AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders

Enza Maria Valente, Francesco Brancati, Jennifer L. Silhavy, Marco Castori, Sarah E. Marsh, Giuseppe Barrano, Enrico Bertini, Eugen Boltshauser, Maha S. Zaki, Alice Abdel-Aleem, Ghada M.H. Abdel-Salam, Emanuele Bellacchio, Roberta Battini, Robert P. Cruse, William B. Dobyns, Kalpathy S. Krishnamoorthy, Clotilde Lagier-Tourenne, Alex Magee, Ignacio Pascual-Castroviejo, Carmelo D. SalpietroDean Sarco, Bruno Dallapiccola, Joseph G. Gleeson

Research output: Contribution to journalArticlepeer-review

106 Scopus citations


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. Interpretation: AHI1 mutations are a frequent cause of disease in patients with specific forms of JSRD.

Original languageEnglish (US)
Pages (from-to)527-534
Number of pages8
JournalAnnals of Neurology
Issue number3
StatePublished - Mar 2006
Externally publishedYes


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