title: AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders.
abstract: OBJECTIVE
  Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. It is characterized by hypoplasia of the cerebellar vermis and a particular midbrain-hindbrain "molar tooth" sign, a finding shared by a group of Joubert syndrome-related disorders (JSRDs), with wide phenotypic variability. The frequency of mutations in the first positionally cloned gene, AHI1, is unknown.
  
  
  METHODS
  We searched for mutations in the AHI1 gene among a cohort of 137 families with JSRD and radiographically proven molar tooth sign.
  
  
  RESULTS
  We identified 15 deleterious mutations in 10 families with pure JS or JS plus retinal and/or additional central nervous system abnormalities. Mutations among families with JSRD including kidney or liver involvement were not detected. Transheterozygous mutations were identified in the majority of those without history of consanguinity. Most mutations were truncating or splicing errors, with only one missense mutation in the highly conserved WD40 repeat domain that led to disease of similar severity.
  
  
  CONCLUSIONS
  AHI1 mutations are a frequent cause of disease in patients with specific forms of JSRD.
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico, Casa Sollievo della Sofferenza, Mendel Institute, Rome, Italy.
authors.forename: Enza Maria
authors.initials: EM
authors.lastname: Valente
authors.forename: Francesco
authors.initials: F
authors.lastname: Brancati
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Silhavy
authors.forename: Marco
authors.initials: M
authors.lastname: Castori
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Marsh
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Barrano
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Eugen
authors.initials: E
authors.lastname: Boltshauser
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.forename: Alice
authors.initials: A
authors.lastname: Abdel-Aleem
authors.forename: Ghada M H
authors.initials: GM
authors.lastname: Abdel-Salam
authors.forename: Emanuele
authors.initials: E
authors.lastname: Bellacchio
authors.forename: Roberta
authors.initials: R
authors.lastname: Battini
authors.forename: Robert P
authors.initials: RP
authors.lastname: Cruse
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: Kalpathy S
authors.initials: KS
authors.lastname: Krishnamoorthy
authors.forename: Clotilde
authors.initials: C
authors.lastname: Lagier-Tourenne
authors.forename: Alex
authors.initials: A
authors.lastname: Magee
authors.forename: Ignacio
authors.initials: I
authors.lastname: Pascual-Castroviejo
authors.forename: Carmelo D
authors.initials: CD
authors.lastname: Salpietro
authors.forename: Dean
authors.initials: D
authors.lastname: Sarco
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport; D000293:Adolescent; D000328:Adult; D000818:Animals; D001927:Brain Diseases / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D001933:Brain Stem / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D025063:Chromosome Disorders / Q000235:genetics / Q000503:physiopathology; D004252:DNA Mutational Analysis / Q000379:methods; D002658:Developmental Disabilities / Q000235:genetics* / Q000503:physiopathology; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D011110:Polymorphism, Genetic
chemical_list: C487178:AHI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport