Analysis of 21 Stargardt's disease families confirms a major locus on chromosome 1p with evidence for non-allelic heterogeneity in a minority of cases.

Abstract

Background-Autosomal recessive Stargardt's disease is a macular degeneration characterised by a juvenile onset and a rapidly progressive course resulting in an atrophic macular area typically surrounded by yeliowish retinal flecks. Method-The disease locus has previously been assigned to markers from chromosome 1p21-pl3 by genetic linkage analysis in eight multiplex Stargardt's disease families.Results-In an extended analysis, the assignment to chromosome lp was confirmed in the majority of the 21 families with Stargardt's disease who were studied. In addition, a series of recombinant chromosomes further narrowed the Stargardt's disease region to an approximately 3 cM interval between markers at D1S424 and DlS497. Conclusion-Multipoint linkage analysis most probably excludes this locus in three of these families suggesting non-allelic heterogeneity with at least one additional minor Stargardt's disease locus. (BrJ Ophthalmol 1996;80:745-749 Here, we report our results on the genetic linkage analysis in 21 Stargardt's disease families. We confirm linkage of the disease locus to chromosome lp21-p13 in the majority of our families. In addition, this study has identified a series of recombinant Stargardt's disease chromosomes which together refine the previous localisation of the disease gene to a small interval on chromosome lp between markers at D1S424 and D1S497. In three out of our 21 Stargardt's disease families we found evidence for non-allelic heterogeneity of this condition suggesting the occurrence of at least one additional minor Stargardt's disease locus. Patients and methods CLINICAL STUDIESForty four affected and 28 non-affected at risk individuals belonging to 21 Stargardt's disease families were recruited from the Eye Care Center Vancouver (Canada) and the Eye Clinic Tubingen (Germany) (Fig 1). At least one patient per family was seen by one of the authors (DW or AE), Dr W Macrae (Toronto) (family 15), or Dr CC Ewing (Saskatoon) (family 13). All families were of white origin except family 1 which originated from China. All affected family members were diagnosed with having typical features of Stargardt's disease including the following criteria: (1) the Weber, Sander, Kopp, Walker, Eckstein, Wissinger, Zrenner, Grimm initial presence of fundus flavimaculatus with yellow 'flecks' in the macular and paramacular areas when patients were seen at younger age; (2) a normal appearance of the optic disc, blood vessels, and peripheral retina; (3) the presence of the typical dark choroid on fluorescein angiography; (4) normal to subnormal electro-oculogram (EOG), normal electroretinogram (ERG) for rods and cones in early stages, and abnormal dark adapted amplitudes of the ERG recordings in advanced cases; (5) mottled pigmentation of the macula; and (6)

Mapping of the rod photoreceptor ABC transporter (ABCR) to 1p21-p22.1 and identification of novel mutations in Stargardt's disease

“…The 15 families with Stargardt's disease analyzed in this study have previously been linked to the STGD1 locus on chromosome 1p13-p21 (Weber et al 1996). All families are of Caucasian origin except family M. which is descended from Chinese ancestors.…”

“…The families were selected on the basis of demonstrated genetic linkage to the STGD1 locus with a conditional probability of being linked higher than 95% (Weber et al 1996). For mutational analyses of part of the ABCR gene, oligonucleotide primers as determined by Allikmets et al (1997) were used and included 21 out of an estimated 51 exons of the gene (F.P.M.…”

“…Originally, the disease locus was mapped to markers on chromosome 1p13-p21 (Kaplan et al 1993). Subsequently, several groups have refined the gene location to an approximately 2-cM interval between markers at D1S406 and D1S236 (e.g., Hoyng et al 1996;Weber et al 1996).…”

Subretinal fibrosis in stargardt's disease: case report

“…It is the most common form of hereditary macular dystrophy and accounts for 7% of all retinal dystrophies (2)(3)(4) . Genetically, STGD is a heterogeneous disorder that is usually inherited as an autosomal recessive disorder but rarely can present as an autosomal dominant trait with a later onset of clinical symptoms (1,5) . The fundus findings may be limited to an atrophic maculopathy, which may have a bull's eye appearance.…”

Recent Advances in the Molecular Genetics of Hereditary Retinal Dystrophies with Primary Involvement of the Macula

“…Several independent linkage studies have mapped the disease locus to chromosome 1p13-p21 [Kaplan et al, 1993;Hoyng et al, 1996;Weber et al, 1996]. A novel member of the ABC transporter superfamily, a gene encoding a retina-specific ABC transporter (ABCR), was localized to the same chromosomal interval and subsequently shown to be mutated in Stargardt's disease patients [Allikmets et al, 1997b].…”