Identification of novel rare mutations of DACT1 in human neural tube defects.
Hum Mutat
; 33(10): 1450-5, 2012 Oct.
Article
em En
| MEDLINE
| ID: mdl-22610794
ABSTRACT
Neural tube defects (NTDs) constitute the second most frequent cause of human congenital abnormalities. Complex multigenetic causes have been suggested to contribute to NTDs. The planar cell polarity (PCP) pathway plays a critical role in neural tube closure in model organisms and in human. Knockout of Dact1 (Dapper, Frodo) leads to deregulated PCP signaling with defective neural tube in mice. Here, we report that five missense heterozygote mutations of the DACT1 gene are specifically identified in 167 stillborn or miscarried Han Chinese fetuses with neural tube defects. Our biochemical analyses revealed that among the five mutations, N356K and R45W show loss-of-function or reduced activities in inducing Dishevelled2 (DVL2) degradation and inhibiting jun-N-terminal kinase (JNK) phosphorylation, implicating mutated DACT1 as a risk factor for human NTDs. Our findings, together with early reports, suggest that rare mutations of the PCP-related genes may constitute a great contribution to human NTDs.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Proteínas Nucleares
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Proteínas Adaptadoras de Transdução de Sinal
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Mutação
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Defeitos do Tubo Neural
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Hum Mutat
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2012
Tipo de documento:
Article