MAP2K1 – Costello syndrome

Genetic evidence for MAP2K1 involvement in Costello syndrome emerges from a comprehensive screen of RAS/MAPK pathway genes in patients with overlapping RASopathy phenotypes. In a cohort of 130 individuals clinically diagnosed with cardio-facio-cutaneous syndrome (CFC), Costello syndrome (CS), or Noonan syndrome (NS), 4 of 20 HRAS-negative CS patients (20%) harbored heterozygous germline MAP2K1 variants identified by Sanger sequencing (PMID:17704260). All 4 variants occurred de novo in parent–offspring trios, supporting an autosomal dominant inheritance without evidence of multiplex familial segregation. A recurrent change, c.199G>A (p.Asp67Asn), localizes to the negative regulatory region of MEK1 and was observed in multiple probands. No additional large pedigrees or segregation beyond the de novo events have been described, limiting the genetic evidence to a single study.

Functional assays demonstrate that germline MAP2K1 variants confer gain-of-function activity consistent with RASopathy pathogenesis. In vitro kinase studies of p.Asp67Asn and other MEK1 mutants show elevated basal MEK1 activity and enhanced ERK phosphorylation compared to wild type, indicating resistance to normal regulatory control (PMID:18413255; PMID:18060073). This biochemical hyperactivation parallels the downstream effects of HRAS mutations in classical Costello syndrome and supports a pathogenic haploinsufficient mechanism driven by constitutive MEK1 activity. No studies to date have refuted the association, but confirmation in additional HRAS-negative CS cases and deeper phenotype correlations are required. Key take-home: Germline MAP2K1 gain-of-function variants account for a subset of HRAS-negative Costello syndrome, warranting inclusion of MAP2K1 in diagnostic gene panels.

References

• Journal of medical genetics • 2007 • Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome. PMID:17704260
• Methods in enzymology • 2008 • Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome. PMID:18413255
• PloS one • 2007 • Mutation analysis of BRAF, MEK1 and MEK2 in 15 ovarian cancer cell lines: implications for therapy. PMID:18060073

Evidence Based Scoring (AI generated)