biostudies-literatureHa TYCUHK VC Discretionary FundInnovation and Technology Commission grant (Mainland-Hong Kong Joint Funding Scheme, MHKJFS)Co-funding Mechaism on Joint Laboratories with the CASCUHK Laboratory Support Special Fund for Key Laboratory for Regenerative Medicine, Ministry of Education, ChinaNSFC/RGC Joint Grant99https://www.ebi.ac.uk/biostudies/studies/S-EPMC11872873biostudies-literatureUnknown82(1)Campomelic Dysplasia (CD) is a rare congenital disease caused by haploinsufficiency (HI) in SOX9. Patients with CD typically present with skeletal abnormalities and 75% of them have sex reversal. In this study, we use CRISPR/Cas9 to generate a human induced pluripotent stem cell (hiPSC) model from a heathy male donor, based on a previously reported SOX9 splice site mutation in a CD patients. This hiPSCs-derived chondrocytes from heterozygotes (HT) and homozygotes (HM) SOX9 mutation carriers showed significant defects in chondrogenesis. Bulk RNA profiling revealed that the BMP-SMAD signaling pathway, ribosome-related, and chromosome segregation-related gene sets were altered in the HT chondrocytes. The profile also showed significant noggin upregulation in CD chondrocytes, with ChIP-qPCR coCellular and molecular life sciences : CMLSSOX9 haploinsufficiency reveals SOX9-Noggin interaction in BMP-SMAD signaling pathway in chondrogenesis.PMC11872873Acc 8601011N_CUHK 434/24N_CUHK 428/22YFJGJS1.0MHP/005/23JLFS/M-403/24Chan SWChan WYLu GLaw PWNMiu KKWang ZHa TYfalseSOX9 haploinsufficiency reveals SOX9-Noggin interaction in BMP-SMAD signaling pathway in chondrogenesis.Campomelic Dysplasia (CD) is a rare congenital disease caused by haploinsufficiency (HI) in SOX9. Patients with CD typically present with skeletal abnormalities and 75% of them have sex reversal. In this study, we use CRISPR/Cas9 to generate a human induced pluripotent stem cell (hiPSC) model from a heathy male donor, based on a previously reported SOX9 splice site mutation in a CD patients. This hiPSCs-derived chondrocytes from heterozygotes (HT) and homozygotes (HM) SOX9 mutation carriers showed significant defects in chondrogenesis. Bulk RNA profiling revealed that the BMP-SMAD signaling pathway, ribosome-related, and chromosome segregation-related gene sets were altered in the HT chondrocytes. The profile also showed significant noggin upregulation in CD chondrocytes, with ChIP-qPCR co2025-01-01T00:00:00Z2025 Mar2025-04-03T23:44:21.161Z2025-04-03T23:44:21.161ZS-EPMC118728734002528010.1007/s00018-025-05622-y