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

M. J M Nowaczyk, B. A. Thompson, S. Zeesman, U. Moog, P. A. Sanchez-Lara, P. L. Magoulas, R. E. Falk, J. E. Hoover-Fong, D. A S Batista, S. M. Amudhavalli, S. M. White, G. E. Graham, Katherine A Rauen

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)138-146
Number of pages9
JournalClinical Genetics
Volume85
Issue number2
DOIs
StatePublished - Feb 2014
Externally publishedYes

Fingerprint

Congenital Heart Defects
Skin Abnormalities
Facial Asymmetry
Phenotype
Haploinsufficiency
Failure to Thrive
Chromosome Deletion
Chin
Mutation
Muscle Hypotonia
Forehead
ras Genes
Germ-Line Mutation
Obstructive Sleep Apnea
Gastroesophageal Reflux
Mitogen-Activated Protein Kinases
Jaw
Nose
Epidermal Growth Factor
Hair

Keywords

  • Cardio-facio-cutaneous syndrome
  • CFC
  • Deletion 19p13.3
  • MAP2K2
  • MEK2
  • Ras/MAPK pathway
  • RASopathy

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Nowaczyk, M. J. M., Thompson, B. A., Zeesman, S., Moog, U., Sanchez-Lara, P. A., Magoulas, P. L., ... Rauen, K. A. (2014). Deletion of MAP2K2/MEK2: A novel mechanism for a RASopathy? Clinical Genetics, 85(2), 138-146. https://doi.org/10.1111/cge.12116

Deletion of MAP2K2/MEK2 : A novel mechanism for a RASopathy? / Nowaczyk, M. J M; Thompson, B. A.; Zeesman, S.; Moog, U.; Sanchez-Lara, P. A.; Magoulas, P. L.; Falk, R. E.; Hoover-Fong, J. E.; Batista, D. A S; Amudhavalli, S. M.; White, S. M.; Graham, G. E.; Rauen, Katherine A.

In: Clinical Genetics, Vol. 85, No. 2, 02.2014, p. 138-146.

Research output: Contribution to journalArticle

Nowaczyk, MJM, Thompson, BA, Zeesman, S, Moog, U, Sanchez-Lara, PA, Magoulas, PL, Falk, RE, Hoover-Fong, JE, Batista, DAS, Amudhavalli, SM, White, SM, Graham, GE & Rauen, KA 2014, 'Deletion of MAP2K2/MEK2: A novel mechanism for a RASopathy?', Clinical Genetics, vol. 85, no. 2, pp. 138-146. https://doi.org/10.1111/cge.12116
Nowaczyk MJM, Thompson BA, Zeesman S, Moog U, Sanchez-Lara PA, Magoulas PL et al. Deletion of MAP2K2/MEK2: A novel mechanism for a RASopathy? Clinical Genetics. 2014 Feb;85(2):138-146. https://doi.org/10.1111/cge.12116
Nowaczyk, M. J M ; Thompson, B. A. ; Zeesman, S. ; Moog, U. ; Sanchez-Lara, P. A. ; Magoulas, P. L. ; Falk, R. E. ; Hoover-Fong, J. E. ; Batista, D. A S ; Amudhavalli, S. M. ; White, S. M. ; Graham, G. E. ; Rauen, Katherine A. / Deletion of MAP2K2/MEK2 : A novel mechanism for a RASopathy?. In: Clinical Genetics. 2014 ; Vol. 85, No. 2. pp. 138-146.
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