Retinitis Pigmentosa 25
A number sign (#) is used with this entry because retinitis pigmentosa-25 (RP25) is caused by homozygous or compound heterozygous mutation in the EYS gene (612424) on chromosome 6q12.
For a phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.
Clinical FeaturesCollin et al. (2008) examined 6 affected individuals from 3 families with retinitis pigmentosa, all but 1 of whom displayed characteristic RP abnormalities including night blindness as the initial symptom, retinal bone-spicule pigmentation and attenuated retinal vessels, constriction of visual fields, and a nonrecordable ERG or ERG responses in a rod-cone pattern. Two unrelated patients had posterior subcapsular cataracts. The authors observed differences in the photoreceptor dystrophy between the families: in 1 patient from family A, the cones were more severely affected than the rods (cone-rod pattern) and kinetic visual fields were not constricted but showed bilateral central scotomas; fundus examination revealed central abnormalities at the level of the retinal pigment epithelium and moderate attenuation of retinal vessels. Her 60-year-old brother also had central fundus lesions, but his ERG showed neither rod nor cone activity. Family B had relatively late onset of a classic form of RP, with preservation of central vision. The proband in family C, who was the youngest patient in the study, was the only one who was legally blind, due to severely constricted visual fields.
MappingRuiz et al. (1998) identified a novel locus for autosomal recessive retinitis pigmentosa (arRP), located on 6q between markers D6S257 and D6S1644, in a region that contains genes encoding subunits GABRR1 (137161) and GABRR2 (137162) of the GABA-C receptor, which is the effector of lateral inhibition in the retina. Indeed, study was undertaken on a candidate gene basis; the workers selected chromosomal regions containing genes that encode the different subunits of the GABA receptors for homozygosity mapping in inbred families affected by arRP. The GABRR1 and GABRR2 genes are located at 6q14-q21.
Khaliq et al. (1999) found linkage of RP to 6q in a 3-generation consanguineous Pakistani family in which RP segregated as an autosomal recessive trait. The pedigree contained 12 affected individuals. Affected individuals experienced night blindness, beginning at approximately 25 years of age, and deterioration of visual acuity (central vision), beginning at approximately 30 years of age. By age 55 to 60 years, many affected subjects had no perception of light in either eye. Khaliq et al. (1999) reduced the critical interval to a 2.4-cM region defined by recombination events in the family. The region, they noted, contained no well-characterized family of genes.
Barragan et al. (2008) conducted a genomewide scan of 3 Spanish RP families, including 2 previously studied by Ruiz et al. (1998), RP5 and RP214, and confirmed linkage to chromosome 6. Barragan et al. (2008) then performed linkage analysis using microsatellite markers spanning the 6p12.1-q15 interval in 18 newly ascertained Spanish arRP families, and found that 5 of the families showed suggestive linkage to the RP25 locus (maximum lod score, 3.63 at D6S1573). A crossover event in 1 of the families refined the critical interval to a 2.67-cM region between D6S257 and D6S1557. The authors stated that these findings confirmed the high prevalence of RP25 among forms of retinitis pigmentosa in the Spanish population, estimated by them to be around 27.7%.
Collin et al. (2008) performed homozygosity mapping in 145 patients with autosomal recessive RP and identified a shared region of homozygosity on chromosome 6 in 2 affected sibs that overlapped with the RP25 locus.
Molecular GeneticsBy direct sequence analysis in 7 Spanish autosomal recessive RP families, Abd El-Aziz et al. (2008) excluded 60 of the approximately 110 genes within the RP25 interval. To investigate whether copy number variation (CNV) exists within RP25, comparative genomic hybridization (CGH) analysis was performed on the consanguineous RP5 family, revealing the presence of a 100-kb deletion in all affected family members that further narrowed the RP25 critical region.
Abd El-Aziz et al. (2008) analyzed 6 predicted genes within the RP25 interval on chromosome 6q12 in 10 Spanish RP families previously linked to the RP25 interval and identified homozygosity or compound heterozygosity for 6 different mutations in a gene they designated EYS (612424). Mutations consisting of 4 deletions and 2 nonsense substitutions (e.g., 612424.0001-612424.0004) led to premature stop codons in 5 unrelated families.
Collin et al. (2008) independently identified the EYS gene and analyzed it in 10 probands with autosomal recessive retinitis pigmentosa, revealing homozygosity for a nonsense mutation (Y3156X; 612424.0005) and a 1-bp deletion (612424.0006) in 2 patients. They subsequently identified the Y3156X mutation in another proband from a group of 131 unrelated RP patients, and haplotype analysis suggested a founder effect. The mutations were absent or present in heterozygosity in unaffected family members.