Genotype and Phenotype Studies in Autosomal Dominant Retinitis Pigmentosa (adRP) of the French Canadian Founder Population

Abstract

PURPOSE.The French Canadian population of Quebec is a unique, well-known founder population with religious, linguistic, and geographic isolation. The genetics of retinitis pigmentosa (RP) in Quebec is not well studied thus far. The purpose of our study was to establish the genetic architecture of autosomal dominant RP (adRP) and to characterize the phenotypes associated with new adRP mutations in Quebec.METHODS. Sanger sequencing of the commonly mutated currently known adRP genes was performed in a clinically well-characterized cohort of 60 adRP French Canadian families. Phenotypes were analyzed by projected visual acuity (best corrected), Goldmann visual fields, optical coherence tomography (OCT), fundus autofluorescence (FAF), and ERG. The potential effect of the novel mutations was assessed using in silico bioinformatic tools. The pathogenicity of all variants was then confirmed by segregation analysis within the families, when available. RESULTS.We identified the causal mutation/gene in 24 of our adRP families, as 24 (40%) of 60 patients had adRP mutations in six known adRP genes. Eleven (46%) of these mutations were in RHO, four mutations (17%) were found in SNRNP200, three mutations (12.5%) in PRPH2/RDS, three mutations (12.5%) in TOPORS, two mutations (8%) in PRPF31, and one mutation (4%) in IMPDH1. Four mutations were novel. We identified new mutations in RHO (p.S270I), PRPF31 (p.R288W), IMPDH1 (p.Q318H), and TOPORS (p.H889R); the rest were previously reported. We present the genotype-phenotype characteristics of the four novel missense mutations.CONCLUSIONS. This is the first large screening of adRP genes in the founder population of Quebec. Our prevalence of known adRP genes is 40% in the French Canadian population, which is lower than in other adRP populations around the world, illustrating the uniqueness of the French Canadian population. Our findings are crucial in expanding the current understanding of the genotypic-phenotypic spectrum of RP and documenting the genetic architecture of our founder population.

Identification of the genetic determinants responsible for retinal degeneration in families of Mexican descent

“…Patients with IMPDH1 mutations have been reported with early childhood onset vision loss with visual acuities from 20/200 to 20/400 by age 40, severe retinal changes by fundus examination, and declared legally blind before age 40 (22–24). The retinal changes observed in these patients were extensive with Bull’s eye maculopathy (24). Overall, the phenotype of pedigree Mex RD11 appears to be less severe compared to the phenotype of patients with IMPDH1 mutations reported in the literature.…”

Spliceosome SNRNP200 Promotes Viral RNA Sensing and IRF3 Activation of Antiviral Response

“…RP is a rare inherited disease of retinal dystrophies with an incidence of one in 3,000–4,000, of which 1.6% bear mutations in the SNRNP200 gene [ 35 ]. The investigated S1087L is a disease-associated mutation with complete penetrance in the RP33-linked family [ 36 – 38 ]. With access to PBMCs of three RP33 patients who had one allele carrying the dominant S1087L or R681C mutation, a decreased IRF3-dependent antiviral response was confirmed, when challenged with SeV, by the specific reduction of IFN-β and IFN-α2 cytokine secretion, without any effect on other tested cytokines ( Fig 9 and S15 Fig ).…”

High prevalence of mutations affecting the splicing process in a Spanish cohort with autosomal dominant retinitis pigmentosa

“…The percentage of adRP probands with mutations affecting either spliceosome core factors or the splice site of several adRP genes accounted for 5–14.5% of all cases of adRP in previous studies474041. With regard to mutations in the SNRNP200 gene, although these were only initially described in two Chinese families2122, they have since been reported to contribute to a significant portion of cases of adRP in the Caucasian population, ranging from 1.5% to 4.2%4404243.…”