RGD Reference Report - Ciliary and centrosomal defects associated with mutation and depletion of the Meckel syndrome genes MKS1 and MKS3. - Rat Genome Database

RGD Reference Report - Ciliary and centrosomal defects associated with mutation and depletion of the Meckel syndrome genes MKS1 and MKS3. - Rat Genome Database

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Ciliary and centrosomal defects associated with mutation and depletion of the Meckel syndrome genes MKS1 and MKS3.
Authors:	Tammachote, R Hommerding, CJ Sinders, RM Miller, CA Czarnecki, PG Leightner, AC Salisbury, JL Ward, CJ Torres, VE Gattone VH, 2ND Harris, PC
Citation:	Tammachote R, etal., Hum Mol Genet. 2009 Sep 1;18(17):3311-23. doi: 10.1093/hmg/ddp272. Epub 2009 Jun 10.
RGD ID:	8554306
Pubmed:	PMID:19515853 (View Abstract at PubMed)
PMCID:	PMC2733821 (View Article at PubMed Central)
DOI:	DOI:10.1093/hmg/ddp272 (Journal Full-text)
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.

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Biological Process

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Tmem67	Rat	cilium assembly	involved_in	IMP		PMID:19515853	UniProt
Tmem67	Rat	negative regulation of centrosome duplication		IMP			RGD

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Mammalian Phenotype

Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Tmem67	Rat	increased kidney epithelial cell primary cilium length		IAGP			RGD
Tmem67	Rat	short sperm flagellum		IAGP			RGD

Objects Annotated

Genes (Rattus norvegicus)

Tmem67 (transmembrane protein 67)

Additional Information