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Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes

Enza Maria Valente1, Clare V Logan, Soumaya Mougou-Zerelli

  • 1Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy. e.valente@css-mendel.it

Nature Genetics
|June 1, 2010
PubMed

Insights

Mutations in the TMEM216 gene cause Joubert syndrome (JBTS) and Meckel syndrome (MKS), which are ciliopathies. TMEM216 protein is crucial for primary cilia formation and function, linking it to various developmental disorders.

Area of Science:

  • Genetics
  • Molecular Biology
  • Developmental Biology

Background:

  • Joubert syndrome (JBTS), related disorders (JSRDs), and Meckel syndrome (MKS) are classified as ciliopathies, a group of genetic disorders affecting the primary cilia.
  • The genetic underpinnings of many ciliopathies remain incompletely understood, necessitating further investigation into novel causative genes and pathways.

Purpose of the Study:

  • To identify the genetic cause of the CORS2 (JBTS2) locus and investigate its relationship with other ciliopathies, specifically MKS.
  • To characterize the function of the TMEM216 gene and its encoded protein in the context of ciliogenesis and disease pathogenesis.

Main Methods:

  • Genetic analysis of patients with CORS2 and MKS to identify mutations in TMEM216.
  • Cellular studies using patient-derived fibroblasts and gene knockdown to assess TMEM216 function in ciliogenesis and centrosomal docking.
  • Zebrafish model to investigate the developmental consequences of TMEM216 disruption.

Main Results:

  • Identified TMEM216 mutations as the cause of both MKS2 and CORS2 (JBTS2), demonstrating allelism between these loci.
  • TMEM216 protein localizes to the base of primary cilia and is essential for ciliogenesis and centrosomal docking; its loss leads to RhoA and Dishevelled hyperactivation.
  • A specific G218T mutation in TMEM216 was found in all tested Ashkenazi Jewish individuals with the condition.
  • TMEM216 interacts with Meckelin, another protein involved in ciliopathies.
  • Knockdown of tmem216 in zebrafish resulted in developmental defects consistent with other ciliary morphants.

Conclusions:

  • TMEM216 is a novel gene implicated in ciliopathies, including JBTS and MKS, and its mutations contribute to a spectrum of related disorders.
  • The findings highlight the critical role of TMEM216 in primary cilia function and centrosome biology, providing insights into the pathogenesis of these developmental conditions.
  • This study supports the concept of allelism among different ciliopathy disorders and expands the repertoire of genes associated with these conditions.

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