TMEM237 Is Mutated in Individuals with a Joubert Syndrome Related Disorder and Expands the Role of the TMEM Family at the Ciliary Transition Zone

Huang, L., Szymanska, K., Jensen, V.L., Janecke, A.R., Innes, A.M., Davis, E.E., Frosk, P., Li, C., Willer, J.R., Chodirker, B.N., Greenberg, C.R., McLeod, D.R., Bernier, F.P., Chudley, A.E., Müller, T., Shboul, M., Logan, C.V., Loucks, C.M., Beaulieu, C.L., Bowie, R.V., Bell, S.M., Adkins, J., Zuniga, F.I., Ross, K.D., Wang, J., Ban, M.R., Becker, C., Nürnberg, P., Douglas, S., Craft, C.M., Akimenko, M.A., Hegele, R.A., Ober, C., Utermann, G., Bolz, H.J., Bulman, D.E., Katsanis, N., Blacque, O.E., Doherty, D., Parboosingh, J.S., Leroux, M.R., Johnson, C.A., and Boycott, K.M.
American journal of human genetics   89(6): 713-730 (Journal)
Registered Authors
Akimenko, Marie-Andree, Davis, Erica, Katsanis, Nicholas, Shboul, Mohammad
MeSH Terms
  • 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
22152675 Full text @ Am. J. Hum. Genet.

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.

Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes