NDT Advance Access published online on February 14, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn033
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Mutations in RPGRIP1L: extending the clinical spectrum of ciliopathies*
1 Division of Nephrology, Université catholique de Louvain Medical School, B-1200 Brussels 2 Division of Ophthalmology, Cliniques de l’Europe, Saint-Michel, B-1040 Brussels, Belgium
Correspondence and offprint requests to: Oliver Devuyst, Division of Nephrology, Université catholique de Louvain Medical School, B-1200 Brussels, Belgium. E-mail: devuyst{at}nefr.ucl.ac.be
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Abstract |
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Identification of genes causing inherited cystic kidney diseases has triggered a major interest for the concept of ‘ciliopathies’. Indeed, almost all of the proteins involved in human renal cystic diseases are expressed in the primary cilium complex located in renal epithelial cells. Primary cilia are cellular extensions containing a microtubule-based axoneme covered by a specialized plasma membrane (Pazour GJ. J Am Soc Nephrol 2004; 15: 2528–2536). The basal body of the cilia, which templates the assembly of the microtubules, contains a centriole, which itself is part of the centrosome. Primary cilia project into the lumen, where they probably sense a variety of stimuli involved in the regulation of cell proliferation and differentiation (Benzing T and Walz G. Curr Opin Nephrol Hypertens 2006; 15: 245–249). Primary cilia are present on almost all human cells, explaining why ciliopathies affect multiple organs. However, the molecular mechanisms, potential connections and clinical variability of these diseases remain poorly understood. The study by Delous et al. gives new insights into the field, by demonstrating that mutations in the RPGRIP1L (retinitis pigmentosa GTPase regulator-interacting protein 1-like) gene cause both Joubert syndrome (JBTS) and Meckel syndrome (MKS), two complex diseases with neurological, renal and ocular manifestations (Nat Genet 2007; 39: 875–881). The protein encoded by RPGRIP1L is located in the primary cilium, and mutations impair its interaction with nephrocystin-4, a protein involved in nephronophthisis. Furthermore, RPGRIP1L knockout mice show a phenotype similar to that observed in foetuses with MKS. These findings, which were also demonstrated in a companion article by Arts et al. (Nat Genet 2007; 39: 882–888), highlight the importance of ciliary dysfunction in cerebello-oculo-renal syndromes and nephronophthisis.
Keywords: cerebello-oculo-renal syndrome; Joubert syndrome; Leber congenital amaurosis; Meckel syndrome; nephronophthisis; Senior–Loken syndrome
* This article is based on the basic science article by Delous M, Baala L, Salomon R et al. The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet 2007; 39: 875–881.
Received for publication: 30. 8.07
Accepted in revised form: 17. 1.08