Mutations in RPGRIP1L: extending the clinical spectrum of ciliopathies

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 microtubulebased axoneme covered by a specialized plasma membrane [1]. 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 [2]. 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 regulatorinteracting protein 1-like) gene cause both Joubert syndrome (JBTS) and Meckel syndrome (MKS), two complex diseases with neurological, renal and ocular manifestations [3]. 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. [4], highlight the importance of ciliary dysfunction in cerebello-oculo-renal syndromes and nephronophthisis.