MAP2K2 – Noonan syndrome

The RASopathies are a group of developmental disorders caused by germline dysregulation of the RAS/MAPK signaling cascade. Noonan syndrome (NS) is an autosomal dominant condition characterized by short stature, congenital heart defects, and distinctive facial features. MAP2K2, encoding MEK2, has emerged as a rare NS gene alongside PTPN11, SOS1, KRAS, RAF1 and others; pathogenic variants in MAP2K2 have been described in familial and sporadic NS patients, as well as in cardio-facio-cutaneous syndrome and mixed phenotypes.

Genetic evidence for MAP2K2 in NS includes segregation of a heterozygous MEK2 variant in a mother–child pair with café-au-lait spots and Noonan-like facies (2 probands) (PMID:24311457). In a cohort of 31 PTPN11-negative NS patients, a MAP2K2 c.171T>A (p.Phe57Leu) variant was identified in one individual, supporting recurrent involvement in NS (PMID:18456719).

The variant spectrum in NS includes missense substitutions clustering in exons 2 and 3 of MAP2K2. A prototypic NS-associated allele is c.171T>A (p.Phe57Leu), reported in an unrelated NS patient (PMID:18456719). No loss-of-function or structural variants in MAP2K2 have been documented in NS to date.

Functional studies demonstrate that MEK2 mutants increase ERK phosphorylation and drive MAPK pathway hyperactivation. The vertically transmitted p.Pro128Gln substitution elevates ERK phosphorylation in HEK293T cells, confirming gain-of-function (PMID:20358587). In a Mek1Y130C mouse model, analogous MEK1 mutations cause pulmonary stenosis and craniofacial dysmorphology, recapitulating aspects of human RASopathies and supporting a shared mechanism (PMID:29590634).

No studies to date have refuted MAP2K2 involvement in NS, and no copy number variants including MAP2K2 have been associated with NS phenotypes in large CNV surveys.

In summary, autosomal dominant MAP2K2 missense variants segregate with NS in families and recur in screening cohorts, and functional assays consistently show gain-of-function effects on MAPK signaling. Although MAP2K2 is a rare NS locus, its identification informs molecular diagnosis, genetic counseling, and may guide targeted MEK inhibitor trials.

Key take-home: MAP2K2 germline missense mutations cause a gain-of-function RASopathy with features overlapping Noonan syndrome, and should be included in diagnostic gene panels.

References

• American journal of medical genetics. Part A • 2014 • Multiple café au lait spots in familial patients with MAP2K2 mutation PMID:24311457
• Journal of medical genetics • 2008 • Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders. PMID:18456719
• American journal of medical genetics. Part A • 2010 • Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission through four generations. PMID:20358587
• Disease models & mechanisms • 2018 • Mek1Y130C mice recapitulate aspects of human cardio-facio-cutaneous syndrome. PMID:29590634

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