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Connective tissue alterations in Fkbp10-/- mice
Caressa D Lietman1, Abbhirami Rajagopal1, Erica P Homan1
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Human Molecular Genetics
|April 30, 2014
Summary
Loss of FKBP65 protein causes brittle bone disorders like Osteogenesis Imperfecta (OI) and Bruck syndrome. FKBP65 is crucial for collagen development, and its absence leads to embryonic lethality and tissue fragility in mice.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Osteogenesis imperfecta (OI) and Bruck syndrome are inherited disorders causing bone fragility.
- FK506-binding protein 10 (FKBP10), encoding FKBP65, is implicated in recessive OI and Bruck syndrome.
- The precise role of FKBP65 in collagen synthesis and extracellular matrix formation remains unclear.
Purpose of the Study:
- To investigate the expression pattern of Fkbp10 during mouse development.
- To analyze the phenotypic consequences of Fkbp10 loss-of-function mutations.
- To elucidate the function of FKBP65 in collagen processing and connective tissue development.
Main Methods:
- Analysis of Fkbp10 gene expression in embryonic and postnatal mouse tissues.
- Generation and characterization of Fkbp10-deficient (Fkbp10(-/-)) mice.
- Biochemical analysis of Type I collagen crosslinking in Fkbp10(-/-) mice.
- Examination of procollagen processing and endoplasmic reticulum morphology in Fkbp10(-/-) fibroblasts.
Main Results:
- Fkbp10 expression is detected early in embryonic development, increasing through gestation and becoming restricted to bone and ligaments postnatally.
- Complete loss of Fkbp10 results in embryonic lethality in mice, with observed growth delay and tissue fragility.
- Collagen isolated from Fkbp10(-/-) embryos exhibits impaired crosslink formation.
- Fkbp10(-/-) fibroblasts display intracellular procollagen retention and endoplasmic reticulum dilation.
Conclusions:
- FKBP65 is essential for embryonic connective tissue development in mice.
- The loss of FKBP65 disrupts collagen maturation, leading to severe skeletal defects.
- The findings link FKBP65 function to the pathogenesis of OI and Bruck syndrome, particularly the bone fragility and contracture phenotypes observed in humans.
