Defective Joint Development and Maintenance in GDF6‐Related Multiple Synostoses Syndrome.

This article focuses on the generation and characterization of a mouse model carrying the Gdf6 p.Tyr443Asn mutation, orthologous to the human GDF6 p.Tyr444Asn mutation that causes multiple synostoses syndrome 4 (SYNS4), a rare genetic disorder marked by multiple joint fusions. The mutant mice recapitulated key SYNS4 features, including joint fusions in wrists, ankles, phalanges, and auditory ossicles, leading to motor coordination defects and progressive conductive hearing loss. Histological and transcriptomic analyses revealed that the mutation disrupts joint interzone formation and enhances bone morphogenetic protein (BMP) signaling, resulting in excessive chondrogenesis and impaired synovial joint development. These findings underscore the critical role of tightly regulated GDF6-mediated BMP signaling in both prenatal joint morphogenesis and postnatal joint maintenance.