Braf-mutant Schwann cells divert to a repair phenotype to induce congenital demyelinating neuropathy [SCP]

RASopathies are a diverse group of developmental disorders associated with germline or somatic mutations in genes of the Mitogen Activated Protein Kinase (MAPK) signaling pathway. We characterized in this dataset a model of Schwann cell differentiation in vitro (Hörner et al. 2021, PMID: 34943800), in which a constitutively active form of the MAPK effector BRAF (Q257R) is endogenously expressed in two patient-derived human induced pluripotent stem cell lines from distinct individuals RMK0056C and RMK0138C, patients with cardio-facio-cutaneous syndrome (OMIM #115150) as previously described (Yeh E, et al. 2018, PMID: 29158583). Two additional healthy donor hiPSC cell lines derived locally from commercially available fibroblasts, AG08H and hFF15, were also used as controls. The RNAseq experiment compares total RNA extracted from the four cell lines of cultures on day 18 (uncommitted Schwann cell precursor[SCP]-like phenotype) and day 31 (engaged SCP-like phenotype) of culture to find differentially expressed genes in the presence of continuous activation of MAPK signaling during early development and differentiation. Overall design: We performed RNA-seq analysis to compare the Schwann cell maturation potential derived from wild-type human induced pluripotent stem cells (HFF15 and AG08H lines) and two mutant lines carrying the Q257R mutation associated with cardio-facio-cutaneous syndrome. The analysis was conducted at two different stages of the differentiation protocol: J18 (precursor Schwann cells) and J31 (immature Schwann cells). After aligning the sequences to the human genome, we conducted a differential gene expression analysis.