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

M J M Nowaczyk1, B A Thompson, S Zeesman

  • 1Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada; Department of Pediatrics, McMaster University, Hamilton, Canada.

Clinical Genetics
|February 6, 2013
PubMed

Insights

RASopathies, genetic disorders affecting the Ras/mitogen-activated protein kinase (Ras/MAPK) pathway, can arise from MEK2 gene deletions. This haploinsufficiency causes distinct developmental and physical features, similar to CFC syndrome.

Area of Science:

  • Genetics
  • Molecular Biology
  • Developmental Biology

Background:

  • RASopathies are genetic syndromes stemming from mutations in the Ras/mitogen-activated protein kinase (Ras/MAPK) pathway.
  • Cardio-facio-cutaneous (CFC) syndrome, a RASopathy, is linked to activating mutations in BRAF, MEK1, MEK2, and KRAS, presenting with craniofacial, skin, hair, and heart defects.

Purpose of the Study:

  • To define the phenotype of seven patients with de novo deletions of chromosome 19p13.3, specifically involving the MEK2 gene.
  • To investigate the impact of MEK2 haploinsufficiency on Ras/MAPK pathway signaling.
  • To compare the clinical features of MEK2 deletion syndrome with existing RASopathies, such as CFC syndrome.

Main Methods:

  • Clinical evaluation of seven patients with 19p13.3 deletions encompassing MEK2.
  • Detailed phenotypic analysis, including craniofacial features, developmental delay, and organ abnormalities.
  • Biochemical analysis of MEK2 and downstream signaling (P-MEK1/2) in patient-derived fibroblasts stimulated with epidermal growth factor.

Main Results:

  • Patients exhibited a distinct phenotype with features overlapping those of CFC syndrome, including tall forehead, midface hypoplasia, developmental delay, hypotonia, heart defects, and integument abnormalities.
  • Fibroblast analysis showed approximately 50% reduced P-MEK1/2 abundance in MEK2-deleted cells compared to controls.
  • Significant alterations in total MEK2 and Sprouty1 protein levels were observed in individuals with MEK2 deletions.

Conclusions:

  • MEK2 haploinsufficiency, resulting from 19p13.3 deletions, leads to a distinct RASopathy phenotype.
  • This study is the first to demonstrate that MEK2 haploinsufficiency, in addition to activating mutations, can dysregulate the Ras/MAPK pathway.
  • MEK2 deletions represent a novel mechanism contributing to RASopathies, expanding the known genetic causes of these syndromes.
Keywords:
CFCMAP2K2MEK2RASopathyRas/MAPK pathwaycardio-facio-cutaneous syndromedeletion 19p13.3

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