RAF1 – Cardio-faciocutaneous Syndrome

Despite the central role of RAF1 in RASopathies, germline RAF1 variants have not been reported in individuals with Cardio-faciocutaneous syndrome to date, leaving direct genetic evidence limited. The autosomal dominant inheritance of other RAS-MAPK gene mutations in CFCS contrasts with the absence of RAF1 mutations among CFCS cohorts tested, suggesting no definitive genotype–phenotype correlation. However, functional studies show that pathogenic RAF1 mutations cluster in conserved region 2 (CR2), leading to decreased phosphorylation at Ser259, dissociation from 14-3-3 proteins, and partial ERK activation, a mechanism consistent with hyperactive MAPK signaling in RASopathies (PMID:20052757). Moreover, in vitro and NMR analyses of the Raf cysteine-rich domain demonstrate that Ras-binding enhances kinase activity and that disruption of these interactions impairs MAPK activation, underscoring RAF1’s potential role in pathway dysregulation (PMID:10777480). Despite robust mechanistic data, the absence of CFCS probands with RAF1 variants precludes a definitive clinical link. Further targeted sequencing in CFCS cohorts is needed to clarify RAF1’s contribution. Key take-home: RAF1 mutations yield functional alterations paralleling CFCS pathogenesis, supporting inclusion in diagnostic panels pending confirmatory genetic evidence.

References

• 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 biological chemistry • 2000 • Elucidation of binding determinants and functional consequences of Ras/Raf-cysteine-rich domain interactions. PMID:10777480

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