Disease relevance of MKS1

• Meckel syndrome (MKS) is a lethal, autosomal recessive disorder characterized by occipital encephalocele, bilateral renal cystic dysplasia, hepatic ductal proliferation, fibrosis and cysts, and polydactyly [1].
• A Meckel syndrome critical region (MKS1) maps to human Chromosome (Chr) 17, in a region of homology to mouse Chr 11 [2].
• The identification of the MKS3 gene as well as the MKS1 gene enables molecular genetic testing for at-risk families, and allows accurate genetic counseling, carrier testing, and prenatal diagnosis [1].
• Pregnancies with MKS fetuses may be associated with an elevated maternal serum alpha-fetoprotein level and an abnormal screening result in the second-trimester maternal serum screening test [1].
• The classic MKS triad of occipital encephalocele, postaxial polydactyly, and bilateral enlarged multicystic kidneys can be diagnosed before the 14th gestational weeks by ultrasonography [1].

High impact information on MKS1

• Mks1 expression in mouse embryos, as determined by in situ hybridization, agrees well with the tissue phenotype of MKS [3].
• Our observation gives support to the clinical and genetic heterogeneity of MKS [4].

Biological relevance of MKS1

• Comparative genomics and proteomics data implicate MKS1 in ciliary functions [3].
• MKS1 localized to basal bodies [5].
• The Caenorhabditis elegans MKS1 homologue localized to the transition zone of sensory cilia [6].
• siRNA-mediated reduction of MKS1 expression in a ciliated epithelial cell-line blocked centriole migration to the apical membrane and consequent formation of the primary cilium [5].
• In-frame deletion of the Caenorhabditis elegans MKS1 homologue in combination with Nephronophthisis gene mutations impaired ciliogenesis [6].
• Loss of MKS1 in mice does not interfere with apical localization of epithelial basal bodies but rather leads to defective cilia formation in most, but not all, tissues [7].
• 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 [8].
• Co-immunoprecipitation experiments show that wild-type meckelin and MKS1 associate [5].

Anatomical context of MKS1

• Both MKS proteins predominantly localized to epithelial cells, including proximal renal tubules and biliary epithelial cells [5].

Other interactions of MKS1

• In the present study, we have investigated the genetic basis of MKS in eight consanguineous kindreds, originating from the Indian sub-continent, that do not show linkage to either MKS1 or MKS2 [9].

Analytical, diagnostic and therapeutic context of MKS1

• Mutation analysis using sequencing of RT-PCR products and Northern blot analysis in MKS patients exclude PNUTL2 as the gene for MKS [10].

References