Normal Ciliogenesis Requires Synergy between the Cystic Kidney Disease Genes MKS-3 and NPHP-4

Abstract

Cilia dysfunction contributes to renal cyst formation in multiple human syndromes including nephronophthisis (NPHP), Meckel-Gruber syndrome (MKS), Joubert syndrome (JBTS), and Bardet-Beidl syndrome (BBS). Although genetically heterogeneous, these diseases share several loci that affect cilia and/or basal body proteins, but the functions and interactions of these gene products are incompletely understood. Here, we report that the ciliated sensory neurons (CSNs) of C. elegans express the putative transmembrane protein MKS-3, which localized to the distal end of their dendrites and to the cilium base but not to the cilium itself. Localization of MKS-3 and other known MKS and NPHP proteins partially overlapped. By analyzing mks-3 mutants, we found that ciliogenesis did not require MKS-3; instead, cilia elongated and cilia-mediated chemoreception was abnormal. Genetic analysis indicated that mks-3 functions in a pathway with other mks genes. Furthermore, mks-1 and mks-3 genetically interacted with a separate pathway (involving nphp-1 and nphp-4) to influence proper positioning, orientation, and formation of cilia. Combined disruption of nphp and mks pathways had cell nonautonomous effects on C. elegans sensilla. Taken together, these data demonstrate the importance of mutational load on the presentation and severity of ciliopathies and expand the understanding of the interactions between ciliopathy genes.

Ciliogenesis inCaenorhabditis elegansrequires genetic interactions between ciliary middle segment localized NPHP-2 (inversin) and transition zone-associated proteins

“…Single mutations in genes encoding TZ complex members yield mild or nonobservable ciliogenic defects. However, in certain pairwise combinations, these mutations cause ciliogenesis defects that are attributable to anomalies in centriole and TZ membrane anchoring (Williams et al, 2008;Williams et al, 2010;Williams et al, 2011). Mammalian NPHP1 (also known as JBTS4) and NPHP4 physically interact to form a complex (Mollet et al, 2002).…”

“…MKS-1, MKSR-1 and MKSR-2 are interdependent for proper localization and they function together with NPHP-1 and NPHP-4 to regulate ciliogenesis (Bialas et al, 2009;Williams et al, 2008). mks-3 (orthologous to MKS3/TMEM67/NPHP11) plays a minor role in sensation-mediated behaviors and genetically interacts with nphp-4 to yield dysfunctional cilia in the double mutant (Williams et al, 2010). Recently, mks-6 (a C2 domain-encoding ortholog of JBTS9/CC2D2A) was shown to function together with nphp-1 or nphp-4 to control centriole and TZ anchoring to the membrane, the initial step of ciliogenesis (Williams et al, 2011).…”

Synergistic Interaction between Ciliary Genes Reflects the Importance of Mutational Load in Ciliopathies

“…In this issue, Williams et al 12 build on these initial observations and provide data that corroborate a synergistic interaction between the ciliogenic MKS and NPHP pathways. To test the hypothesis that perturbation of either pathway alone is not sufficient to disrupt ciliogenesis but disruption of both together lead to a ciliary defect, the authors analyzed mks3 mutants, nphp4 mutants, and double mutants to determine whether they would display defects in ciliogenesis, ciliary positioning, and proper sensory function of cilia.…”

“…This study by Williams et al 12 offers a deeper understanding of the importance of mutational load on the presentation and severity of ciliopathies and expands the understanding of the synergistic interactions between ciliopathy genes. Further analysis will hopefully allow targeted therapies to alleviate the morbidity and mortality associated with these devastating diseases.…”

“…Given the prominent role of JAK2 activation in chronic myeloproliferative disorders, a number of JAK2 inhibitors have been developed and are in clinical trials. 12 Should these inhibitors be safe and effective, they may play a new role in preventing JAK2 activation and progression of diabetic kidney disease and other complications. The formation of renal cysts occurs in roughly 10 to 15% of the population, 1 and although simple cysts are largely asymptomatic, the formation of multiple cysts can be extremely detrimental.…”