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

Abstract

Despite rapid advances in disease gene identification, the predictive power of the genotype remains limited, in part due 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 patients 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 229T-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.

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

“…Although we cannot exclude the possibility that a second pathogenic mutation resides within intronic or regulatory regions of the gene, it is also plausible that the identified change could act as a genetic modifier of the clinical phenotype in an oligogenic context, and that digenic mutations may reside in another gene. This intriguing mechanism has been already postulated for several ciliopathies including Bardet-Biedl syndrome, NPH and even JSRD, [22][23][24][25] and could also help explain the intra-familial variability observed in some INPP5E-mutated families. To this end, the systematic genetic screening of multiple ciliopathy genes based on innovative technologies such as next-generation-sequencing is expected to give a main contribution to clarify the molecular basis underlying the clinical complexity of JSRD and other ciliopathies.…”

Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet–Biedl syndrome

“…These phenotypes are consistent with abnormal planar cell polarity (PCP) signaling (21,22,24,25), which likely underlies several clinical phenotypes in patients who have BBS, including hearing defects (20), neural tube closure abnormalities (26), renal cyst formation (27), and possibly obesity and cognitive impairment (28). The fact that these observations are likely relevant to the etiopathology of BBS (20,21,(23)(24)(25), and true for all seven bbs orthologues tested (bbs1, bbs4, bbs6, bbs10, bbs12, mks1, and cep290) as well for as the three BBS modifiers mgc1203, mks3, and rpgrip1l, suggested that they might represent useful assays for all BBS genes. We therefore designed translation-blocking morpholinos (MOs) against bbs1-12 ( and SI Appendix, Table S1) and injected each into WT embryos at varying concentrations to establish a survival curve (SI Appendix, Table S3) from which to derive the optimal working MO concentration (minimal cytotoxicity, maximal phenotype).…”

“…Given that most of these variants can be found in homozygosity in control individuals suggests that they are insufficient to cause disease. However, we wondered whether they might interact with strong mutations to potentiate BBS, as shown recently for one of them, the A229T allele in RPGRIP1L (23).…”

“…BBS is also a representative of the ciliopathy disease spectrum, a group of disorders characterized by defects in ciliary structure and/or ciliary signal output (18). Hallmarks of BBS include retinal degeneration, obesity, hypogonadism, polydactyly, renal dysfunction, and mental retardation (19).We and others have shown that the zebrafish provides experimentally tractable and physiologically relevant models of important aspects of ciliary dysfunction (2,15,17,(20)(21)(22)(23). Moreover, human mRNA for ciliopathy genes can rescue both morphant and mutant zebrafish phenotypes efficiently, providing a robust platform for interpretation of the pathological relevance of identified missense alleles, whose causal relation to the disorder cannot be proven definitively with genetic arguments alone (15,17,22,23).…”

“…Moreover, human mRNA for ciliopathy genes can rescue both morphant and mutant zebrafish phenotypes efficiently, providing a robust platform for interpretation of the pathological relevance of identified missense alleles, whose causal relation to the disorder cannot be proven definitively with genetic arguments alone (15,17,22,23).…”