SOX9 Haploinsufficiency reveals SOX9-Noggin to BMP-SMAD signaling pathway in chondrogenesis

SOX9 is well-known for its role in chondrogenesis and gonadogensis. Campomelic Dysplasia (CD) is an example of SOX9 haploinsufficiency-caused rare congenital disease, in which the patients are reported to have skeletal abnormalities. In this study, we created a hiPSC-modeling CD patient and investigated the effect of SOX9 on the regulation of chondrocyte differentiation in BMP-SMAD signaling in vitro. In the CD patient transcriptome, the BMP-SMAD signaling pathway and ribosome-related and chromosome segregation-related gene sets were altered. Upon further experimentation, noggin was found to be significantly upregulated in HT and HM mutants. The overexpression of SOX9 also showed upregulation in SOX9 and COL2A1. . We hope this finding can give a better picture of the dosage-dependent role of SOX9 in chondrogenesis and reveal the manifestation of skeletal dysplasia in CD patients, thereby helping to develop better drugs for these patients. Overall design: Two SOX9-mutant hiPSC lines, including heterogeneous (HT) and homogeneous (HM) mutations, were generated from a healthy male donor with the mutation designed to mimick medical literature reporting the SOX9 mutation in a CD patient. To investigate the SOX9 dosage effect on cartilage development, hiPSCs were differentiated into chondrocytes and performed transcriptome analysis on Day 14 using the WT (SOX9+/+) and the HT (SOX9+/-) samples.