Mutations in <em>MAP3K7</em> and <em>TAB2</em> cause a distinct autosomal dominant form of frontometaphyseal dysplasia through a gain-of-function mechanism — ASN Events
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Mutations in MAP3K7 and TAB2 cause a distinct autosomal dominant form of frontometaphyseal dysplasia through a gain-of-function mechanism (#29)

Emma M Wade 1 , Zandra A Jenkins 1 , Philip B Daniel 1 , Aideen McInerney-Leo 2 , Paul J Leo 2 , Tim Morgan 1 , Marie Claude Addor 3 , Lesley C Adès 4 , Debora Bertola 5 , Axel Bohring 6 , Erin Carter 7 , Tae-Joon Cho 8 , Christa M de Geus 9 , Hans-Christoph Duba 10 , Elaine Fletcher 11 , Kinga Hadzsiev 12 , Chong A Kim 5 , Deborah Krakow 13 , Eva Morava 14 , Teresa Neuhann 15 , David Sillence 16 , Andrea Superti-Furga 17 , Hermine E Veenstra-Knol 9 , Dagmar Wieczorek 18 , Louise C Wilson 19 , Raoul CM Hennekam 20 , Andrew J Sutherland-Smith 21 , Tim M Strom 22 , Andrew OM Wilkie 23 , Matt A Brown 2 , Emma L Duncan 2 24 25 , David M Markie 1 , Stephen P Robertson 1
  1. University of Otago, Dunedin, OTAGO, New Zealand
  2. Translational Genomics Group, Institute of Health and Biomedical Innovation, Woolloongabba, Queensland, Australia
  3. Service de Genetique, Medicale Maternite, CHUV, Lausanna, Switzerland
  4. Discipline of Pediatrics and Child Health, University of Sydney and Department of Clinical Genetics, Westmead, Sydney, Australia
  5. Genetics Unity, Instituto da Crianca, Hospital das Clinicas da Faculdade de Medicina, Sao Paulo, Brazil
  6. Institut fur Humangenetik, Universitatsklinikum Munster, Munster, Germany
  7. Kathryn O. and Alan C. Greenburg Center for Skeletal Dysplasias , Hospital for Special Surgery , New York, USA
  8. Division of Pediatric Orthopedics, Seoul National University, Seoul, Republic of Korea
  9. Department of Genetics, University Medical Centre Groningen, Groningen, The Netherlands
  10. Zentrum Medizinische Genetik Linz, Kepler Universitatsklinikum Med Campus IV, Linz, Austria
  11. SE Scotland Clinical Genetics Service, Western General Hospital , Edinburgh, UK
  12. Department of Medical Genetics, University of Pecs, Pecs, Hungary
  13. David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
  14. Pediatrics, University Hospital Leuven, Leuven, Belgium
  15. MGZ, Medical Genetics Center, Munich, Germany
  16. Department of Genetic Medicine, Westmead Hospital and Discipline of Genetic Medicine, Sydney, Australia
  17. Department of Pediatrics, University of Lausanne, CHUV, Switzerland
  18. Institut fur Humangenetik, Universitatsklinikum Dusseldorf, Heinrich-Heine-Universitat, Dusseldorf, Germany
  19. Clinical Genetics Unit, Great Ormond Street Hospital for Children, London, UK
  20. Department of Pediatrics, University of Amsterdam, Amsterdam, The Netherlands
  21. Institute of Fundamental Sciences, Massey University, Palmerston North , New Zealand
  22. Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany
  23. Weatherall Institute of Molecular Medicine, University of Oxford and John Radcliffe Hospital, Oxford, UK
  24. Royal Brisbane and Women’s Hospital, Herston, Australia
  25. University of Queensland Diamantina Institute at Translational Research Institute, Woolloongabba, Australia

Frontometaphyseal dysplasia (FMD) is a rare, sclerosing skeletal dysplasia which primarily affects the long bones and the skull. Approximately 50% of cases are caused by gain-of-function mutations in the X-linked gene FLNA. X-linked FMD is therefore allelic to a spectrum of other skeletal dysplasias, the otopalatodigital spectrum disorders. FLNA encodes the actin-binding protein filamin A and it is uncertain why gain-of-function should lead to these hyperostosis phenotypes. Here we describe how gain-of-function mutations in two further genes, MAP3K7 and TAB2 cause an autosomal dominant form of FMD (AD-FMD), and account for the condition in the other half of individuals. These mutations lead to hyperphosphorylation of the TAK1 protein, encoded by MAP3K7, and increase the activity of the p38 kinase, an important downstream output of the TAK1 signalling complex. These findings suggest the pathogenesis of gain-of-function FLNA mutations may be mediated by misregulation of signalling through TAK1. By studying a cohort of 20 individuals with AD-FMD, we found all individuals have the necessary diagnostic criteria of FMD but also important distinguishing features to differentiate it from X-linked FMD. Individuals with AD-FMD are more likely to be deaf, and have scoliosis and cervical fusions. Additionally, there are features found exclusively in AD-FMD including valgus deformity of the feet, intellectual disability, and predisposition to keloid scarring. Furthermore genotype-phenotype correlations can be drawn within AD-FMD, with those patients with N-terminal substitutions in TAK1 having a milder phenotype than other individuals with AD-FMD. This study reveals important clinical distinctions between the forms of FMD to aid diagnosis and suggests that filamin A and the TAK1 complex are part of the same biochemical pathway which regulates bone development and homeostasis.