RESUMO
Since 1996, a European network has been organized from Rennes, France and holoprosencephalic files were collected for clinical and molecular study. Familial instances of typical and atypical holoprosencephaly (HPE) were found in 30% of cases. All affected children had psychomotor delay with microcephaly, often associated with endocrine, digestive, and respiratory abnormalities, and thermal dysregulation. Among 173 subjects in the molecular study, 28 heterozygous mutations were identified (16%): 15 SHH mutations, 6 ZIC2 mutations, 5 SIX3 mutations, and 2 TGIF mutations.
Assuntos
Holoprosencefalia/genética , Holoprosencefalia/patologia , Adulto , Encéfalo/anormalidades , Criança , Sistema Endócrino/anormalidades , Proteínas do Olho , Feminino , Feto , Trato Gastrointestinal/anormalidades , Proteínas Hedgehog , Proteínas de Homeodomínio/genética , Humanos , Masculino , Microcefalia/patologia , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares , Fenótipo , Transtornos Psicomotores/patologia , Proteínas Repressoras/genética , Sistema Respiratório/patologia , Transativadores/genética , Fatores de Transcrição/genética , Proteína Homeobox SIX3RESUMO
Holoprosencephaly (HPE) is the most common severe brain anomaly in humans, which results from incomplete cleavage of the forebrain during early embryogenesis. The aetiology of HPE is very heterogeneous. Among the genetic factors, TGIF ( TG-interacting factor), which codes for a transcription factor modulating the signalling pathway of TGF-beta, was previously implicated. We investigated 127 HPE probands by sequencing their TGIF gene and identified the first nonsense mutation reported so far and also a novel missense mutation, in two families that presented a large range of disease severity. The low number of mutations in TGIF suggests that this gene has no major contribution to the aetiology of HPE and our study confirms the wide clinical heterogeneity of the disease.