Arts Heleen H, Doherty Dan, van Beersum Sylvia E C, Parisi Melissa A, Letteboer Stef J F, Gorden Nicholas T, Peters Theo A, Märker Tina, Voesenek Krysta, Kartono Aileen, Ozyurek Hamit, Farin Federico M, Kroes Hester Y, Wolfrum Uwe, Brunner Han G, Cremers Frans P M, Glass Ian A, Knoers Nine V A M, Roepman Ronald
Department of Human Genetics, Radboud University Nijmegen Medical Centre and Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands.
Nat Genet. 2007 Jul;39(7):882-8. doi: 10.1038/ng2069. Epub 2007 Jun 10.
Protein-protein interaction analyses have uncovered a ciliary and basal body protein network that, when disrupted, can result in nephronophthisis (NPHP), Leber congenital amaurosis, Senior-Løken syndrome (SLSN) or Joubert syndrome (JBTS). However, details of the molecular mechanisms underlying these disorders remain poorly understood. RPGRIP1-like protein (RPGRIP1L) is a homolog of RPGRIP1 (RPGR-interacting protein 1), a ciliary protein defective in Leber congenital amaurosis. We show that RPGRIP1L interacts with nephrocystin-4 and that mutations in the gene encoding nephrocystin-4 (NPHP4) that are known to cause SLSN disrupt this interaction. RPGRIP1L is ubiquitously expressed, and its protein product localizes to basal bodies. Therefore, we analyzed RPGRIP1L as a candidate gene for JBTS and identified loss-of-function mutations in three families with typical JBTS, including the characteristic mid-hindbrain malformation. This work identifies RPGRIP1L as a gene responsible for JBTS and establishes a central role for cilia and basal bodies in the pathophysiology of this disorder.
蛋白质-蛋白质相互作用分析揭示了一种纤毛和基体蛋白网络，该网络一旦被破坏，可能导致肾单位肾痨（NPHP）、莱伯先天性黑蒙、Senior-Løken综合征（SLSN）或Joubert综合征（JBTS）。然而，这些疾病潜在的分子机制细节仍知之甚少。RPGRIP1样蛋白（RPGRIP1L）是RPGRIP1（RPGR相互作用蛋白1）的同源物，RPGRIP1是一种在莱伯先天性黑蒙中存在缺陷的纤毛蛋白。我们发现RPGRIP1L与肾囊肿蛋白-4相互作用，并且已知导致SLSN的肾囊肿蛋白-4（NPHP4）编码基因中的突变会破坏这种相互作用。RPGRIP1L广泛表达，其蛋白质产物定位于基体。因此，我们将RPGRIP1L作为JBTS的候选基因进行分析，并在三个患有典型JBTS（包括特征性中后脑畸形）的家族中鉴定出功能丧失突变。这项工作确定RPGRIP1L是导致JBTS的基因，并确立了纤毛和基体在该疾病病理生理学中的核心作用。
