title: Heterozygous Mutations in MAP3K7, Encoding TGF-β-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 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.
authors.affiliation: 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.
authors.forename: Carine
authors.initials: C
authors.lastname: Le Goff
authors.affiliation: Greenwood Genetic Center Greenville Office, 14 Edgewood Drive, Greenville, SC 29605, USA.
authors.forename: Curtis
authors.initials: C
authors.lastname: Rogers
authors.affiliation: 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.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Le Goff
authors.affiliation: Pediatric Endocrinology, Gynecology and Diabetes, Centre des Maladies Endocriniennes Rares de la Croissance, Hôpital Universitaire Necker-Enfants Malades, 75015 Paris, France.
authors.forename: Graziella
authors.initials: G
authors.lastname: Pinto
authors.affiliation: Centre de Référence Malformations Cardiaques Congénitales Complexes-M3C, Hôpital Universitaire Necker-Enfants Malades, Université Paris Descartes, 75015 Paris, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Bonnet
authors.affiliation: 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.
authors.forename: Maya
authors.initials: M
authors.lastname: Chrabieh
authors.affiliation: Genomic Platform, INSERM UMR 1163, Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Alibeu
authors.affiliation: Bioinformatic Platform, INSERM UMR 1163, Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nistchke
authors.affiliation: 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.
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.affiliation: 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.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: 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.
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
mesh_terms: D000015:Abnormalities, Multiple; D000293:Adolescent; D000328:Adult; D002348:Carpal Bones / Q000002:abnormalities*; D002574:Cervical Vertebrae / Q000002:abnormalities*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005347:Fibroblasts; D005786:Gene Expression Regulation; D006312:Hearing Loss, Bilateral; D006314:Hearing Loss, Conductive / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics*; D020935:MAP Kinase Signaling System; D008297:Male; D008944:Mitral Valve Insufficiency / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010026:Osteosclerosis; D013577:Syndrome; D013639:Tarsal Bones / Q000002:abnormalities*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D053583:Interleukin-1beta; D020930:MAP Kinase Kinase Kinases; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7