Abstract
Abstract: :
Purpose: The French Canadian population of Quebec represents a genetically isolated population of 7 million people, where many hereditary disorders exhibit the founder effect. We estimate that 2000 people suffer from retinitis pigmentosa (RP), and our aim is to genotype this RP population by linkage strategies and mutation analyses of known RP genes, in an attempt to identify the most prevalent loci and establish genotype-phenotype correlations. Methods: We chose distal and proximal single tandem repeat polymorphisms (STRPs) for the 34 known RP loci i.e 5 XRRP, 13 ADRP, and 16 ARRP loci, using CEPH, Marshfield, and GDB databases. PCR fragments were radiolabelled, and electrophoresed, allowing us to genotype individuals based on the number of repeats (i.e fragment size). LOD scores were calculated, and MLINK software was used for analyses. DHPLC (Transgenomics), and automated sequencing (ABI) were used for mutation screening. All patients underwent full eye exams, including ERGs and visual fields. Results: We collected the DNA and phenotype of 800 RP patients. We also found 9 large RP pedigrees. The first one is a 6 generation RP family with an apparent dominant mode of inheritance with 26 affecteds (10 males, 16 females). Linkage was excluded from 13 ADRP loci ( LOD -4.2 to -17.3). We eventually found linkage to DXS991, our marker for the RP2 locus. We found that the phenotypes (N=22) can be grouped into 4 categories: 1. males (9) were severely affected, with onset at age 11, and legal blindness in the twenties, 2. asymptomatic females (9) with mild ERG and patchy retinal changes, 3. asymmetrical disease in females (2) with non-detectable ERGs in one eye and measurable ERGs in the other, and 4. severely affected females (2) with onset in their twenties, and legal blindness in their thirties. A second XRRP family linked to DXS8025 (LOD 1.2), our marker for the RP3 locus, and a third ADRP family has been excluded from the RP1, RP4, and RP9 loci, so far. Conclusion: Our strategy has allowed us to genotype several large French Canadian RP families, provided initial genotype-phenotype correlations, and will now allow us to test for high frequency mutations in our 800 isolated RP cases. A molecular diagnosis of RP aids in premarital carrier assessment, prenatal diagnosis, and our global attempt to reclassify this important disease at the molecular level.
Keywords: 418 gene mapping • 562 retinal degenerations: hereditary • 517 photoreceptors