Single-molecule force measurement via optical tweezers reveals different kinetic features of two BRaf mutants responsible for cardio-facial-cutaneous (CFC) syndrome.
We report the case of a 4-year-old girl who presented a CFC syndrome, confirmed by the presence of a pathogenic R257Q BRAF gene mutation, together with a muscular CoQ10 deficiency.
Mutations in the RAS-MAPK pathway have recently been reported in both of these syndromes, with HRAS mutations characteristic for CS and BRAF and MEK1/2 mutations for CFC.
Cardio-facio-cutaneous (CFC) syndrome is one of the RASopathies and is caused by alteration of activity through the Ras/mitogen-activated protein kinase (MAPK) pathway due to heterozygous de novo mutations in protein kinases BRAF, MEK1, or MEK2.
We recently demonstrated that mice expressing a Braf Q241R mutation, which corresponds to the most frequent BRAF mutation (Q257R) in CFC syndrome, on a C57BL/6J background are embryonic/neonatal lethal, with multiple congenital defects, preventing us from analyzing the phenotypic consequences after birth.
This discovery provided a clue to identification of germline mutations in Kirsten-RAS (KRAS), BRAF and mitogen-activated protein kinase kinase 1 and 2 (MAP2K1/MAP2K2) in patients with CFC syndrome.
As the role of the RAS/MAPK pathway in HCM pathogenesis is unclear, we generated a human induced pluripotent stem cell (hiPSC) model for CFCS from three patients with activating BRAF mutations.