2. Academic Validation
  3. TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone

TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone

  • Am J Hum Genet. 2011 Dec 9;89(6):713-30. doi: 10.1016/j.ajhg.2011.11.005.
Lijia Huang 1,  Katarzyna Szymanska,  Victor L Jensen,  Andreas R Janecke,  A Micheil Innes,  Erica E Davis,  Patrick Frosk,  Chunmei Li,  Jason R Willer,  Bernard N Chodirker,  Cheryl R Greenberg,  D Ross McLeod,  Francois P Bernier,  Albert E Chudley,  Thomas Müller,  Mohammad Shboul,  Clare V Logan,  Catrina M Loucks,  Chandree L Beaulieu,  Rachel V Bowie,  Sandra M Bell,  Jonathan Adkins,  Freddi I Zuniga,  Kevin D Ross,  Jian Wang,  Matthew R Ban,  Christian Becker,  Peter Nürnberg,  Stuart Douglas,  Cheryl M Craft,  Marie-Andree Akimenko,  Robert A Hegele,  Carole Ober,  Gerd Utermann,  Hanno J Bolz,  Dennis E Bulman,  Nicholas Katsanis,  Oliver E Blacque,  Dan Doherty,  Jillian S Parboosingh,  Michel R Leroux,  Colin A Johnson,  Kym M Boycott
Affiliations

Affiliation

  • 1 Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
PMID: 22152675 DOI: 10.1016/j.ajhg.2011.11.005
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.

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