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J Med Genet doi:10.1136/jmedgenet-2012-101132
  • New loci
  • Short report

Mutations in TMEM231 cause Joubert syndrome in French Canadians

  1. Jacques L Michaud1
  1. 1Centre of Excellence in Neurosciences of Université de Montréal and Sainte-Justine Hospital Research Center, Montréal, Quebec, Canada
  2. 2McGill University and Genome Quebec Innovation Centre, Montréal, Quebec, Canada
  3. 3Department of Ophthalmology, Sainte-Justine Hospital Research Center, Montréal, Quebec, Canada
  4. 4Division of Pediatric Neurology, Montreal Children's Hospital-McGill University Health Center, Montreal, Quebec, Canada
  5. 5Division of Medical Genetics, Sainte Justine Hospital, Montréal, Quebec, Canada
  6. 6Department of Human Genetics, McGill University, Montréal, Quebec, Canada
  7. 7Division of Pediatric Neurology, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
  8. 8Division of Genetics, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
  9. 9FORGE steering committee are listed in the acknowledgments
  10. 10Department of Medicine, Centre of Excellence in Neurosciences of Université de Montréal, Montréal, Quebec, Canada
  1. Correspondence to Dr Jacques L Michaud, Centre of Excellence in Neurosciences of Université de Montréal and Sainte-Justine Hospital Research Center, CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montreal, Quebec, Canada H3T 1C5; jacques.michaud{at}recherche-ste-justine.qc.ca
  • Received 22 June 2012
  • Revised 20 August 2012
  • Accepted 21 August 2012
  • Published Online First 25 September 2012

Abstract

Background Joubert syndrome (JBTS) is a predominantly autosomal recessive disorder characterised by a distinctive midhindbrain malformation, oculomotor apraxia, breathing abnormalities and developmental delay. JBTS is genetically heterogeneous, involving genes required for formation and function of non-motile cilia. Here we investigate the genetic basis of JBTS in 12 French–Canadian (FC) individuals.

Methods and results Exome sequencing in all subjects showed that six of them carried rare compound heterozygous mutations in CC2D2A or C5ORF42, known JBTS genes. In addition, three individuals (two families) were compound heterozygous for the same rare mutations in TMEM231(c.12T>A[p.Tyr4*]; c.625G>A[p.Asp209Asn]). All three subjects showed a severe neurological phenotype and variable presence of polydactyly, retinopathy and renal cysts. These mutations were not detected among 385 FC controls. TMEM231 has been previously shown to localise to the ciliary transition zone, and to interact with several JBTS gene products in a complex involved in the formation of the diffusion barrier between the cilia and plasma membrane. siRNA knockdown of TMEM231 was also shown to affect barrier integrity, resulting in a reduction of cilia formation and ciliary localisation of signalling receptors.

Conclusions Our data suggest that mutations in TMEM231 cause JBTS, reinforcing the relationship between this condition and the disruption of the barrier at the ciliary transition zone.

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