TENT5A-associated osteogenesis imperfecta: long-term follow-up and molecular insights

Stefanie Stasek; Frank Zaucke; Alice Stephan; Julia Etich; Matthias Mörgelin; Ulrich Baumann; Mirko Rehberg; Susanna Reincke; Oliver Semler; Heike Hoyer-Kuhn

doi:10.1093/jbmrpl/ziaf083

TENT5A-associated osteogenesis imperfecta: long-term follow-up and molecular insights

JBMR Plus. 2025 May 11;9(7):ziaf083. doi: 10.1093/jbmrpl/ziaf083. eCollection 2025 Jul.

Authors

Affiliations

¹ Department of Pediatric and Adolescent Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.
² Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Department of Trauma Surgery and Orthopedics, University Hospital, Goethe University Frankfurt, 60590 Frankfurt/Main, Germany.
³ Colzyx AB, Medicon Village, SE-223 63 Lund, Sweden.
⁴ Department of Chemistry, Institute of Biochemistry, University of Cologne, 50674 Cologne, Germany.

Abstract

OI is a genetically diverse disorder characterized by bone fragility and deformities, with most cases attributed to dominant mutations in collagen I-related genes. However, mutations in TENT5A, encoding a poly(A) polymerase, have recently been implicated in severe, recessive forms of OI. We reported 3 individuals from a consanguineous family with a novel homozygous TENT5A variant (c.672G>T, p.Arg224Ser). Our patients presented with severe bone fragility, generalized osteopenia, skeletal deformities, short stature, and early wheelchair dependence. Patient-derived fibroblasts demonstrated impaired collagen secretion and disorganized fibril network formation. Our findings provide new insights into the complex pathophysiology of TENT5A-associated OI and underscore the need for further research into its role in skeletal homeostasis.

Keywords: FAM46a; bisphosphonates; collagen I; growth hormone deficiency; skeletal dysplasias.