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In Vivo Modeling of the Morbid Human Genome using Danio rerio
Published on: August 24, 2013
Novel FKBP10 Mutation in Iranian Patients with Osteogenesis Imperfecta: Insights from Whole-Exome Sequencing to
Moslem Hoseinbeyki1, Shirin Moradifard1, Fatemeh Mirkhani1
1Biochemistry Department, Pasteur Institute of Iran, Tehran, Iran.
Background:
Osteogenesis imperfecta 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. 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. 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.
