AUTOSOMAL RECESSIVE RETINITIS-PIGMENTOSA AND CONE-ROD DYSTROPHY CAUSED BY SPLICE-SITE MUTATIONS IN THE STARGARDTS-DISEASE GENE ABCR

Ophthalmological and molecular genetic studies were performed in a con sanguineous family with individuals showing either retinitis pigmentos a (RP) or cone-rod dystrophy (CRD). Assuming pseudodominant (recessive ) inheritance of allelic defects, linkage analysis positioned the caus al gene at 1p21-p13 (lod score 4.22), a genomic segment known to harbo r the ABCR gene involved in Stargardt's disease (STGD) and age-related macular degeneration (AMD). We completed the exon-intron structure of the ABCR gene and detected a severe homozygous 5' splice site mutatio n, IVS30+1G-->T, in the four RP patients. The five CRD patients in thi s family are compound heterozygotes for the IVS30+1G-->T mutation and a 5' splice site mutation in intron 40 (IVS40+5G-->A). Both splice sit e mutations were found heterozygously in two unrelated STGD patients, but not in 100 control individuals. In these patients the second mutat ion was either a missense mutation or unknown. Since thus far no STGD patients have been reported to carry two ABCR null alleles and taking into account that the RP phenotype is more severe than the STGD phenot ype, we hypothesize that the intron 30 splice site mutation represents a true null allele. Since the intron 30 mutation is found heterozygou sly in the CRD patients, the IVS40+5G-->A mutation probably renders th e exon 40 5' splice site partially functional. These results show that mutations in the ABCR gene not only result in STGD and AMD, but can a lso cause autosomal recessive RP and CRD. Since the heterozygote frequ ency for ABCR mutations is estimated at 0.02, mutations in ABCR might be an important cause of autosomal recessive and sporadic forms of RP and CRD.