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Am J Hum Genet. 2016 Aug 4;99(2):407-13. doi: 10.1016/j.ajhg.2016.06.005. Epub 2016 Jul 14.

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

Author information

1
Department of Medical Genetics, Reference Center for Skeletal Dysplasia, INSERM UMR 1163, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, Paris Descartes-Sorbonne Paris Cité University, AP-HP, Institut Imagine, and Hôpital Universitaire Necker-Enfants Malades, 75015 Paris, France.
2
Greenwood Genetic Center Greenville Office, 14 Edgewood Drive, Greenville, SC 29605, USA.
3
Sorbonne Universités, UPMC Univ. Paris 06, INSERM, ICAN, Institute of Cardiometabolism and Nutrition (UMR_S1166), Integrative Biology of Atherosclerosis Team, 91 Boulevard de l'Hôpital, 75013 Paris, France.
4
Pediatric Endocrinology, Gynecology and Diabetes, Centre des Maladies Endocriniennes Rares de la Croissance, Hôpital Universitaire Necker-Enfants Malades, 75015 Paris, France.
5
Centre de Référence Malformations Cardiaques Congénitales Complexes-M3C, Hôpital Universitaire Necker-Enfants Malades, Université Paris Descartes, 75015 Paris, France.
6
Necker Branch, Laboratory of Human Genetics of Infectious Diseases, UMR 1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants Malades, 75015 Paris, France.
7
Genomic Platform, INSERM UMR 1163, Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France.
8
Bioinformatic Platform, INSERM UMR 1163, Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France.
9
Necker Branch, Laboratory of Human Genetics of Infectious Diseases, UMR 1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants Malades, 75015 Paris, France; Pediatric Hematology-Immunology-Rheumatology Unit, AP-HP, Hôpital Universitaire Necker-Enfants Malades, 75015 Paris, France; Study Center of Immunodeficiencies, Hôpital Universitaire Necker-Enfants Malades, AP-HP, 75015 Paris, France.
10
Department of Medical Genetics, Reference Center for Skeletal Dysplasia, INSERM UMR 1163, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, Paris Descartes-Sorbonne Paris Cité University, AP-HP, Institut Imagine, and Hôpital Universitaire Necker-Enfants Malades, 75015 Paris, France. Electronic address: valerie.cormier-daire@inserm.fr.

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 β (TGF-β)-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-β-driven target genes was impaired. These findings support the loss of transcriptional control of the TGF-β-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.

PMID:
27426734
PMCID:
PMC4974068
DOI:
10.1016/j.ajhg.2016.06.005
[Indexed for MEDLINE]
Free PMC Article

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