title: Mutations in TMEM231 cause Joubert syndrome in French Canadians.
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.
  
  
  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.
authors.affiliation: Centre of Excellence in Neurosciences of Université de Montréal and Sainte-Justine Hospital Research Center, Montreal, Quebec, Canada H3T 1C5.
authors.forename: Myriam
authors.initials: M
authors.lastname: Srour
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Schwartzentruber
authors.forename: Lysanne
authors.initials: L
authors.lastname: Patry
authors.forename: Luis H
authors.initials: LH
authors.lastname: Ospina
authors.forename: Michael I
authors.initials: MI
authors.lastname: Shevell
authors.forename: Valérie
authors.initials: V
authors.lastname: Désilets
authors.forename: Sylvia
authors.initials: S
authors.lastname: Dobrzeniecka
authors.forename: Géraldine
authors.initials: G
authors.lastname: Mathonnet
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Lemyre
authors.forename: Christine
authors.initials: C
authors.lastname: Massicotte
authors.forename: Damian
authors.initials: D
authors.lastname: Labuda
authors.forename: Dina
authors.initials: D
authors.lastname: Amrom
authors.forename: Eva
authors.initials: E
authors.lastname: Andermann
authors.forename: Guillaume
authors.initials: G
authors.lastname: Sébire
authors.forename: Bruno
authors.initials: B
authors.lastname: Maranda
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
mesh_terms: D000015:Abnormalities, Multiple; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001921:Brain / Q000473:pathology; D002170:Canada / Q000208:ethnology; D002526:Cerebellar Diseases / Q000175:diagnosis / Q000235:genetics*; D002531:Cerebellum / Q000002:abnormalities; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005124:Eye Abnormalities / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D023061:Gene Order; D006801:Humans; D007223:Infant; D052177:Kidney Diseases, Cystic / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D012160:Retina / Q000002:abnormalities; D016415:Sequence Alignment; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; C578841:TMEM231 protein, human