title: RP1L1 variants are associated with a spectrum of inherited retinal diseases including retinitis pigmentosa and occult macular dystrophy.
abstract: In one consanguineous family with retinitis pigmentosa (RP), a condition characterized by progressive visual loss due to retinal degeneration, homozygosity mapping, and candidate gene sequencing suggested a novel locus. Exome sequencing identified a homozygous frameshifting mutation, c.601delG, p.Lys203Argfs*28, in RP1L1 encoding RP 1-like1, a photoreceptor-specific protein. A screen of a further 285 unrelated individuals with autosomal recessive RP identified an additional proband, homozygous for a missense variant, c.1637G>C, p.Ser546Thr, in RP1L1. A distinct retinal disorder, occult macular dystrophy (OCMD) solely affects the central retinal cone photoreceptors and has previously been reported to be associated with variants in the same gene. The association between mutations in RP1L1 and the disorder OCMD was explored by screening a cohort of 28 unrelated individuals with the condition; 10 were found to harbor rare (minor allele frequency ≤0.5% in the 1,000 genomes dataset) heterozygous RP1L1 missense variants. Analysis of family members revealed many unaffected relatives harboring the same variant. Linkage analysis excluded the possibility of a recessive mode of inheritance, and sequencing of RP1, a photoreceptor protein that interacts with RP1L1, excluded a digenic mechanism involving this gene. These findings imply an important and diverse role for RP1L1 in human retinal physiology and disease.
authors.affiliation: University College London Institute of Ophthalmology, London, UK.
authors.forename: Alice E
authors.initials: AE
authors.lastname: Davidson
authors.forename: Panagiotis I
authors.initials: PI
authors.lastname: Sergouniotis
authors.forename: Donna S
authors.initials: DS
authors.lastname: Mackay
authors.forename: Genevieve A
authors.initials: GA
authors.lastname: Wright
authors.forename: Naushin H
authors.initials: NH
authors.lastname: Waseem
authors.forename: Michel
authors.initials: M
authors.lastname: Michaelides
authors.forename: Graham E
authors.initials: GE
authors.lastname: Holder
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Robson
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
mesh_terms: D000328:Adult; D000368:Aged; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D015331:Cohort Studies; D003241:Consanguinity; D059472:Exome; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D056426:Genetic Loci; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012160:Retina / Q000473:pathology*; D012174:Retinitis Pigmentosa / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D005136:Eye Proteins; C474032:RP1L1 protein, human