RAF1 – Noonan syndrome

Noonan syndrome is an autosomal dominant RASopathy characterized by short stature, congenital heart defects, craniofacial dysmorphism, and variable multisystem involvement. Germline gain-of-function variants in RAF1, encoding the serine/threonine kinase C-RAF, have been implicated in approximately 3–5% of Noonan syndrome cases, often with a high prevalence of hypertrophic cardiomyopathy (PMID:17603483). Initial reports identified missense mutations clustered around the CR2 inhibitory phosphorylation site, notably affecting Ser259 and adjacent residues, suggesting a critical role in autoinhibition.

In a cohort of 231 mutation-negative Noonan syndrome patients, 18 individuals harbored heterozygous RAF1 missense variants, all presenting with hypertrophic cardiomyopathy (95% vs 18% in NS overall) (PMID:17603483). Subsequent case series documented de novo and familial RAF1 mutations (e.g., c.770C>T (p.Ser257Leu), c.782C>T (p.Pro261Leu), c.781C>G (p.Pro261Arg)) segregating with Noonan features and HCM in multiple pedigrees. One familial p.Ser427Gly mutation was observed in an adult proband and her affected mother, confirming vertical transmission and phenotype concordance (PMID:30204961).

RAF1-associated Noonan syndrome follows an autosomal dominant inheritance pattern, with both de novo and inherited cases reported. Segregation analysis across kindreds has confirmed at least 1 additional affected relative carrying pathogenic RAF1 alleles. The recurrent hotspot c.770C>T (p.Ser257Leu) exemplifies the variant spectrum, with over 20 unique missense variants now described, predominantly clustering in the CR2 regulatory domain.

Functional characterization demonstrates that NS-associated RAF1 mutants display increased kinase activity and enhanced MEK-ERK signaling. Mutations flanking Ser259 disrupt 14-3-3 binding and autoinhibitory phosphorylation, leading to constitutive activation of downstream MAPK effectors (PMID:20052757).

A Raf1(L613V) knock-in mouse model recapitulates key Noonan features—including short stature, craniofacial dysmorphism, and cardiac hypertrophy—and pharmacologic MEK inhibition normalized growth and cardiac phenotypes, confirming pathogenic mechanism and therapeutic targetability (PMID:21339642). Multiple in vitro and in vivo assays corroborate that RAF1 variants drive disease via gain-of-function in the Ras-MAPK pathway.

Integration of genetic and functional evidence supports a definitive association between RAF1 and Noonan syndrome. RAF1 testing is recommended in mutation-negative NS cases, particularly those with hypertrophic cardiomyopathy or a family history, to guide prognosis, surveillance, and potential MEK-pathway–directed therapies.

Key Take-home: RAF1 gain-of-function mutations cause autosomal dominant Noonan syndrome with a high risk of hypertrophic cardiomyopathy, supported by robust genetic and functional data informing diagnosis and targeted treatment.

References

• Nature Genetics • 2007 • Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. PMID:17603483
• Human Mutation • 2010 • Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation. PMID:20052757
• The Journal of Clinical Investigation • 2011 • MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1(L613V) mutation. PMID:21339642

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