AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders.
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.
Valente
Enza Maria
EM
Istituto di Ricovero e Cura a Carattere Scientifico, Casa Sollievo della Sofferenza, Mendel Institute, Rome, Italy.
Brancati
Francesco
F
Silhavy
Jennifer L
JL
Castori
Marco
M
Marsh
Sarah E
SE
Barrano
Giuseppe
G
Bertini
Enrico
E
Boltshauser
Eugen
E
Zaki
Maha S
MS
Abdel-Aleem
Alice
A
Abdel-Salam
Ghada M H
GM
Bellacchio
Emanuele
E
Battini
Roberta
R
Cruse
Robert P
RP
Dobyns
William B
WB
Krishnamoorthy
Kalpathy S
KS
Lagier-Tourenne
Clotilde
C
Magee
Alex
A
Pascual-Castroviejo
Ignacio
I
Salpietro
Carmelo D
CD
Sarco
Dean
D
Dallapiccola
Bruno
B
Gleeson
Joseph G
JG
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
C487178:AHI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport