Complete exon-intron structure of the RPGR-interacting protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis

Gerber, Sylvie; Perrault, Isabelle; Hanein, Sylvain; Barbet, Fabienne; Ducroq, Dominique; Ghazi, Imad; Martin‐Coignard, Dominique; Leowski, Corinne; Homfray, Tessa; Dufier, Jean‐Louis; Münnich, Arnold; Kaplan, Josseline; Rozet, Jean–Michel

doi:10.1038/sj.ejhg.5200689

Cited by 135 publications

(88 citation statements)

References 20 publications

(33 reference statements)

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“…The shared subcellular properties of RPGRIP1 and nephrocystin-4 are further strengthened by the panretinal colocalization of nephrocystin-4 and RPGRIP1 isoforms containing The sequence variants that were analyzed in the yeast two-hybrid system in this study are annotated; the other missense mutations that have been reported (9,29,31) are indicated by filled circles. (B) Wild-type and mutated human RPGRIP1 C2-C proteins (fused to GAL4-AD) were assessed for interaction with nephrocystin-4-I, fused to the GAL4-BD domain.…”

Section: Discussionmentioning

confidence: 99%

Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis or Leber congenital amaurosis-associated mutations

Roepman

Letteboer²,

Arts³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

110

108

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RPGR-interacting protein 1 (RPGRIP1) is a key component of cone and rod photoreceptor cells, where it interacts with RPGR (retinitis pigmentosa GTPase regulator). Mutations in RPGRIP1lead to autosomal recessive congenital blindness [Leber congenital amaurosis (LCA)]. Most LCA-associated missense mutations in RPGRIP1 are located in a segment that encodes two C2 domains. Based on the C2 domain of novel protein kinase C (PKC ), we built a 3D-homology model for the C-terminal C2 domain of RPGRIP1. This model revealed a potential Ca 2؉ -binding site that was predicted to be disrupted by a missense mutation in RPGRIP1, which was previously identified in an LCA patient. Through yeast two-hybrid screening of a retinal cDNA library, we found this C2 domain to specifically bind to nephrocystin-4, encoded by NPHP4. Mutations in NPHP4 are associated with nephronophthisis and a combination of nephronophthisis and retinitis pigmentosa called Senior-Løken syndrome (SLSN). We show that RPGRIP1 and nephrocystin-4 interact strongly in vitro and in vivo, and that they colocalize in the retina, matching the panretinal localization pattern of specific RPGRIP1 isoforms. Their interaction is disrupted by either mutations in RPGRIP1, found in patients with LCA, or by mutations in NPHP4, found in patients with nephronophthisis or SLSN. Thus, we provide evidence for the involvement of this disrupted interaction in the retinal dystrophy of both SLSN and LCA patients.T he X-linked gene RPGR (retinitis pigmentosa GTPase regulator) is mutated in patients with retinitis pigmentosa type 3 (RP3) (1, 2), cone or cone-rod dystrophy (COD1) (3, 4), atrophic macular degeneration (5), and RP in combination with impaired hearing and sinorespiratory infections (6). All RP3-associated missense mutations in RPGR have been identified in the N-terminal RCC1-homologous domain, and they disrupt the interaction with the C-terminal domain of RPGR-interacting protein 1 (RPGRIP1) (7,8). Mutations in RPGRIP1 lead to Leber congenital amaurosis (LCA), a genetically heterogeneous recessive disorder that is regarded to be the earliest and most severe form of all retinal dystrophies (9, 10). LCA accounts for at least 5% of all retinal dystrophies and is one of the main causes for blindness in children (11). RPGR and RPGRIP1 isoforms have been found to colocalize at the connecting cilia as well as the outer segments of rod and cone photoreceptors (12, 13). Differential localization among species has also been reported (12,14), and different isoforms of RPGRIP1 have been described resulting from splicing variation (7,14,15). The distinct partitioning of a subset of RPGRIP1 isoforms between the nuclear and cytoplasmic compartments combined with the differential and limited proteolysis of RPGRIP1 among retinal neurons, and the impact of LCA-linked mutations in RPGRIP1 in these processes, support the involvement of nucleocytoplasmatic signaling processes mediated by RPGRIP1 and its interacting partners in the pathogenesis of LCA, RP3, and allied diseases (15, 16). The pres...

