A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies.

TitleA common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies.
Publication TypeJournal Article
Year of Publication2009
AuthorsKhanna, H, Davis, EE, Murga-Zamalloa, CA, Estrada-Cuzcano, A, Lopez, I, Hollander, AI den, Zonneveld, MN, Othman, MI, Waseem, N, Chakarova, CF, Maubaret, C, Diaz-Font, A, MacDonald, I, Muzny, DM, Wheeler, DA, Morgan, M, Lewis, LR, Logan, CV, Tan, PL, Beer, MA, Inglehearn, CF, Lewis, RA, Jacobson, SG, Bergmann, C, Beales, PL, Attié-Bitach, T, Johnson, CA, Otto, EA, Bhattacharya, SS, Hildebrandt, F, Gibbs, RA, Koenekoop, RK, Swaroop, A, Katsanis, N
JournalNat Genet
Volume41
Issue6
Pagination739-45
Date Published2009 Jun
ISSN1546-1718
KeywordsAdaptor Proteins, Signal Transducing, Alleles, Animals, Bardet-Biedl Syndrome, Ciliary Body, Europe, Genetic Variation, GTP Phosphohydrolases, Humans, Mutation, Polymorphism, Single Nucleotide, Retinal Degeneration, Retinitis Pigmentosa, RNA, Messenger, Uveitis, Zebrafish
Abstract

Despite rapid advances in the identification of genes involved in disease, the predictive power of the genotype remains limited, in part owing to poorly understood effects of second-site modifiers. Here we demonstrate that a polymorphic coding variant of RPGRIP1L (retinitis pigmentosa GTPase regulator-interacting protein-1 like), a ciliary gene mutated in Meckel-Gruber (MKS) and Joubert (JBTS) syndromes, is associated with the development of retinal degeneration in individuals with ciliopathies caused by mutations in other genes. As part of our resequencing efforts of the ciliary proteome, we identified several putative loss-of-function RPGRIP1L mutations, including one common variant, A229T. Multiple genetic lines of evidence showed this allele to be associated with photoreceptor loss in ciliopathies. Moreover, we show that RPGRIP1L interacts biochemically with RPGR, loss of which causes retinal degeneration, and that the Thr229-encoded protein significantly compromises this interaction. Our data represent an example of modification of a discrete phenotype of syndromic disease and highlight the importance of a multifaceted approach for the discovery of modifier alleles of intermediate frequency and effect.

DOI10.1038/ng.366
Alternate JournalNat. Genet.
PubMed ID19430481
PubMed Central IDPMC2783476
Grant ListR01DK064614 / DK / NIDDK NIH HHS / United States
G0700073 / / Medical Research Council / United Kingdom
R01 DK072301 / DK / NIDDK NIH HHS / United States
R01DK068306 / DK / NIDDK NIH HHS / United States
R01 HD042601-06 / HD / NICHD NIH HHS / United States
R01EY007961 / EY / NEI NIH HHS / United States
/ / Intramural NIH HHS / United States
R01 DK075972-01A2 / DK / NIDDK NIH HHS / United States
R01DK069274 / DK / NIDDK NIH HHS / United States
R01 DK068306 / DK / NIDDK NIH HHS / United States
R01 EY007961 / EY / NEI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R01 DK075972 / DK / NIDDK NIH HHS / United States
R01 DK069274 / DK / NIDDK NIH HHS / United States
G0801843 / / Medical Research Council / United Kingdom
F32 DK079541 / DK / NIDDK NIH HHS / United States
R01 HD042601 / HD / NICHD NIH HHS / United States
R01 DK064614 / DK / NIDDK NIH HHS / United States
R01DK075972 / DK / NIDDK NIH HHS / United States
R01HD04260 / HD / NICHD NIH HHS / United States
R01DK072301 / DK / NIDDK NIH HHS / United States
R01 DK072301-04 / DK / NIDDK NIH HHS / United States