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

2006; Wiley; Volume: 59; Issue: 3 Linguagem: Inglês

10.1002/ana.20749

1531-8249

Enza Maria Valente, Francesco Brancati, Jennifer L. Silhavy, Marco Castori, Sarah 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, I Pascual-Castroviejo, Carmelo Salpietro, Dean Sarco, Bruno Dallapiccola, Joseph G. Gleeson,

Renal and related cancers

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.We searched for mutations in the AHI1 gene among a cohort of 137 families with JSRD and radiographically proven molar tooth sign.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.AHI1 mutations are a frequent cause of disease in patients with specific forms of JSRD.