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


Alanay Y. , Avaygan H., Camacho N., ÜTİNE G. E. , Boduroglu K., Aktas D., ...More

AMERICAN JOURNAL OF HUMAN GENETICS, vol.86, no.4, pp.551-559, 2010 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 86 Issue: 4
  • Publication Date: 2010
  • Doi Number: 10.1016/j.ajhg.2010.02.022
  • Title of Journal : AMERICAN JOURNAL OF HUMAN GENETICS
  • Page Numbers: pp.551-559

Abstract

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.