MAP2K1 – Noonan syndrome

Noonan syndrome (NS) is a multisystem autosomal dominant RASopathy characterized by congenital heart defects, short stature, facial dysmorphism, and variable developmental delay. Germline mutations in MAP2K1 (encoding MEK1) account for approximately 4% of PTPN11/SOS1-negative NS cases, establishing an autosomal dominant inheritance for MAP2K1-related NS (PMID:18456719).

Genetic evidence includes identification of MAP2K1 variants in 3/70 NS probands lacking PTPN11/SOS1/KRAS mutations, notably c.608A>C (p.Glu203Ala) (PMID:18456719). In a South African cohort, MAP2K1-c.389A>G (p.Tyr130Cys) was found in 2/16 unrelated probands (31.2%) with phenotypically typical NS (PMID:31057598). Segregation analysis demonstrated cosegregation of a MAP2K1 variant with NS in three affected relatives across a single pedigree (PMID:21784453).

Functional assays and animal models provide concordant support. The Mek1Y130C mouse recapitulates NS phenotypes including pulmonary artery stenosis and craniofacial anomalies, with hyperactivated ERK signaling in affected tissues (PMID:29590634). Biochemical studies show that negative-regulatory region substitutions (e.g., Phe-53 variants) destabilize the inactive conformation of MEK1, enhancing its phosphorylation by RAF and downstream ERK activation (PMID:29018093).

No conflicting reports dispute MAP2K1’s role; copy-number analyses have excluded dosage effects, and no refuting variants have been described. The aggregate data satisfy ClinGen criteria for a Definitive gene–disease association, with strong genetic and functional evidence.

Key Take-home: MAP2K1 should be included in diagnostic NS gene panels and informs personalized surveillance and potential targeted therapy.

References

• Journal of medical genetics • 2008 • Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders. PMID:18456719
• The Journal of pediatrics • 2011 • Spectrum of mutations in Noonan syndrome and their correlation with phenotypes. PMID:21784453
• Disease models & mechanisms • 2018 • Mek1Y130C mice recapitulate aspects of human cardio-facio-cutaneous syndrome. PMID:29590634
• Frontiers in genetics • 2019 • Noonan Syndrome in South Africa: Clinical and Molecular Profiles. PMID:31057598
• The Journal of biological chemistry • 2017 • How activating mutations affect MEK1 regulation and function. PMID:29018093

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