ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies

Abstract

ABCA4, also called ABCR, is a retinal-specific member of the ATP-binding cassette (ABC) family that functions in photoreceptor outer segments as a flipase of all trans retinal. Homozygous and compound heterozygous ABCA4 mutations are associated with various autosomal recessive retinal dystrophies, such as Stargardt disease. The authors analyzed a cohort of 29 arRP families for the mutations in ABCA4 with a commercial microarray, ABCR-400, in addition to direct sequencing and segregation analysis, and identified both mutant alleles in two families (7%): compound heterozygosity for missense (R602W) and nonsense (R408X) alleles and homozygosity for a complex [L541P; A1038V] allele. The missense mutations were analyzed functionally in the photoreceptors of Xenopus laevis tadpoles, which revealed mislocalization of ABCA4 protein. These mutations cause retention of ABCA4 in the photoreceptor inner segment, likely by impairing correct folding, resulting in the total absence of physiologic protein function. Patients with different retinal dystrophies harboring two misfolding alleles exhibit early age-of-onset (AO) (5 to 12 years) of retinal disease. These data suggest that a class of ABCA4 mutants may be an important determinant of the AO of disease.—Hans E. Grossniklaus