RESUMO
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.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Encefalopatias/genética , Deficiências do Desenvolvimento/genética , Mutação , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transporte Vesicular , Adolescente , Adulto , Animais , Encefalopatias/diagnóstico , Encefalopatias/fisiopatologia , Tronco Encefálico/patologia , Criança , Pré-Escolar , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/fisiopatologia , Análise Mutacional de DNA/métodos , Deficiências do Desenvolvimento/fisiopatologia , Saúde da Família , Feminino , Frequência do Gene , Humanos , Lactente , Imageamento por Ressonância Magnética/métodos , Masculino , Modelos Moleculares , Polimorfismo GenéticoRESUMO
Congenital fibrosis of the extraocular muscles type 1 (CFEOM1; OMIM #135700) is an autosomal dominant strabismus disorder associated with defects of the oculomotor nerve. We show that individuals with CFEOM1 harbor heterozygous missense mutations in a kinesin motor protein encoded by KIF21A. We identified six different mutations in 44 of 45 probands. The primary mutational hotspots are in the stalk domain, highlighting an important new role for KIF21A and its stalk in the formation of the oculomotor axis.