RESUMO
We performed whole-exome sequencing of a family with autosomal dominant Dandy-Walker malformation and occipital cephaloceles and detected a mutation in the extracellular matrix (ECM) protein-encoding gene NID1. In a second family, protein interaction network analysis identified a mutation in LAMC1, which encodes a NID1-binding partner. Structural modeling of the NID1-LAMC1 complex demonstrated that each mutation disrupts the interaction. These findings implicate the ECM in the pathogenesis of Dandy-Walker spectrum disorders.
Assuntos
Síndrome de Dandy-Walker/genética , Encefalocele/genética , Laminina/genética , Glicoproteínas de Membrana/genética , Mutação , Exoma , Matriz Extracelular/genética , Humanos , Laminina/química , Laminina/metabolismo , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/metabolismo , Estrutura Terciária de Proteína , Análise de Sequência de DNARESUMO
PURPOSE: To identify causes of nonsyndromic cleft lip and palate in a Vietnamese population. METHODS: In this study, 175 families with at least one case of cleft lip and/or palate were studied using the candidate genes TGFA, MSX1, and TGFB3. RESULTS: Transmission distortion for alleles of MSX1 were demonstrated for the whole population and two missense mutations were identified, including one (P147Q) that is found in approximately 2% of the population. The P147Q appears to arise from a founder individual based on shared haplotypes in unrelated families. CONCLUSIONS: MSX1 contributes to nonsyndromic clefting in a Vietnamese population, and consistent with other studies, identifiable mutations in this gene cause about 2% of cases of nonsyndromic clefting.