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Heterozygous Mutations in MAP3K7, Encoding TGF-?-Activated Kinase 1, Cause Cardiospondylocarpofacial Syndrome.

ABSTRACT: Cardiospondylocarpofacial (CSCF) syndrome is characterized by growth retardation, dysmorphic facial features, brachydactyly with carpal-tarsal fusion and extensive posterior cervical vertebral synostosis, cardiac septal defects with valve dysplasia, and deafness with inner ear malformations. Whole-exome sequencing identified heterozygous MAP3K7 mutations in six distinct CSCF-affected individuals from four families and ranging in age from 5 to 37 years. MAP3K7 encodes transforming growth factor ? (TGF-?)-activated kinase 1 (TAK1), which is involved in the mitogen-activated protein kinase (MAPK)-p38 signaling pathway. MAPK-p38 signaling was markedly altered when expression of non-canonical TGF-?-driven target genes was impaired. These findings support the loss of transcriptional control of the TGF-?-MAPK-p38 pathway in fibroblasts obtained from affected individuals. Surprisingly, although TAK1 is located at the crossroad of inflammation, immunity, and cancer, this study reports MAP3K7 mutations in a developmental disorder affecting mainly cartilage, bone, and heart.

SUBMITTER: Le Goff C 

PROVIDER: S-EPMC4974068 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Heterozygous Mutations in MAP3K7, Encoding TGF-β-Activated Kinase 1, Cause Cardiospondylocarpofacial Syndrome.

Le Goff Carine C   Rogers Curtis C   Le Goff Wilfried W   Pinto Graziella G   Bonnet Damien D   Chrabieh Maya M   Alibeu Olivier O   Nistchke Patrick P   Munnich Arnold A   Picard Capucine C   Cormier-Daire Valérie V  

American journal of human genetics 20160714 2

Cardiospondylocarpofacial (CSCF) syndrome is characterized by growth retardation, dysmorphic facial features, brachydactyly with carpal-tarsal fusion and extensive posterior cervical vertebral synostosis, cardiac septal defects with valve dysplasia, and deafness with inner ear malformations. Whole-exome sequencing identified heterozygous MAP3K7 mutations in six distinct CSCF-affected individuals from four families and ranging in age from 5 to 37 years. MAP3K7 encodes transforming growth factor β  ...[more]

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