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First published online 10 February 2009
doi: 10.1242/jcs.028621

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

Nathan J. Bialas^1,*, Peter N. Inglis^1,*, Chunmei Li^1,*, Jon F. Robinson², Jeremy D. K. Parker¹, Michael P. Healey¹, Erica E. Davis², Chrystal D. Inglis¹, Tiina Toivonen³, David C. Cottell³, Oliver E. Blacque⁴, Lynne M. Quarmby¹, Nicholas Katsanis^2,5,6 and Michel R. Leroux^1,

¹ Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada
² McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
³ Electron Microscopy Laboratory, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
⁴ School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
⁵ Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
⁶ Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

Author for correspondence (e-mail: leroux{at}sfu.ca)

Accepted 20 October 2008

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.

Key words: Meckel syndrome, Cilia, Basal body, Ciliopathy, Insulin, Signaling

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