RRC ID 46123
Author Huang L, Szymanska K, Jensen VL, Janecke AR, Innes AM, Davis EE, Frosk P, Li C, Willer JR, Chodirker BN, Greenberg CR, McLeod DR, Bernier FP, Chudley AE, Müller T, Shboul M, Logan CV, Loucks CM, Beaulieu CL, Bowie RV, Bell SM, Adkins J, Zuniga FI, Ross KD, Wang J, Ban MR, Becker C, Nürnberg P, Douglas S, Craft CM, Akimenko MA, Hegele RA, Ober C, Utermann G, Bolz HJ, Bulman DE, Katsanis N, Blacque OE, Doherty D, Parboosingh JS, Leroux MR, Johnson CA, Boycott KM.
Title TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone.
Journal Am J Hum Genet
Abstract Joubert syndrome related disorders (JSRDs) have broad but variable phenotypic overlap with other ciliopathies. The molecular etiology of this overlap is unclear but probably arises from disrupting common functional module components within primary cilia. To identify additional module elements associated with JSRDs, we performed homozygosity mapping followed by next-generation sequencing (NGS) and uncovered mutations in TMEM237 (previously known as ALS2CR4). We show that loss of the mammalian TMEM237, which localizes to the ciliary transition zone (TZ), results in defective ciliogenesis and deregulation of Wnt signaling. Furthermore, disruption of Danio rerio (zebrafish) tmem237 expression produces gastrulation defects consistent with ciliary dysfunction, and Caenorhabditis elegans jbts-14 genetically interacts with nphp-4, encoding another TZ protein, to control basal body-TZ anchoring to the membrane and ciliogenesis. Both mammalian and C. elegans TMEM237/JBTS-14 require RPGRIP1L/MKS5 for proper TZ localization, and we demonstrate additional functional interactions between C. elegans JBTS-14 and MKS-2/TMEM216, MKSR-1/B9D1, and MKSR-2/B9D2. Collectively, our findings integrate TMEM237/JBTS-14 in a complex interaction network of TZ-associated proteins and reveal a growing contribution of a TZ functional module to the spectrum of ciliopathy phenotypes.
Volume 89(6)
Pages 713-30
Published 2011-12-9
DOI 10.1016/j.ajhg.2011.11.005
PII S0002-9297(11)00483-6
PMID 22152675
PMC PMC3234373
MeSH Abnormalities, Multiple Adult Animals Bardet-Biedl Syndrome / genetics Caenorhabditis elegans / genetics Caenorhabditis elegans / ultrastructure Case-Control Studies Cell Line Cerebellar Diseases / genetics* Cerebellum / abnormalities Child Child, Preschool Chromosome Mapping Cilia / genetics* Cilia / metabolism Eye Abnormalities / genetics* Female Gene Expression Gene Knockdown Techniques Gene Knockout Techniques Genetic Association Studies Haplotypes Humans Infant Infant, Newborn Kidney Diseases, Cystic / genetics* Male Membrane Proteins / genetics* Membrane Proteins / metabolism Mice Microscopy, Electron, Transmission Multiprotein Complexes / metabolism Mutation* Polymorphism, Single Nucleotide Retina / abnormalities Sequence Analysis, DNA Wnt Proteins / metabolism Wnt Signaling Pathway Zebrafish / embryology Zebrafish / genetics
IF 9.924
Times Cited 112
WOS Category GENETICS & HEREDITY
Resource
C.elegans tm2452 tm3100 tm2547 tm925