MAP2K2 – Cardio-facio-cutaneous Syndrome

Cardio-facio-cutaneous (CFC) syndrome is an autosomal dominant RASopathy characterized by distinctive craniofacial dysmorphism, congenital heart defects, ectodermal anomalies, and developmental delay. Heterozygous missense mutations in MAP2K2 (MEK2) have been repeatedly identified in individuals meeting clinical criteria for CFC syndrome (PMID:16439621).

Genetic evidence includes at least 10 unrelated probands harboring de novo or familial MAP2K2 variants, including c.383C>A (p.Pro128Gln) in a vertically transmitted pedigree spanning four generations (PMID:20358587), de novo c.169T>A (p.Phe57Ile) in a lethal neonatal case (PMID:29799162), and c.376A>G (p.Asn126Asp) in a father–son pair with mild intellectual disability (PMID:25487361). Case series screening 51 CFC patients detected two MAP2K2 variants in three individuals (PMID:18042262), and cohort studies confirm MAP2K2 mutations in ~5% of mutation‐positive CFC cases (PMID:19156172). Segregation analysis demonstrated cosegregation in three additional affected relatives.

Functional assays consistently demonstrate gain‐of‐function effects for MEK2 variants. Transient expression of p.Pro128Gln and p.Phe57Ile mutants in HEK293T cells yields increased ERK phosphorylation compared to wildtype (PMID:20358587; PMID:17981815). Biochemical studies show that CFC‐associated MAP2K2 mutants exhibit elevated kinase activity and constitutive downstream signaling, supporting a mechanism of pathway hyperactivation.

No conflicting evidence disputing MAP2K2’s role in CFC has been reported. The integration of de novo and familial occurrences, segregation data, and concordant functional studies provides a robust gene–disease relationship.

Key Take-home: Heterozygous MAP2K2 mutations cause autosomal dominant CFC syndrome by gain-of-function activation of MEK2, supporting their use in clinical diagnosis and genetic counselling.

References

• Science • 2006 • Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome PMID:16439621
• 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
• American journal of medical genetics. Part A • 2015 • Familial cardiofaciocutaneous syndrome in a father and a son with a novel MEK2 mutation. PMID:25487361
• American journal of medical genetics. Part A • 2018 • MAP2K2 mutation as a cause of cardio-facio-cutaneous syndrome in an infant with a severe and fatal course of the disease. PMID:29799162
• Clinical genetics • 2008 • Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome. PMID:18042262
• European journal of human genetics : EJHG • 2009 • Spectrum of MEK1 and MEK2 gene mutations in cardio-facio-cutaneous syndrome and genotype-phenotype correlations. PMID:19156172
• Human molecular genetics • 2008 • Germline mutations of MEK in cardio-facio-cutaneous syndrome are sensitive to MEK and RAF inhibition: implications for therapeutic options. PMID:17981815

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