Iranian Biomedical Journal

en Novel FKBP10 Mutation in Iranian Patients with Osteogenesis Imperfecta: Insights from Whole-Exome Sequencing to Molecular Dynamics Molecular Genetics & Genomics Molecular Genetics & Genomics مقاله کامل Full Length/Original Article <div style="text-align: justify;">Background: Osteogenesis imperfecta (OI) is a rare hereditary disorder affecting bone and connective tissue. While most cases are linked to autosomal dominant mutations in the COL1A1 and COL1A2 genes, FKBP10 variants are associated with the autosomal recessive form of OI, type XI. The study represents the first cohort-based evaluation of the FKBP10 mutational spectrum in Iranian patients, leading to the discovery of a novel variant. Methods: Thirty Iranian patients clinically diagnosed with OI were enrolled for genetic analysis. Whole-exome sequencing (WES) was performed to identify pathogenic variants, validated by PCR and sanger sequencing in patients and their parents. To explore the biological relevance of the identified variants, we constructed PPI networks and performed functional enrichment analysis using the ClueGO plugin. Molecular dynamics (MD) simulations with GROMACS were used to assess the structural impact of the mutations. Results: Among 30 families, four exhibited pathogenic FKBP10 variants. Three patients were homozygous for the previously reported mutation c.831dupC: p.G278Rfs95), while the fourth harbored a novel homozygous deletion (c.855_859del: p. G286Lfs84). Network analysis revealed significant involvement of CRTAP, IFITM5, SERPINF1, PPIB, FKBP10, P3H1, SERPINH1, and PLOD2 in collagen-related pathways. Computational modeling and MD simulations indicated reduced flexibility and more compact folding in the mutant FKBP10 protein, which aligns with impaired protein function and defective collagen processing.  Conclusion: This study reports a novel FKBP10 variant and presents the first cohort-based analysis of FKBP10 mutations in Iranian patients with OI. It demonstrates the value of combining WES with computational modeling to elucidate the molecular mechanisms underlying OI. </div> FKBP10 protein, Frameshift mutation, Exome sequencing, Osteogenesis imperfecta 437 450 http://ibj.pasteur.ac.ir/browse.php?a_code=A-10-576-2&slc_lang=en&sid=1 Moslem Hoseinbeyki hoseinbeyki@yahoo.com 0009-0008-6199-9395 No Biochemistry Department, Pasteur Institute of Iran Shirin Moradifard moradifard_sh70@yahoo.com 0009-0000-0778-2998 No Biochemistry Department, Pasteur Institute of Iran Fatemeh Mirkhani afsanehmirkhani@yahoo.com No Biochemistry Department, Pasteur Institute of Iran Fatemeh Sadat Shariati fshareati@yahoo.com 0000-0002-9920-9431 No Biochemistry Department, Pasteur Institute of Iran Parastoo Ehsani P_ehsani@yahoo.com 0000-0003-3592-2008 No Molecular Biology Department, Pasteur Institute of Iran, Tehran, Iran. Mohammad Reza Alaei Alaee2003@yahoo.com 0000-0002-9920-9431 Yes Department of Pediatric Endocrinology and Metabolism, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences Mina Ebrahimi-Rad* minebrad@pasteur.ac.ir 0000-0002-4208-2206 No Biochemistry Department, Pasteur Institute of Iran