title: Compound heterozygosity of two novel truncation mutations in RP1 causing autosomal recessive retinitis pigmentosa.
abstract: Purpose. To evaluate the phenotypic effects of two novel frameshift mutations in the RP1 gene in a Chinese pedigree of autosomal recessive retinitis pigmentosa (ARRP). Methods. Family members of a proband with ARRP were screened for RP1, RHO, NR2E3, and NRL mutations by direct sequencing. Detected RP1 mutations were genotyped in 225 control subjects. Since one family member with the RP1 deletion mutation in exon 2 was found to have age-related macular degeneration (AMD) but not RP, exons 2 and 3 of RP1 were screened in 120 patients with exudative AMD. Major AMD-associated SNPs in the HTRA1 and CFH genes were also investigated. Results. Two novel frameshift mutations in RP1, c.5_6delGT and c.4941_4942insT, were identified in the pedigree. They were absent in 225 control subjects. Family members who were compound heterozygous for the nonsense mutations had early-onset and severe RP, whereas those with only one mutation did not have RP. No mutations in RHO, NR2E3, and NRL were identified in the pedigree. Subject I:2 with AMD carried both at-risk genotypes at HTRA1 rs11200638 and CFH rs800292. No mutation in RP1 exons 2 and 3 was identified in 120 AMD patients. Conclusions. This report is the first to associate ARRP with compound heterozygous nonsense mutations in RP1. Identification of the nonsense-mediated mRNA decay (NMD)-sensitive mutation c.5_6delGT provided further genetic evidence that haploinsufficiency of RP1 is not responsible for RP. The authors propose four classes of truncation mutations in the RP1 gene with different effects on the etiology of RP.
authors.affiliation: Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong.
authors.forename: Li Jia
authors.initials: LJ
authors.lastname: Chen
authors.forename: Timothy Y Y
authors.initials: TY
authors.lastname: Lai
authors.forename: Pancy O S
authors.initials: PO
authors.lastname: Tam
authors.forename: Sylvia W Y
authors.initials: SW
authors.lastname: Chiang
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Shi
authors.initials: S
authors.lastname: Lam
authors.forename: Ricky Y K
authors.initials: RY
authors.lastname: Lai
authors.forename: Dennis S C
authors.initials: DS
authors.lastname: Lam
authors.forename: Chi Pui
authors.initials: CP
authors.lastname: Pang
mesh_terms: D000293:Adolescent; D000368:Aged; D000369:Aged, 80 and over; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics; D002648:Child; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D005808:Genes, Recessive; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics; D008297:Male; D008869:Microtubule-Associated Proteins; D008875:Middle Aged; D057093:Orphan Nuclear Receptors / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D012174:Retinitis Pigmentosa / Q000235:genetics*; D012243:Rhodopsin / Q000235:genetics; D055815:Young Adult
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D005136:Eye Proteins; D008869:Microtubule-Associated Proteins; C403073:NR2E3 protein, human; C490037:NRL protein, human; D057093:Orphan Nuclear Receptors; C120042:RP1 protein, human; D012243:Rhodopsin