MAP2K1 – Cardio-facio-cutaneous Syndrome

Cardio-facio-cutaneous (CFC) syndrome is a rare multisystem disorder characterized by craniofacial dysmorphology, ectodermal abnormalities, congenital cardiac defects, short stature, and neurodevelopmental delay. Heterozygous de novo mutations in MAP2K1 (MEK1) affecting the RAS/MAPK pathway have been identified as causative.

Genetic evidence supporting MAP2K1 involvement includes 11 unrelated probands with de novo missense variants in MAP2K1, notably c.389A>G (p.Tyr130Cys) (PMID:16439621), presenting with the CFC phenotype. Variants localize to exons 2 and 3 within the regulated kinase domain and are absent in healthy controls.

Inheritance is autosomal dominant, and all reported cases were sporadic de novo events (PMID:24637312; PMID:19156172). No familial segregation has been observed.

Functional assays demonstrate that pathogenic MAP2K1 mutations enhance MEK1 kinase activity and downstream ERK phosphorylation. In vitro studies show increased autophagy and p-ERK-dependent cell cycle progression in neural cell models expressing c.389A>G (p.Tyr130Cys) and c.383G>T (p.Gly128Val) variants (PMID:31972311).

A Mek1Y130C mouse model recapitulates key CFC features including pulmonary artery stenosis, cranial dysmorphia, and astrocyte/oligodendrocyte anomalies, confirming the pathogenic role of MEK1 p.Tyr130Cys in vivo (PMID:29590634).

No conflicting evidence has been reported, and extensive functional concordance across cellular and animal models supports a gain-of-function mechanism. These data establish a definitive association between MAP2K1 and CFC syndrome.

Key Take-home: De novo gain-of-function MAP2K1 variants are a definitive cause of autosomal dominant CFC syndrome, informing genetic diagnosis and highlighting MEK inhibition as a therapeutic avenue.

References

• Journal of clinical research in pediatric endocrinology • 2014 • Cardio-facio-cutaneous syndrome with precocious puberty, growth hormone deficiency and hyperprolactinemia. PMID:24637312
• Science • 2006 • Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. PMID:16439621
• European journal of human genetics • 2009 • Spectrum of MEK1 and MEK2 gene mutations in cardio-facio-cutaneous syndrome and genotype-phenotype correlations. PMID:19156172
• Gene • 2020 • Cardio-facio-cutaneous syndrome-associated pathogenic MAP2K1 variants activate autophagy. PMID:31972311
• Disease models & mechanisms • 2018 • Mek1Y130C mice recapitulate aspects of human cardio-facio-cutaneous syndrome. PMID:29590634

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