing Variants and Their Associated Phenotype in a Large French Stargardt Cohort

“…Given the large number of variants reported in ABCA4 [12], most of them being polymorphisms, the identification of true disease-causing mutations is often challenging [5,13,14]. …”

A Computational Approach From Gene to Structure Analysis of the Human ABCA4 Transporter Involved in Genetic Retinal Diseases

“…7,14,15 ABCA4 was the first ABCA-transporter that has been linked to various genetic retinal diseases, such as (Stargardt disease, cone dystrophy, and retinitis pigmentosa). [18][19][20][21][22][23] Some ABCA4 sequence variants also have been considered as a risk factor for the development of AMD, 24,25 a frequent progressive degener-ation of central retina, with a high prevalence in elderly people. 26,27 Stargardt disease (STGD1) is the most common inherited juvenile macular degeneration and is associated with a reduction of central visual acuity.…”