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Published January 1, 2010 | Version v1
Journal article Open

Mutations in the Gene Encoding the RER Protein FKBP65 Cause Autosomal-Recessive Osteogenesis Imperfecta

Creators

  • 1. Hacettepe Univ, Fac Med, Pediat Genet Unit, Dept Pediat, TR-06100 Ankara, Turkey
  • 2. Univ Calif Los Angeles, David Geffen Sch Med, Dept Orthopaed Surg, Los Angeles, CA 90095 USA
  • 3. Hacettepe Univ, Fac Med, Pediat Pathol Unit, TR-06100 Ankara, Turkey
  • 4. Yeditepe Univ, Dept Pediat, TR-34755 Istanbul, Turkey
  • 5. Univ Freiburg, Ctr Pediat & Adolescent Med, D-79106 Freiburg, Germany
  • 6. Univ Freiburg, Dept Dermatol, D-79106 Freiburg, Germany
  • 7. Cent Calif, Genet Med, Fresno, CA 93710 USA
  • 8. Univ Washington, Dept Pathol, Seattle, WA 98195 USA
  • 9. Univ Washington, Dept Orthopaed & Sports Med, Seattle, WA 98195 USA
  • 10. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

Description

Osteogenesis imperfecta is a clinically and genetically heterogeneous brittle bone disorder that results from defects in the synthesis, structure, or posttranslational modification of type I procollagen. Dominant forms of OI result from mutations in COL1A1 or COL1A2, which encode the chains of the type I procollagen heterotrimer. The mildest form of OI typically results from diminished synthesis of structurally normal type 1 procollagen, whereas moderately severe to lethal forms of OI usually result from structural defects in one of the type 1 procollagen chains. Recessively inherited OI, usually phenotypically severe, has recently been shown to result from defects in the prolyl-3-hydroxylase complex that lead to the absence of a single 3-hydroxyproline at residue 986 of the alpha 1 (I) triple helical domain. We studied a cohort of five consanguineous Turkish families, originating from the Black Sea region of Turkey, with moderately severe recessively inherited OI and identified a novel locus for OI on chromosome 17. In these families, and in a Mexican-American family, homozygosity for mutations in FKBP10, which encodes FKBP65, a chaperone that participates in type 1 procollagen folding, was identified. Further, we determined that FKBP10 mutations affect type I procollagen secretion. These findings identify a previously unrecognized mechanism in the pathogenesis of OI.

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