A linkage survey of 20 dominant retinitis pigmentosa families: frequencies of the nine known loci and evidence for further heterogeneity.

Abstract

Autosomal dominant retinitis pigmentosa (ADRP) is caused by mutations in two known genes, rhodopsin and peripherin/ Rds, and seven loci identified only by linkage analysis. Rhodopsin and peripherin/ Rds have been estimated to account for 20-31% and less than 5% of ADRP, respectively. No estimate of frequency has previously been possible for the remaining loci, since these can only be implicated when families are large enough for linkage analysis. We have carried out such analyses on 20 unrelated pedigrees with 11 or more meioses. Frequency estimates based on such a small sample provide only broad approximations, while the above estimations are based on mutation detection in much larger clinic based patient series. However, when markers are informative, linkage analysis cannot fail to detect disease causation at a locus, whereas mutation detection techniques might miss some mutations. Also diagnosing dominant RP from a family history taken in a genetic clinic may not be reliable. It is therefore interesting that 10 (50%) of the families tested have rhodopsin-RP, suggesting that, in large clearly dominant RP pedigrees, rhodopsin may account for a higher proportion of disease than had previously been suspected. Four (20%) map to chromosome 19q, implying that this is the second most common ADRP locus. One maps to chromosome 7p, one to 17p, and one to 17q, while none maps to Icen, peripherin/Rds, 8q, or 7q. Three give exclusion of all of these loci, showing that while the majority of dominant RP maps to the known loci, a snaJli proportion derives from loci yet to be identified. (JMed Genet 1998;35:1-5)

A new locus (RP31) for autosomal dominant retinitis pigmentosa maps to chromosome 9p

“…Previously published data indicate the existence of additional adRP loci in the human genome (Inglehearn et al 1998). We have now identified a family with autosomal dominant retinitis pigmentosa that clearly demonstrates the presence of a new RP locus (RP31) on the short arm of chromosome 9, and is the only lineage of adRP known to map to this region.…”

Genomic characterization of human SEC14L1 splice variants within a 17q25 candidate tumor suppressor gene region and identification of an unrelated embedded expressed sequence tag

“…Mutations in both TTPA (Yokota et al 1997) and CR-ALBP (Maw et al 1997) have been identified in retinitis pigmentosa (RP) patients, leading to progressive blindness. While TTPA and CRALBP are just two of a number of genes implicated in RP (Phelan and Bok 2000), families exist that are not linked to any of these known genes (Inglehearn et al 1998) and should, therefore, be investigated for SEC14L1 alterations. Coding exon-specific PCR primers presented here will aid in further investigation of SEC14L1 in these diseases.…”

A Molecular Case Report of Autosomal Dominant Retinitis Pigmentosa: RP1/RHO Sequence Variants in a Turkish Family

“…Relative involvement of the RHO gene mutations in the pathogenesis of adRP was found less in Italy than in U.S. and UK populations. RHO gene mutations were found in 16% of Italian families, similar to Spain, southern France, and the Far East (Bareil et al, 1999;Milla et al, 2002;Wada et al, 2003;Zhang et al, 2002); and 25-50% in the populations of the United States and the United Kingdom (Inglehearn et al, 1998;Sohocki et al, 2001). Low frequencies of RHO mutations were reported to be due to ethnic variation, small sample sizes, and molecular methods to detect mutations.…”

“…Recent mutation screening data suggested RHO as the most commonly involved gene in adRP (25-50% of cases) followed by RP1 gene (5-10%), RDS (5%), and IMPDH1 (5-10%) (Inglehearn et al, 1998;Jay, 1982;Sohocki et al, 2001). Basically, RHO and RP1 genes are the most commonly mutated genes reported for RP, therefore constituted our basic research area.…”