Delous Marion, Baala Lekbir, Salomon Rémi, Laclef Christine, Vierkotten Jeanette, Tory Kàlmàn, Golzio Christelle, Lacoste Tiphanie, Besse Laurianne, Ozilou Catherine, Moutkine Imane, Hellman Nathan E, Anselme Isabelle, Silbermann Flora, Vesque Christine, Gerhardt Christoph, Rattenberry Eleanor, Wolf Matthias T F, Gubler Marie Claire, Martinovic Jéléna, Encha-Razavi Féréchté, Boddaert Nathalie, Gonzales Marie, Macher Marie Alice, Nivet Hubert, Champion Gérard, Berthélémé Jean Pierre, Niaudet Patrick, McDonald Fiona, Hildebrandt Friedhelm, Johnson Colin A, Vekemans Michel, Antignac Corinne, Rüther Ulrich, Schneider-Maunoury Sylvie, Attié-Bitach Tania, Saunier Sophie
Institut National de la Santé et de la Recherche Médicale (INSERM) U-574, Hôpital Necker-Enfants Malades, 75015 Paris, France.
Nat Genet. 2007 Jul;39(7):875-81. doi: 10.1038/ng2039. Epub 2007 Jun 10.
Cerebello-oculo-renal syndrome (CORS), also called Joubert syndrome type B, and Meckel (MKS) syndrome belong to the group of developmental autosomal recessive disorders that are associated with primary cilium dysfunction. Using SNP mapping, we identified missense and truncating mutations in RPGRIP1L (KIAA1005) in both CORS and MKS, and we show that inactivation of the mouse ortholog Rpgrip1l (Ftm) recapitulates the cerebral, renal and hepatic defects of CORS and MKS. In addition, we show that RPGRIP1L colocalizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4, known genes associated with MKS, CORS and nephronophthisis (a related renal disorder and ciliopathy). In addition, the RPGRIP1L missense mutations found in CORS individuals diminishes the interaction between RPGRIP1L and nephrocystin-4. Our findings show that mutations in RPGRIP1L can cause the multiorgan phenotypic abnormalities found in CORS or MKS, which therefore represent a continuum of the same underlying disorder.
小脑-眼-肾综合征（CORS），也称为B型朱伯特综合征，以及梅克尔（MKS）综合征属于与原发性纤毛功能障碍相关的常染色体隐性发育障碍组。通过单核苷酸多态性（SNP）定位，我们在CORS和MKS中均鉴定出RPGRIP1L（KIAA1005）中的错义突变和截短突变，并且我们表明小鼠直系同源基因Rpgrip1l（Ftm）的失活概括了CORS和MKS的脑、肾和肝缺陷。此外，我们表明RPGRIP1L与NPHP6和NPHP4的蛋白质产物共定位于基体和中心体，NPHP6和NPHP4是与MKS、CORS和肾单位肾痨（一种相关的肾脏疾病和纤毛病）相关的已知基因。此外，在CORS个体中发现的RPGRIP1L错义突变减少了RPGRIP1L与肾囊肿蛋白-4之间的相互作用。我们的研究结果表明，RPGRIP1L中的突变可导致CORS或MKS中发现的多器官表型异常，因此它们代表了同一潜在疾病的连续体。
