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

被引:63
作者
Bialas, Nathan J. [1 ]
Inglis, Peter N. [1 ]
Li, Chunmei [1 ]
Robinson, Jon F. [2 ]
Parker, Jeremy D. K. [1 ]
Healey, Michael P. [1 ]
Davis, Erica E. [2 ]
Inglis, Chrystal D. [1 ]
Toivonen, Tiina [6 ]
Cottell, David C. [6 ]
Blacque, Oliver E. [5 ]
Quarmby, Lynne M. [1 ]
Katsanis, Nicholas [2 ,3 ,4 ]
Leroux, Michel R. [1 ]
机构
[1] Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC V5A 1S6, Canada
[2] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA
[3] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA
[4] Johns Hopkins Univ, Sch Med, Dept Mol Biol, Baltimore, MD 21205 USA
[5] Univ Coll Dublin, UCD Conway Inst, Sch Biomol & Biomed Sci, Dublin 4, Ireland
[6] Univ Coll Dublin, UCD Conway Inst, Electron Microscopy Lab, Dublin 4, Ireland
基金
加拿大健康研究院; 爱尔兰科学基金会; 加拿大自然科学与工程研究理事会;
关键词
Meckel syndrome; Cilia; Basal body; Ciliopathy; Insulin; Signaling; BARDET-BIEDL-SYNDROME; BASAL BODY PROTEOME; CAENORHABDITIS-ELEGANS; INTRAFLAGELLAR TRANSPORT; PRIMARY CILIUM; GRUBER-SYNDROME; CENTROSOMAL PROTEIN; JOUBERT-SYNDROME; SENSORY CILIA; LIFE-SPAN;
D O I
10.1242/jcs.028621
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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, MKS1 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.
引用
收藏
页码:611 / 624
页数:14
相关论文
共 79 条
[1]  
Alexiev BA, 2006, ARCH PATHOL LAB MED, V130, P1236
[2]   Gapped BLAST and PSI-BLAST: a new generation of protein database search programs [J].
Altschul, SF ;
Madden, TL ;
Schaffer, AA ;
Zhang, JH ;
Zhang, Z ;
Miller, W ;
Lipman, DJ .
NUCLEIC ACIDS RESEARCH, 1997, 25 (17) :3389-3402
[3]   Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome [J].
Ansley, SJ ;
Badano, JL ;
Blacque, OE ;
Hill, J ;
Hoskins, BE ;
Leitch, CC ;
Kim, JC ;
Ross, AJ ;
Eichers, ER ;
Teslovich, TM ;
Mah, AK ;
Johnsen, RC ;
Cavender, JC ;
Lewis, RA ;
Leroux, MR ;
Beales, PL ;
Katsanis, N .
NATURE, 2003, 425 (6958) :628-633
[4]   Regulation of lifespan by sensory perception in Caenorhabditis elegans [J].
Apfeld, J ;
Kenyon, C .
NATURE, 1999, 402 (6763) :804-809
[5]   Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome [J].
Arts, Heleen H. ;
Doherty, Dan ;
van Beersum, Sylvia E. C. ;
Parisi, Melissa A. ;
Letteboer, Stef J. F. ;
Gorden, Nicholas T. ;
Peters, Theo A. ;
Maerker, Tina ;
Voesenek, Krysta ;
Kartono, Aileen ;
Ozyurek, Hamit ;
Farin, Federico M. ;
Kroes, Hester Y. ;
Wolfrum, Uwe ;
Brunner, Han G. ;
Cremers, Frans P. M. ;
Glass, Ian A. ;
Knoers, Nine V. A. M. ;
Roepman, Ronald .
NATURE GENETICS, 2007, 39 (07) :882-888
[6]   Decoding cilia function: Defining specialized genes required for compartmentalized cilia biogenesis [J].
Avidor-Reiss, T ;
Maer, AM ;
Koundakjian, E ;
Polyanovsky, A ;
Keil, T ;
Subramaniam, S ;
Zuker, CS .
CELL, 2004, 117 (04) :527-539
[7]   Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome [J].
Baala, Lekbir ;
Audollent, Sophie ;
Martinovic, Jelena ;
Ozilou, Catherine ;
Babron, Marie-Claude ;
Sivanandamoorthy, Sivanthiny ;
Saunier, Sophie ;
Salomon, Remi ;
Gonzales, Marie ;
Rattenberry, Eleanor ;
Esculpavit, Chantal ;
Toutain, Annick ;
Moraine, Claude ;
Parent, Philippe ;
Marcorelles, Pascale ;
Dauge, Marie-Christine ;
Roume, Joelle ;
Le Merrer, Martine ;
Meiner, Vardiella ;
Meir, Karen ;
Menez, Francoise ;
Beaufrere, Anne-Marie ;
Francannet, Christine ;
Tantau, Julia ;
Sinico, Martine ;
Dumez, Yves ;
MacDonald, Fiona ;
Munnich, Arnold ;
Lyonnet, Stanislas ;
Gubler, Marie-Claire ;
Genin, Emmanuelle ;
Johnson, Colin A. ;
Vekemans, Michel ;
Encha-Razavi, Ferechte ;
Attie-Bitach, Tania .
AMERICAN JOURNAL OF HUMAN GENETICS, 2007, 81 (01) :170-179
[8]   The ciliopathies: An emerging class of human genetic disorders [J].
Badano, Jose L. ;
Mitsuma, Norimasa ;
Beales, Phil L. ;
Katsanis, Nicholas .
ANNUAL REVIEW OF GENOMICS AND HUMAN GENETICS, 2006, 7 :125-148
[9]   Sensory roles of neuronal cilia:: Cilia development, morphogenesis, and function in C-elegans [J].
Bae, Young-Kyung ;
Barr, Maureen M. .
FRONTIERS IN BIOSCIENCE-LANDMARK, 2008, 13 :5959-5974
[10]   Loss of nephrocystin-3 function can cause embryonic lethality, meckel-gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia [J].
Bergmann, Carsten ;
Fliegauf, Manfred ;
Bruechle, Nadina Ortiz ;
Frank, Valeska ;
Olbrich, Heike ;
Kirschner, Jan ;
Schermer, Bernhard ;
Schmedding, Ingolf ;
Kispert, Andreas ;
Kraenzlin, Bettina ;
Nuernberg, Gudrun ;
Becker, Christian ;
Grimm, Tiemo ;
Girschick, Gundula ;
Lynch, Sally A. ;
Kelehan, Peter ;
Senderek, Jan ;
Neuhaus, Thomas J. ;
Stallmach, Thomas ;
Zentgraf, Hanswalter ;
Nuernberg, Peter ;
Gretz, Norbert ;
Lo, Cecilia ;
Lienkamp, Soeren ;
Schaefer, Tobias ;
Walz, Gerd ;
Benzing, Thomas ;
Zerres, Klaus ;
Omran, Heymut .
AMERICAN JOURNAL OF HUMAN GENETICS, 2008, 82 (04) :959-970