Khanna, al. A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies. Nature Genet.41, 739-745

Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, USA.
Nature Genetics (Impact Factor: 29.35). 06/2009; 41(6):739-45. DOI: 10.1038/ng.366
Source: PubMed


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.

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    • "Both isoforms contain a common amino (N) terminal RCC1-like domain (Meindl et al. 1996) (encoded by exons 2-11) which has recently been shown to play the role of a guanine nucleotide exchange factor (GEF) by directly interacting with the GDP-bound form of the small GTPase RAB8A (Murga-Zamalloa et al. 2010a). RPGR has also been shown to interact directly or via molecular complexes with PDE6d (Linari et al. 1999), a number of ciliary proteins including RPGR-interacting protein 1 (RPGRIP1) (Boylan and Wright 2000; Roepman et al. 2000; Hong et al. 2001), nephrocystins NPHP1 (Murga- Zamalloa et al. 2010b), NPHP4 (Murga-Zamalloa et al. 2010b), NPHP5/IQCB1 (Otto et al. 2005), NPHP6/CEP290 (Chang et al. 2006), NPHP8/RPGRIP1L (Khanna et al. 2009), chromosome-associated proteins (SMC1 and SMC3) (Khanna et al. 2005), the centrosomal protein NPM1 (Shu et al. 2005), and intraflagellar transport (Tg737/Polaris/IFT88) and microtubule motor (dynactin subunits, kinesin-II) proteins (Khanna et al. 2005). Exon ORF15 encodes for a highly repetitive glutamic acid rich region whose function is currently unknown, however its C-terminus has been recently shown to interact with whirlin, which is a member of the Usher interactome (Wright et al. 2012). "
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    ABSTRACT: X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene is a severe and early onset form of retinal degeneration, and no treatment is currently available. Recent evidence in two clinically relevant canine models shows that adeno-associated viral (AAV)-mediated RPGR gene transfer to rods and cones can prevent disease onset and rescue photoreceptors at early- and mid-stages of degeneration. There is thus a strong incentive for conducting long-term, preclinical efficacy and safety studies, while concomitantly pursuing the detailed phenotypic characterization of XLRP disease in patients that may benefit from such corrective therapy.
    Cold Spring Harbor Perspectives in Medicine 10/2014; 5(2). DOI:10.1101/cshperspect.a017392 · 9.47 Impact Factor
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    • "RPGRIP1L is considered a close homolog of RPGRIP1 and has the same domain architecture (Figure 1A). Previous yeast-twohybrid experiments described binding of the C-terminal domain of RPGRIP1L to RPGR as well (Khanna et al., 2009). To investigate the interaction between RPGR and RPGRIP1L, we created constructs for the C-terminal domain of RPGRIP1L starting from amino acids M1037, L1070, S1109, T1137 and P1145 (Figure 1A), producing RID-like (RIDL) domains of 279, 246, 207, 179, and 171 residues. "
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    ABSTRACT: RPGR-interacting protein 1 (RPGRIP1) is mutated in the eye disease Leber congenital amaurosis (LCA) and its structural homolog, RPGRIP1-like (RPGRIP1L), is mutated in many different ciliopathies. Both are multidomain proteins that are predicted to interact with retinitis pigmentosa G-protein regulator (RPGR). RPGR is mutated in X-linked retinitis pigmentosa and is located in photoreceptors and primary cilia. We solved the crystal structure of the complex between the RPGR-interacting domain (RID) of RPGRIP1 and RPGR and demonstrate that RPGRIP1L binds to RPGR similarly. RPGRIP1 binding to RPGR affects the interaction with PDEδ, the cargo shuttling factor for prenylated ciliary proteins. RPGRIP1-RID is a C2 domain with a canonical β sandwich structure that does not bind Ca(2+) and/or phospholipids and thus constitutes a unique type of protein-protein interaction module. Judging from the large number of C2 domains in most of the ciliary transition zone proteins identified thus far, the structure presented here seems to constitute a cilia-specific module that is present in multiprotein transition zone complexes.
    Cilia 06/2014; 4(Suppl 1). DOI:10.1016/j.celrep.2014.05.049
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    • "2006b; Khanna et al. 2009). "
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    ABSTRACT: Bardet-Biedl syndrome (BBS) is a model ciliopathy characterized by a wide range of clinical variability. The heterogeneity of this condition is reflected in the number of underlying gene defects and the epistatic interactions between the proteins encoded. BBS is generally inherited in an autosomal recessive trait. However, in some families, mutations across different loci interact to modulate the expressivity of the phenotype. In order to investigate the magnitude of epistasis in one BBS family with remarkable intrafamilial phenotypic variability, we designed an exome sequencing-based approach using SOLID 5500xl platform. This strategy allowed the reliable detection of the primary causal mutations in our family consisting of two novel compound heterozygous mutations in McKusick-Kaufman syndrome (MKKS) gene (p.D90G and p.V396F). Additionally, exome sequencing enabled the detection of one novel heterozygous NPHP4 variant which is predicted to activate a cryptic acceptor splice site and is only present in the most severely affected patient. Here, we provide an exome sequencing analysis of a BBS family and show the potential utility of this tool, in combination with network analysis, to detect disease-causing mutations and second-site modifiers. Our data demonstrate how next-generation sequencing (NGS) can facilitate the dissection of epistatic phenomena, and shed light on the genetic basis of phenotypic variability.
    03/2014; 2(2):124-33. DOI:10.1002/mgg3.50
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