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

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

  • Am J Hum Genet. 2016 Aug 4;99(2):407-13. doi: 10.1016/j.ajhg.2016.06.005.
Carine Le Goff 1,  Curtis Rogers 2,  Wilfried Le Goff 3,  Graziella Pinto 4,  Damien Bonnet 5,  Maya Chrabieh 6,  Olivier Alibeu 7,  Patrick Nistchke 8,  Arnold Munnich 1,  Capucine Picard 9,  Valérie Cormier-Daire 10
Affiliations

Affiliations

  • 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: [email protected].
PMID: 27426734 DOI: 10.1016/j.ajhg.2016.06.005
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.

Figures