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Am J Hum Genet. 2016 Aug 4;99(2):392-406. doi: 10.1016/j.ajhg.2016.05.024. Epub 2016 Jul 15.

Mutations in MAP3K7 that Alter the Activity of the TAK1 Signaling Complex Cause Frontometaphyseal Dysplasia.

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Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
Royal Brisbane and Women's Hospital, Herston, QLD 4029, Australia.
Service de Génétique Médicale Maternité, CHUV, Lausanne 1011, Switzerland.
Discipline of Pediatrics and Child Health and Department of Clinical Genetics, University of Sydney and The Children's Hospital, Westmead, Sydney, NSW 2145, Australia.
Genetics Unit, Instituto da Criança, Hospital das Clinicas da Faculdade de Medicina, São Paulo 05403-000, Brazil.
Institut fur Humangenetik, Universitatsklinikum Munster, Munster 48149, Germany.
Kathryn O. and Alan C. Greenberg Center for Skeletal Dysplasias, Hospital for Special Surgery, New York, NY 10021, USA.
Division of Pediatric Orthopedics, Seoul National University Children's Hospital, Seoul 28, Republic of Korea.
Zentrum Medizinische Genetik Linz, Med Campus IV, Kepler Universitätsklinikum, Krankenhausstrasse, 26-30, 4020 Linz, Austria.
South East Scotland Clinical Genetics Service, Western General Hospital, Edinburgh EH4 2XU, UK.
David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
Hayward Genetics Center, Tulane University Medical School, New Orleans, LA 70112 USA.
MGZ-Medical Genetics Center, Munich 80335, Germany.
Department of Pediatrics, CHUV and University of Lausanne, Lausanne 1015, Switzerland.
University Medical Center, Groningen 9713, the Netherlands.
Institute of Human Genetics, Heinrich Heine University, Dusseldorf 40225, Germany.
Clinical Genetics Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam 1105, Netherlands.
Institute of Fundamental Sciences, Massey University, Palmerston North 4474, New Zealand.
Institut für Humangenetik, Helmholtz Zentrum München, Neuherberg, Munich 85764, Germany.
Weatherall Institute of Molecular Medicine, University of Oxford and John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand. Electronic address:


Frontometaphyseal dysplasia (FMD) is a progressive sclerosing skeletal dysplasia affecting the long bones and skull. The cause of FMD in some individuals is gain-of-function mutations in FLNA, although how these mutations result in a hyperostotic phenotype remains unknown. Approximately one half of individuals with FMD have no identified mutation in FLNA and are phenotypically very similar to individuals with FLNA mutations, except for an increased tendency to form keloid scars. Using whole-exome sequencing and targeted Sanger sequencing in 19 FMD-affected individuals with no identifiable FLNA mutation, we identified mutations in two genes-MAP3K7, encoding transforming growth factor β (TGF-β)-activated kinase (TAK1), and TAB2, encoding TAK1-associated binding protein 2 (TAB2). Four mutations were found in MAP3K7, including one highly recurrent (n = 15) de novo mutation (c.1454C>T [ p.Pro485Leu]) proximal to the coiled-coil domain of TAK1 and three missense mutations affecting the kinase domain (c.208G>C [p.Glu70Gln], c.299T>A [p.Val100Glu], and c.502G>C [p.Gly168Arg]). Notably, the subjects with the latter three mutations had a milder FMD phenotype. An additional de novo mutation was found in TAB2 (c.1705G>A, p.Glu569Lys). The recurrent mutation does not destabilize TAK1, or impair its ability to homodimerize or bind TAB2, but it does increase TAK1 autophosphorylation and alter the activity of more than one signaling pathway regulated by the TAK1 kinase complex. These findings show that dysregulation of the TAK1 complex produces a close phenocopy of FMD caused by FLNA mutations. Furthermore, they suggest that the pathogenesis of some of the filaminopathies caused by FLNA mutations might be mediated by misregulation of signaling coordinated through the TAK1 signaling complex.

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