Michael Danciger, Vickie Heilbron, Yong-Qing Gao, Dan-Yun Zhao, Samuel G. Jacobson, and Debora B. Farber | Mol. Vis. | Volume 2 (10) | 1996 | molvis.org/molvis/v2/a10/
Based on average estimates of the prevalence of non-syndromic retinitis pigmentosa (RP) at 1/4,000, there are approximately 1.5 million people in the world with this inherited, progressive, degenerative disease of the retinal photoreceptor cells which often leads to blindness. About 50% of these cases are inherited in an autosomal recessive manner (AR). With the approach of screening the exons of candidate genes in large numbers of unrelated ARRP probands, mutations associated with disease have been found in several candidate genes expressed in rod photoreceptors at very low frequency: RHO, encoding rhodopsin, 1/126 patients screened; PDE6B (click to continue reading)
Based on average estimates of the prevalence of non-syndromic retinitis pigmentosa (RP) at 1/4,000, there are approximately 1.5 million people in the world with this inherited, progressive, degenerative disease of the retinal photoreceptor cells which often leads to blindness (1,2,3). About 50% of these cases are inherited in an autosomal recessive manner (AR).
With the approach of screening the exons of candidate genes in large numbers of unrelated ARRP probands, mutations associated with disease have been found in several candidate genes expressed in rod photoreceptors at very low frequency: RHO, encoding rhodopsin, 1/126 patients screened (4); PDE6B, encoding the beta-subunit of rod cGMP-phosphodiesterase, 4/88 patients (5); PDE6A, encoding the alpha-subunit of rod cGMP-phosphodiesterase, 2/173 patients (6); and CNCG, encoding the alpha-subunit of the rod cGMP-gated channel, 3/173 patients (7). With the approach of linkage analysis in large families, two ARRP loci have so far been discovered: 1q31-q32.1 (8,9) and 6p, distal to RDS-peripherin (10). Also, linkage analysis of an informative consanguineous family led to the discovery of a second homozygous RHO mutation (11).
ARRP tends to appear most often in small nuclear families that by themselves are not informative enough to yield significant linkage data, and screening all the exons of candidate genes like PDE6A and PDE6B (each with 22 exons) in large numbers of unrelated probands is costly and time consuming. Therefore, we have taken the approach of studying candidate genes in small nuclear ARRP families with a double screening protocol. Linkage analyses of markers close to the loci of the candidate genes are performed first, and any families where a gene locus clearly does not segregate with disease are ruled out from further study of that gene. DNAs of the probands from the remaining families (where the gene locus cannot be ruled out from segregating with disease) are then screened for mutations in the exons of the candidate gene by SSCPE (single strand conformation polymorphism electrophoresis) and DGGE (denaturing gradient gel electrophoresis). Any exonic variants found are sequenced directly and analyzed within the corresponding family to see if they appear to segregate with disease. With this approach we studied 24 families with inherited retinal degenerations (14 with typical RP) for mutations in the genes PDE6B, MYL5, PDE6C, CNCG, RHO, ROM1 and RDS-peripherin. We have reported two typical ARRP families where the affecteds uniquely inherited compound heterozygous mutations in the PDE6B gene (12). With a similar approach, homozygous mutations also have been found in PDE6B in the affecteds of two other ARRP families (13,14).
References
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