Mutations in FKBp10, which result in bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen

Ulrike Schwarze, Tim Cundy, Shawna M. Pyott, Helena E. Christiansen, Madhuri R. Hegde, Ruud A. Bank, Gerard Pals, Arunkanth Ankala, Karen Conneely, Laurie Seaver, Suzanne M. Yandow, Ellen Raney, Dusica Babovic-Vuksanovic, Joan Stoler, Ziva Ben-Neriah, Reeval Segel, Sari Lieberman, Liesbeth Siderius, Aida Al-Aqeel, Mark HannibalLouanne Hudgins, Elizabeth Mcpherson, Michele Clemens, Michael D. Sussman, Robert D. Steiner, John Mahan, Rosemarie Smith, Kwame Anyane-Yeboa, Julia Wynn, Karen Chong, Tami Uster, Salim Aftimos, V. Reid Sutton, Elaine C. Davis, Lammy S. Kim, Mary Ann Weis, David Eyre, Peter H. Byers

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92 Scopus citations

Abstract

Although biallelic mutations in non-collagen genes account for <10% of individuals with osteogenesis imperfecta, the characterization of these genes has identified new pathways and potential interventions that could benefit even those with mutations in type I collagen genes. We identified mutations in FKBP10, which encodes the 65 kDa prolyl cis-trans isomerase, FKBP65, in 38 members of 21 families with OI. These include 10 families from the Samoan Islands who share a founder mutation. Of the mutations, three are missense; the remainder either introduce premature termination codons or create frameshifts both of which result in mRNA instability. In four families missense mutations result in loss of most of the protein. The clinical effects of these mutations are short stature, a high incidence of joint contractures at birth and progressive scoliosis and fractures, but there is remarkable variability in phenotype even within families. The loss of the activity of FKBP65 has several effects: type I procollagen secretion is slightly delayed, the stabilization of the intact trimer is incomplete and there is diminished hydroxylation of the telopeptide lysyl residues involved in intermolecular cross-link formation in bone. The phenotype overlaps with that seen with mutations in PLOD2 (Bruck syndrome II), which encodes LH2, the enzyme that hydroxylates the telopeptide lysyl residues. These findings define a set of genes, FKBP10, PLOD2 and SERPINH1, that act during procollagen maturation to contribute to molecular stability and post-translational modification of type I procollagen, without which bone mass and quality are abnormal and fractures and contractures result.

Original languageEnglish (US)
Article numberdds371
Pages (from-to)1-17
Number of pages17
JournalHuman molecular genetics
Volume22
Issue number1
DOIs
StatePublished - Jan 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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