Retinitis Pigmentosa 33
A number sign (#) is used with this entry because of evidence that retinitis pigmentosa-33 (RP33) is caused by heterozygous mutation in the SNRNP200 gene (601664) on chromosome 2q11.
For a phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.
Clinical FeaturesZhao et al. (2006) reported a Chinese family in which 13 members spanning 4 generations developed retinitis pigmentosa in an autosomal dominant pattern of inheritance. Affected individuals developed night blindness at about 16 to 18 years of age. Subsequently, visual acuity gradually decreased with accompanying progressive loss of peripheral visual fields. Funduscopic findings were variable, but included waxy-pale discs, attenuation of retinal arterioles, bone-spicule pigmentation, and atrophy of the retinal pigment epithelium. Electroretinogram (ERG) responses were decreased.
Li et al. (2010) examined 12 affected members of a 4-generation Chinese family segregating nonsyndromic autosomal dominant RP. The average age at onset was 7 to 8 years, although some individuals were affected slightly later, at 10 to 11 years of age. Affected individuals had narrowing of the visual fields and night blindness accompanied by loss of visual acuity; fundus photographs showed changes typical of RP, including a waxy, pale optic disc, attenuation of retinal arteries, and bone spicule pigment deposits in the midperiphery of the retina. The visual fields of affected individuals progressively narrowed with age, eventually leading to loss of peripheral vision with relative preservation of central vision, even in a 14-year-old girl. Affected individuals had typical RP changes on ERG, including loss of both the rod and, in more advanced cases, cone responses. Results from a 45-year-old severely affected man showed little detectable activity under either photopic or scotopic conditions. However, the photopic and 30-MHz flicker response from the more mildly affected 14-year-old girl showed preservation of cone cell function, whereas the rod response decreased under scotopic conditions, consistent with a predominantly rod pathology. A multifocal ERG in the girl also showed functional preservation in the central macular area and decreased signal in the peripheral macular area.
Liu et al. (2012) studied 5 affected members of a 4-generation Chinese family with nonsyndromic adRP. Night blindness was always the presenting symptom and the age at onset was between 10 and 15 years. Affected members also reported gradual decline in visual acuity and progressive visual field loss in the fifth decade of life. Funduscopic examination showed typical changes of RP, and ERGs showed reduced or nonrecordable responses. Angle-closure glaucoma was also diagnosed in the fifth decade of life in 2 affected women: examination of 1 of the women revealed a shallow anterior chamber and an enlarged cup-to-disc ratio in both eyes; examination in the other woman could not be performed due to bulbous keratopathy.
MappingBy genomewide scan of a Chinese family with autosomal dominant retinitis pigmentosa (adRP), Zhao et al. (2006) identified a candidate disease locus, RP33, on chromosome 2q11.2 (maximum multipoint lod score of 4.69 at marker D2S2222). Haplotype analysis defined a 4.8-cM (9.5-Mb) interval at 2cen-q12.1 between D2S2159 and D2S1343. Molecular analysis excluded mutations in the SEMA4C (604462), CNGA3 (600053), HNK1ST (CHST10; 606376), and MERTK (604705) genes.
In a 4-generation Chinese family segregating adRP, Li et al. (2010) performed a screen for 17 known adRP loci, obtaining negative lod scores with all markers except on chromosome 2. Fine mapping with additional markers at chromosome 2q11 yielded maximum 2-point lod scores of 3.5 and 3.46 at D2S2333 and D2S2216, respectively (theta = 0 for both). Haplotype analysis and recombination events narrowed the critical region to an interval between D2S286 proximally and D2S347 distally.
Molecular GeneticsIn a 4-generation Chinese family with adRP mapping to chromosome 2cen-q12.1, previously studied by Zhao et al. (2006), Zhao et al. (2009) analyzed the candidate gene SNRNP200 and identified a heterozygous missense mutation (S1087L; 601664.0001) that segregated fully with the disease and was not found in 400 controls.
In a 4-generation Chinese family with adRP mapping to chromosome 2q11, Li et al. (2010) sequenced the SNRNP200 (ASCC3L1) gene and identified a heterozygous missense mutation (R1090L; 601664.0002) that segregated with the disease and was not found in 100 ethnically matched controls.
Liu et al. (2012) performed exome sequencing in the proband of a 4-generation Chinese family with adRP and identified a heterozygous missense mutation in the SNRNP200 gene (Q885E; 601664.0003) that segregated with disease in the family and was not found in 100 controls. Two affected individuals were also diagnosed with angle-closure glaucoma; Liu et al. (2012) noted that the association might be fortuitous.