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Deletion of MAP2K2/MEK2: A novel mechanism for a RASopathy? #MMPMID23379592
Nowaczyk MJ; Thompson BA; Zeesman S; Moog U; Sanchez-Lara PA; Magoulas PL; Falk RE; Fong JH; Batista DA; Amudhavalli SM; White SM; Graham GE; Rauen KA
Clin Genet 2014[Feb]; 85 (2): 138-46 PMID23379592show ga
RASopathies are a class of genetic syndromes caused by germline mutations in genes encoding 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, GE reflux and integument abnormalities. Analysis of EGF 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.
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Clin+Genet 2014 ; 85 (2): 138-46
