Abstract Osteogenesis imperfecta (OI) encompasses a genetically diverse spectrum of skeletal dysplasias, commonly linked to pathogenic variants in COL1A1 and COL1A2. Emerging data identify TENT5A—a noncanonical cytoplasmic poly (A) polymerase essential for mRNA stability of extracellular matrix proteins—as a novel OI gene. However, human phenotypes associated with TENT5A impairment and its molecular underpinnings remain poorly characterized. We performed detailed clinical, biochemical, and transcriptomic characterization of a Palestinian male with homozygous TENT5A variant (NM₀01370434: c. 972CG, p. Ile324Met). Functional studies were conducted on patient-derived fibroblasts subjected to osteogenic induction, assessing matrix mineralization, mRNA expression, poly (A) tail dynamics (via Nanopore direct RNA sequencing), and stress response. RNA-seq and qPCR were used to profile osteogenic and epigenetic gene expression. Despite normal stature and preserved long bone architecture, the proband exhibited recurrent small bone fractures and persistently elevated alkaline phosphatase. Fibroblasts from the proband demonstrated reduced mineralization and significantly shortened poly (A) tails in COL1A1 and COL1A2 transcripts, corresponding to decreased expression. Transcriptomic analysis revealed downregulation of key extracellular matrix (ECM), osteogenic, and chromatin-regulatory genes, alongside increased ribosomal transcripts and translational machinery. Poly (A) tail shortening was selective, affecting ECM and regulatory genes but sparing housekeeping genes. Under metabolic stress, TENT5A-impaired fibroblasts showed markedly reduced viability, indicating broader cellular vulnerability. Despite these molecular disruptions, clinical severity remained mild, possibly modulated by early bisphosphonate therapy. This case defines a distinct form of OI arising from post-transcriptional dysregulation in matrix-producing cells. TENT5A alteration compromises ECM production by destabilizing collagen mRNAs, disrupting osteogenic and epigenetic programs, and impairing cellular resilience. Our findings identify a novel homozygous TENT5A variant and demonstrate its pathogenic effect on osteoblast function and matrix mineralization, supporting the inclusion of TENT5A in diagnostic panels for unexplained skeletal fragility.
Guo et al. (Thu,) studied this question.