Functional interactions between the ciliopathy-associated Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins

Meckel syndrome (MKS) is a ciliopathy characterized by encephalocele, cystic renal disease, liver fibrosis and polydactyly. An identifying feature of MKS1, one of six MKS-associated proteins, is the presence of a B9 domain of unknown function. Using phylogenetic analyses, we show that this domain oc...

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Published inJournal of cell science Vol. 122; no. 5; pp. 611 - 624
Main Authors Bialas, Nathan J, Inglis, Peter N, Li, Chunmei, Robinson, Jon F, Parker, Jeremy D.K, Healey, Michael P, Davis, Erica E, Inglis, Chrystal D, Toivonen, Tiina, Cottell, David C, Blacque, Oliver E, Quarmby, Lynne M, Katsanis, Nicholas, Leroux, Michel R
Format Journal Article
LanguageEnglish
Published England The Company of Biologists Limited 01.03.2009
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Summary:Meckel syndrome (MKS) is a ciliopathy characterized by encephalocele, cystic renal disease, liver fibrosis and polydactyly. An identifying feature of MKS1, one of six MKS-associated proteins, is the presence of a B9 domain of unknown function. Using phylogenetic analyses, we show that this domain occurs exclusively within a family of three proteins distributed widely in ciliated organisms. Consistent with a ciliary role, all Caenorhabditis elegans B9-domain-containing proteins, MKS-1 and MKS-1-related proteins 1 and 2 (MKSR-1, MKSR-2), localize to transition zones/basal bodies of sensory cilia. Their subcellular localization is largely co-dependent, pointing to a functional relationship between the proteins. This localization is evolutionarily conserved, because the human orthologues also localize to basal bodies, as well as cilia. As reported for MKS1, disrupting human MKSR1 or MKSR2 causes ciliogenesis defects. By contrast, single, double and triple C. elegans mks/mksr mutants do not display overt defects in ciliary structure, intraflagellar transport or chemosensation. However, we find genetic interactions between all double mks/mksr mutant combinations, manifesting as an increased lifespan phenotype, which is due to abnormal insulin-IGF-I signaling. Our findings therefore demonstrate functional interactions between a novel family of proteins associated with basal bodies or cilia, providing new insights into the molecular etiology of a pleiotropic human disorder.
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These authors contributed equally to this work
Author for correspondence (e-mail: leroux@sfu.ca)
Supplementary material available online at http://jcs.biologists.org/cgi/content/full/122/5/611/DC1
We would like to thank the C. elegans Genetics Center (CGC) and Shohei Mitani (National BioResource Project, University of Tokyo, Japan) for providing C. elegans strains used in this study, and the WestGrid computer cluster for phylogenetic analyses. This research is funded by grants from the March of Dimes (M.R.L.), NSERC (L.M.Q.), grant R01HD04260 from the National Institute of Child Health and Development, R01DK072301 and R01DK075972 from the National Institute of Diabetes, and Digestive and Kidney Disorders (N.K), and the Science Foundation Ireland PIYRA (O.E.B.). M.R.L. holds scholar awards from Canadian Institutes of Health Research and Michael Smith Foundation for Health Research (MSFHR). E.E.D. acknowledges an NRSA fellowship (F32 DK079541-01) and a doctoral fellowship from the Visual Neuroscience Training Program (National Eye Institute). P.N.I. and M.P.H. acknowledge MSFHR scholarships; P.N.I. also holds an NSERC doctoral research award. Deposited in PMC for release after 12 months.
ISSN:0021-9533
1477-9137
DOI:10.1242/jcs.028621