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RP1L1 Variants are Associated with a Spectrum of Inherited Retinal Diseases Including Retinitis Pigmentosa and Occult Macular Dystrophy
Author(s) -
Davidson Alice E.,
Sergouniotis Panagiotis I.,
Mackay Donna S.,
Wright Genevieve A.,
Waseem Naushin H.,
Michaelides Michel,
Holder Graham E.,
Robson Anthony G.,
Moore Anthony T.,
Plagnol Vincent,
Webster Andrew R.
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22264
Subject(s) - retinitis pigmentosa , biology , missense mutation , genetics , proband , retinal degeneration , exome sequencing , disease gene identification , exome , locus (genetics) , compound heterozygosity , genetic heterogeneity , macular dystrophy , allele , mutation , gene , phenotype
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.601del G , p. L ys203 A rgfs*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.1637 G > C , p. S er546 T hr, 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 RP 1 L 1 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 RP 1 L 1, excluded a digenic mechanism involving this gene. These findings imply an important and diverse role for RP 1 L 1 in human retinal physiology and disease.