title: Allelic heterogeneity and genetic modifier loci contribute to clinical variation in males with X-linked retinitis pigmentosa due to RPGR mutations.
abstract: Mutations in RPGR account for over 70% of X-linked retinitis pigmentosa (XlRP), characterized by retinal degeneration and eventual blindness. The clinical consequences of RPGR mutations are highly varied, even among individuals with the same mutation: males demonstrate a wide range of clinical severity, and female carriers may or may not be affected. This study describes the phenotypic diversity in a cohort of 98 affected males from 56 families with RPGR mutations, and demonstrates the contribution of genetic factors (i.e., allelic heterogeneity and genetic modifiers) to this diversity. Patients were categorized as grade 1 (mild), 2 (moderate) or 3 (severe) according to specific clinical criteria. Patient DNAs were genotyped for coding SNPs in 4 candidate modifier genes with products known to interact with RPGR protein: RPGRIP1, RPGRIP1L, CEP290, and IQCB1. Family-based association testing was performed using PLINK. A wide range of clinical severity was observed both between and within families. Patients with mutations in exons 1-14 were more severely affected than those with ORF15 mutations, and patients with predicted null alleles were more severely affected than those predicted to make RPGR protein. Two SNPs showed association with severe disease: the minor allele (N) of I393N in IQCB1 (p = 0.044) and the common allele (R) of R744Q in RPGRIP1L (p = 0.049). These data demonstrate that allelic heterogeneity contributes to phenotypic diversity in XlRP and suggest that this may depend on the presence or absence of RPGR protein. In addition, common variants in 2 proteins known to interact with RPGR are associated with severe disease in this cohort.
authors.affiliation: School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
authors.forename: Abigail T
authors.initials: AT
authors.lastname: Fahim
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Bowne
authors.forename: Lori S
authors.initials: LS
authors.lastname: Sullivan
authors.forename: Kaylie D
authors.initials: KD
authors.lastname: Webb
authors.forename: Jessica T
authors.initials: JT
authors.lastname: Williams
authors.forename: Dianna K
authors.initials: DK
authors.lastname: Wheaton
authors.forename: David G
authors.initials: DG
authors.lastname: Birch
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Daiger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000483:Alleles; D000951:Antigens, Neoplasm / Q000235:genetics; D002148:Calmodulin-Binding Proteins / Q000235:genetics; D018797:Cell Cycle Proteins; D015331:Cohort Studies; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics*; D060045:Genes, Modifier / Q000235:genetics*; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000473:pathology; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology; D012720:Severity of Illness Index
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000951:Antigens, Neoplasm; D002148:Calmodulin-Binding Proteins; D018797:Cell Cycle Proteins; C493903:Cep290 protein, human; D003598:Cytoskeletal Proteins; D005136:Eye Proteins; C498171:IQCB1 protein, human; D009363:Neoplasm Proteins; D011506:Proteins; C099929:RPGR protein, human; C415903:RPGRIP1 protein, human; C532826:RPGRIP1L protein, human