title: Functional interactions between the ciliopathy-associated Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins.
abstract: 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.
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Bialas
authors.forename: Peter N
authors.initials: PN
authors.lastname: Inglis
authors.forename: Chunmei
authors.initials: C
authors.lastname: Li
authors.forename: Jon F
authors.initials: JF
authors.lastname: Robinson
authors.forename: Jeremy D K
authors.initials: JD
authors.lastname: Parker
authors.forename: Michael P
authors.initials: MP
authors.lastname: Healey
authors.forename: Erica E
authors.initials: EE
authors.lastname: Davis
authors.forename: Chrystal D
authors.initials: CD
authors.lastname: Inglis
authors.forename: Tiina
authors.initials: T
authors.lastname: Toivonen
authors.forename: David C
authors.initials: DC
authors.lastname: Cottell
authors.forename: Oliver E
authors.initials: OE
authors.lastname: Blacque
authors.forename: Lynne M
authors.initials: LM
authors.lastname: Quarmby
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Michel R
authors.initials: MR
authors.lastname: Leroux
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D002923:Cilia / Q000378:metabolism / Q000473:pathology*; D019143:Evolution, Molecular; D006801:Humans; D008969:Molecular Sequence Data; D010641:Phenotype; D010802:Phylogeny; D011506:Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology
chemical_list: D029742:Caenorhabditis elegans Proteins; C509165:MKS1 protein, human; D011506:Proteins; D011993:Recombinant Fusion Proteins