RASopathies, rare congenital syndromes affecting multiple organ systems, often include peripheral neuropathy of unknown origin. While RASopathy gene variants are protooncogenic, how timing of onset changes prenatal pathogenicity remains unclear. This study investigates the links between Braf, a mitogen-activated protein kinase (MAPK) effector, and peripheral neuropathy. Targeting Braf(V600E), an oncogenic variant in mosaic RASopathies, to embryonic Mpz-expressing cells in mice triggered a congenital Charcot-Marie-Tooth-like degenerative neuropathy, with hyperplastic nerves, hindlimb weakness, and unexpectedly reduced body size. Constitutively active Braf expanded a Jun+ Schwann cell repair state, impairing myelination. Patient-derived iPSCs with the cardio-facio-cutaneous syndromeassociated BRAF Q257R variant also failed to differentiate into mature Schwann cells compared to WT, instead exhibiting progenitor or repair-type transcriptional profiles. These findings implicate somatic mosaicism in the unresolved genetic heterogeneity of neuropathies and expand the candidate gene list. A MAPK-dependent mechanism ties neural crest-derived Schwann cell dysfunction to both body growth and nerve homeostasis.
Maréchal et al. (Fri,) studied this question.