The present study is, to the best of our knowledge, the first to provide direct evidence that RSPRY1 deficiency leads to overactivation of the TGF-β signaling pathway, revealing a novel molecular mechanism underlying the pathogenesis of spondyloepimetaphyseal dysplasia (SEMD). The gene discussed is TGFB1; the disease is spondyloepimetaphyseal dysplasia, matrilin-3 type.