Get access

Deletion of MAP2K2/MEK2: a novel mechanism for a RASopathy?

Authors

  • M.J.M. Nowaczyk,

    Corresponding author
    1. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
    2. Department of Pediatrics, McMaster University, Hamilton, Canada
    • Corresponding author: Małgorzata J. M. Nowaczyk, MD, Department of

      Pathology and Molecular Medicine,

      McMaster University, 1200 Main Street

      West, Room 3N16, Hamilton, ON L8S 4J9, USA.

      Tel.: 905-521-5085;

      fax: 905-521-2651;

      e-mail: nowaczyk@hhsc.ca

    Search for more papers by this author
  • B.A. Thompson,

    1. Department of Pediatrics, University of California, San Francisco, CA, USA
    Search for more papers by this author
  • S. Zeesman,

    1. Department of Pediatrics, McMaster University, Hamilton, Canada
    Search for more papers by this author
  • U. Moog,

    1. Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
    Search for more papers by this author
  • P.A. Sanchez-Lara,

    1. Children's Hospital Los Angeles, Departments of Pathology and Pediatrics, Keck School of Medicine; Center for Craniofacial Molecular Biology (CCMB), Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA
    Search for more papers by this author
  • P.L. Magoulas,

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
    Search for more papers by this author
  • R.E. Falk,

    1. Department of Pathology and Laboratory Medicine, Medical Genetics Institute, Cedars-Sinai Medical Center and David Geffen School of Medicine, University of California, Los Angeles, CA, USA
    Search for more papers by this author
  • J.E. Hoover-Fong,

    1. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA
    Search for more papers by this author
  • D.A.S. Batista,

    1. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA
    2. Department of Pathology, Johns Hopkins University, Baltimore, MD, USA
    Search for more papers by this author
  • S.M. Amudhavalli,

    1. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA
    Search for more papers by this author
  • S.M. White,

    1. Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia
    2. Department of Paediatrics, University of Melbourne, Melbourne, Australia
    Search for more papers by this author
  • G.E. Graham,

    1. Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
    Search for more papers by this author
  • K.A. Rauen

    1. Department of Pediatrics, University of California, San Francisco, CA, USA
    Search for more papers by this author

  • None of the authors have conflicts of interest relating to the contents of this manuscript.

Abstract

RASopathies are a class of genetic syndromes caused by germline mutations in genes encoding Ras/mitogen-activated protein kinase (Ras/MAPK) pathway components. Cardio-facio-cutaneous (CFC) syndrome is a RASopathy characterized by distinctive craniofacial features, skin and hair abnormalities, and congenital heart defects caused by activating mutations of BRAF, MEK1, MEK2, and KRAS. We define the phenotype of seven patients with de novo deletions of chromosome 19p13.3 including MEK2; they present with a distinct phenotype but have overlapping features with CFC syndrome. Phenotypic features of all seven patients include tall forehead, thick nasal tip, underdeveloped cheekbones, long midface, sinuous upper vermilion border, tall chin, angular jaw, and facial asymmetry. Patients also have developmental delay, hypotonia, heart abnormalities, failure to thrive, obstructive sleep apnea, gastroesophageal reflux and integument abnormalities. Analysis of epidermal growth factor-stimulated fibroblasts revealed that P-MEK1/2 was ∼50% less abundant in cells carrying the MEK2 deletion compared to the control. Significant differences in total MEK2 and Sprouty1 abundance were also observed. Our cohort of seven individuals with MEK2 deletions has overlapping features associated with RASopathies. This is the first report suggesting that, in addition to activating mutations, MEK2 haploinsufficiency can lead to dysregulation of the MAPK pathway.

Ancillary