Novel ABCA4 compound heterozygous mutations cause severe progressive autosomal recessive cone-rod dystrophy presenting as Stargardt disease

[摘要] Purpose: To identify the gene causing asevere form of progressive autosomal recessive cone-rod dystrophypresenting as Stargardt disease and to characterize clinical featuresin a large American family. Methods: We characterized an Americanfamily who had an unusual retinal dystrophy with clinical features ofStargardt disease and severe progressive cone-rod dystrophy. Familymembers underwent complete ocular examinations with evaluation ofvisual acuity, visual fields, fundus examination, fluoresceinangiography, and electroretinography. Genome-wide linkage analysis ofthe family was performed using 408 microsatellite markers spanning theentire human genome. Direct DNA sequence analysis was used formutational analysis of the ABCA4 gene in all exons andexon-intron boundary regions and for testing cosegregation of themutations with the disease in the family. DNA sequence analysis wasused to determine the presence of the mutations in 200 unrelatedcontrols. Results: The proband presented with aclinical phenotype that was initially compatible with Stargardtdisease, only to progress to a severe cone-rod dystrophy over thecourse of a few years. The disease-causing gene in the family waslinked to the ABCA4 locus on chromosomal 1p22. One novelmutation, c.655A>T, was identified in exon 6 and another novelsplicing mutation, c.5312+3A>T, was identified in intron 37 of ABCA4.The mutations were not present in 200 controls. The two affectedsisters in this pedigree were compound heterozygotes for the mutations.Unaffected family members either did not carry either or had only oneof the two mutations. Conclusions: We have identified twonovel ABCA4 mutations, c.655A>T and c.5312+3A>T. Whenpresent as a compound heterozygous state, the mutations cause aphenotype of retinal dystrophy that initially manifests as Stargardtdisease and slowly progresses to a severe cone-rod dystrophy. Theseresults expand the wide range of clinical manifestations of ABCA4mutations.

[学科分类] 生物化学/生物物理