Mutations of the retinal specific ATP binding transporter gene (ABCR) in asingle family segregating both autosomal recessive retinitis pigmentosa RP19 and Stargardt disease: evidence of clinical heterogeneity at this locus

Stargardt disease (STGD) is an autosomal recessive macular dystrophy of chi ldhood characterised by bilateral loss of central vision over a period of s everal months. STGD has been mapped to chromosome 1p22.1 and recently ascri bed to mutations in the retinal specific ATP binding transporter gene (ABCR ). The fundus flavimaculatus with macular dystrophy (FFM), an autosomal rec essive condition responsible for gradual loss of visual acuity in adulthood (second to third decade) has also been mapped to the same locus. However, a gene for autosomal recessive retinitis pigmentosa with distinctive featur es of choriocapillaris atrophy at an advanced stage (RP19) has been mapped to the genetic interval encompassing the STGD gene on chromosome 1p (D1S435 -D1S236), raising the question of whether, despite striking differences in clinical course and presentation, RP19 and STGD might be allelic disorders at the ABCR locus. In a family segregating RP and STGD in two first cousins, we found that het erozygosity for a splicing mutation in the ABCR gene (1938-1 G-->A) resulte d in STGD while hemizygosity for this splice mutation resulted in RP, and w hen studying the RP patient's parents, we found a maternal non-contribution with apparent segregation of a null allele ascribed to a partial deletion of the ABCR gene. The present study shows that, despite striking clinical differences, RP19 a nd STGD are allelic disorders at the ABCR locus.