A novel locus (RP33) for autosomal dominant retinitis pigmentosa mapping to chromosomal region 2cen-q12.1

Abstract

Retinitis pigmentosa (RP) is a heterogeneous group of progressive degenerative disorders of the retina with a strong genetic component. Here, we report the clinical and genetic findings in a Chinese family in which autosomal dominant RP (adRP) was inherited by 13 affected members in four generations. Using a genome-wide linkage screening approach, a novel disease locus (RP33) was assigned to the long arm of chromosome 2. A maximum multi-point LOD score of 4.69 was reached at marker D2S2222 in 2q11.2. Meiotic recombination events in affected members placed RP33 in a 15.5 cM region between D2S329 and D2S2229. From meiotic recombinations in two unaffected members RP33 was further refined to a 4.8 cM (9.5 Mb) interval flanked by D2S2159 and D2S1343 in chromosomal region 2cen-q12.1. No disease-associated mutations were detected in the candidate genes SEMA4C, CNGA3 or HNK1ST from within the region. MERTK, a known disease gene for autosomal recessive RP located close to RP33 was similarly excluded. Clinically, the family presented relatively late onset of night blindness, gradually decreased visual acuity, progressive loss of peripheral visual field and typical RP fundus changes in the mid-periphery of the retina. In conclusion, a novel locus for adRP has been assigned to chromosomal region 2cen-q12.1, which in the present kindred was associated with a relatively late onset form of the disease.

Targeted Sequencing of 179 Genes Associated with Hereditary Retinal Dystrophies and 10 Candidate Genes Identifies Novel and Known Mutations in Patients with Various Retinal Diseases

“…In order to appropriately evaluate the efficiency of the targeted gene sequencing approach, all pedigrees were recruited within a period of 1 year with broad selection criteria, so that the pedigrees may represent the occurrence of HRDs in different parts of China. All patients underwent routine ophthalmic examinations as described previously, 17 with visual field and electroretinography (ERG) tests. Optical coherence tomography (OCT) was performed on patients with macular involvement.…”

Retinitis Pigmentosa Mutations in Bad Response to Refrigeration 2 (Brr2) Impair ATPase and Helicase Activity

“…Despite being a viable mutation in both humans and S. cerevisiae, the R1107L RP mutation is correlated to an earlier age of onset of blindness in humans and more reduced yeast growth at cold temperature than the N1104L RP mutation (18,19,30). The weak binding exhibited by ⌬247-Brr2(R1107L) for U4/U6 suggests that the in vivo phenotypes may be due at least partially to reduced interactions with the U4/U6 snRNA duplex we observed in vitro.…”

“…Although in vitro biochemical assays cannot replicate the full complexity of the in vivo environment, it is striking that the trends of both the in vitro mechanistic experiments and the in vivo phenotypes correlate. For example, the age of onset for vision loss in humans is younger for people with the R1107L mutation (19) compared with the mutation at position 1104 (30), indicating a stronger phenotype.…”

Knocking DownSnrnp200Initiates Demorphogenesis of Rod Photoreceptors in Zebrafish

“…RNA was isolated from 10 zebrafish embryos from each injection group, followed by reverse-transcriptase polymerase chain reaction (RT-PCR) to generate cDNA templates [9, 21]. PCR was subsequently conducted on the obtained cDNA to verify the effectiveness of Snrnp200 -MO and amplify the targeted region of the cbln1 gene with primers detailed in Supplementary Table S1 using a previously defined protocol [9, 21].…”