A rare 5'UTR variant in SEC24D reveals translational dysfunction in osteogenesis imperfecta: a roadmap for RNA therapeutic rescue.

Osteogenesis imperfecta (OI) is a rare genetically heterogeneous connective tissue disorder primarily characterized by bone fragility, along with additional features such as blue sclerae, short stature, and dentinogenesis imperfecta. Although OI mainly presents an autosomal dominant inheritance pattern, over the past two decades, at least 17 genes have been implicated in autosomal recessive OI. In this study, we identified a novel homozygous non-coding variant, c.-167C > T, in the 5' untranslated region (5'UTR) of the SEC24D gene in a family with three affected individuals exhibiting a severe form of OI, craniofacial malformations and skull ossification defects. This is the first reported homozygous pathogenic non-coding variant in SEC24D, expanding the genetic landscape of OI. The variant is located in-frame with the opening reading frame and predicted to introduce a new upstream translation start codon (uATG) in the 5'UTR, disturbing the translational efficiency of the canonical initiation codon, a mechanism with direct implications for RNA-based therapeutic approach. Functional studies in patient-derived fibroblasts confirmed that SEC24D protein expression was significantly reduced while mRNA levels remained unchanged, suggesting a post-transcriptional regulatory mechanism. To address this translational defect, we designed and evaluated antisense oligonucleotides (ASOs) to modulate the translation of SEC24D. ASO treatment successfully increased SEC24D protein levels, demonstrating the potential of RNA-based therapies to modulate translation in genetic disorders caused by non-coding variants. Our findings provide a proof of concept for RNA-targeted therapeutics in OI, reinforcing the importance of investigating non-coding regions in genetic disease mechanisms. These results open new avenues for personalized RNA therapy in conditions linked to translational dysregulation.