Ciliary and centrosomal defects associated with mutation and depletion of the Meckel syndrome genes MKS1 and MKS3

Abstract

Meckel syndrome (MKS) is a lethal disorder characterized by renal cystic dysplasia, encephalocele, polydactyly and biliary dysgenesis. It is highly genetically heterogeneous with nine different genes implicated in this disorder. MKS is thought to be a ciliopathy because of the range of phenotypes and localization of some of the implicated proteins. However, limited data are available about the phenotypes associated with MKS1 and MKS3, and the published ciliary data are conflicting. Analysis of the wpk rat model of MKS3 revealed functional defects of the connecting cilium in the eye that resulted in lack of formation of the outer segment, whereas infertile wpk males developed spermatids with very short flagella that did not extend beyond the cell body. In wpk renal collecting duct cysts, cilia were generally longer than normal, with additional evidence of cells with multiple primary cilia and centrosome over-duplication. Kidney tissue and cells from MKS1 and MKS3 patients showed defects in centrosome and cilia number, including multi-ciliated respiratory-like epithelia, and longer cilia. Stable shRNA knockdown of Mks1 and Mks3 in IMCD3 cells induced multi-ciliated and multi-centrosomal phenotypes. These studies demonstrate that MKS1 and MKS3 are ciliopathies, with new cilia-related eye and sperm phenotypes defined. MKS1 and MKS3 functions are required for ciliary structure and function, including a role in regulating length and appropriate number through modulating centrosome duplication.

Nedd9 restrains renal cystogenesis in Pkd1 −/− mice

“…At present, studies of the role of cilia in cystic syndromes suggest a bifurcated action dependent on the context of the initiating lesion (36)(37)(38)(39). Although loss of cilia due to inactivating mutations in IFT proteins can independently induce cystogenesis, recent strong evidence supports the idea that in the context of lesions in Pkd1 that cause defective signaling from cilia, the removal of cilia suppresses cyst formation (36,37).…”

A role for the Golgi matrix protein giantin in ciliogenesis through control of the localization of dynein-2

“…Length control in primary cilia has been linked to several developmental disorders, for example mutations in MKS3 (Tammachote et al, 2009) or NEK8 (Sohara et al, 2008) lead to cilium elongation and polycystic kidney disease. Severe ciliopathy phenotypes without overt morphological defects in cilia have been seen in both animal models [including deletion of IFT-B component IFT80 (Rix et al, 2011)] and patient groups [such as those with mutations in DYNC2H1 (Schmidts et al, 2013)].…”

Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity

“…Structural and functional cilia defects, including length abnormalities, have been characterized in several types of PKD, including the infantile onset autosomal recessive form (ARPKD, MIM no. 263200) (8)(9)(10)(11)(12). However, no clear ciliary structural abnormalities have been described in PKD1 (13)(14)(15).…”