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Section: Discussionmentioning

confidence: 99%

Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis or Leber congenital amaurosis-associated mutations

Roepman

Letteboer²,

Arts³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

110

108

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“…Since RPGRIP1 interacts with the RCC1 domain, it potentially interacts with all splice variants known in humans. Further evidence for a retina-specific function of the proposed RPGR/ RPGRIP1 complex comes from the discovery of recessive mutations in RPGRIP1 in 6% of patients with Leber congenital amaurosis (LCA) Gerber et al, 2001], a severe retinal dystrophy clinically related to RP [for a review, see Perrault et al, 1999].…”

Section: Retina-specific Phenotypementioning

confidence: 99%

Mutations ofRPGR in X-linked retinitis pigmentosa (RP3)

Vervoort

Wright

2002

Hum. Mutat.

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Mutations in RPGR, retinitis pigmentosa GTPase regulator, are associated with RP3 type of Xlinked retinitis pigmentosa, a severe, non-syndromic form of retinal degeneration. In the majority of subjects RPGR mutations are associated with a typical rod-cone degeneration, but in a small number, cone-rod dystrophy, deafness, and abnormalities in respiratory cilia have been noted. Alternative splicing of RPGR is complex in all species examined. In RP3 patients, mutations have been found in exons 1 14 and ORF15, thus delineating a transcript necessary for normal retinal function in humans. The great majority of mutations are predicted to result in premature termination of translation. These mutations are scattered over exons 1 14 and ORF15, while most missense mutations occur in a domain with homology to the protein RCC1, encoded by exons 1 10. Exon ORF15 is a hot spot for mutation, at least in the British population, in which it harbors 80% of the mutations found within a sample of 47 X-linked retinitis pigmentosa patients. Most RPGR mutations are unique to single families, which makes it difficult to demonstrate phenotype genotype correlations. Hum Mutat 19:486 500, 2002.

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“…60%) [Perrault et al, 1999;Hanein et al, 2004]. Up to date, 13 LCA genes have been mapped, 10 of which have been identified: GUCY2D/retGC1 [Perrault et al, 1996], RPE65 [Marlhens et al, 1997], CRX [Swaroop et al, 1999], AIPL1 [Sohocki et al, 2000], RPGRIP1 [Dryja et al, 2001;Gerber et al, 2001], CRB1 [den Hollander et al, 2001;Gerber et al, 2002], LRAT [Thompson and Gal, 2003], TULP1 , RDH12 [Janecke et al, 2004;Perrault et al, 2004], CEP290 [den Hollander et al, 2006;Perrault et al, 2007]. Mutations in 3/10of them were shown to account for LCA type I (GUCY2D, RPGRIP1, CEP290) while, although less frequent, LCA type II was hitherto accounted for by mutations in 7/10 genes (RPE65, CRX, AIPL1, CRB1, LRAT TULP12, RDH12) [Perrault et al, 1999;Hanein et al, 2004;Perrault et al, 2004;Perrault et al, 2007].…”

Section: Introductionmentioning

confidence: 99%

Mutations in LCA5 are an uncommon cause of Leber congenital amaurosis (LCA) type II

et al. 2007

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Leber congenital amaurosis (LCA) is the earliest and most severe form of inherited retinal dystrophy responsible for blindness or severe visual impairment at birth or within the first months of life. Up to date, ten LCA genes have been identified. Three of them account for ca. 43% of families and are responsible for a congenital severe stationary cone-rod dystrophy (Type I, 60 % of LCA) while the seven remaining genes account for 32% of patients and are responsible for a progressive yet severe rod-cone dystrophy (Type II, 40 % of LCA ). Recently, mutations in LCA5, encoding the ciliary protein lebercilin, were reported to be a rare cause of leber congenital amaurosis. The purpose of this study was to evaluate the involvement of this novel gene and to look for genotype-phenotype correlations. Here we report the identification of three novel LCA5 mutations (3/3 homozygous) in three families confirming the modest implication of this gene in our series (3/179; 1.7%). Besides, we suggest that the phenotype of these patients affected with a particularly severe form of LCA type II may represent a continuum with LCA type I.

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Complete exon-intron structure of the RPGR-interacting protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis

Cited by 135 publications

References 20 publications

Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis or Leber congenital amaurosis-associated mutations

Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis or Leber congenital amaurosis-associated mutations

Mutations ofRPGR in X-linked retinitis pigmentosa (RP3)

Mutations in LCA5 are an uncommon cause of Leber congenital amaurosis (LCA) type II

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