title: Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen.
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.
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195-7470, USA.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schwarze
authors.forename: Tim
authors.initials: T
authors.lastname: Cundy
authors.forename: Shawna M
authors.initials: SM
authors.lastname: Pyott
authors.forename: Helena E
authors.initials: HE
authors.lastname: Christiansen
authors.forename: Madhuri R
authors.initials: MR
authors.lastname: Hegde
authors.forename: Ruud A
authors.initials: RA
authors.lastname: Bank
authors.forename: Gerard
authors.initials: G
authors.lastname: Pals
authors.forename: Arunkanth
authors.initials: A
authors.lastname: Ankala
authors.forename: Karen
authors.initials: K
authors.lastname: Conneely
authors.forename: Laurie
authors.initials: L
authors.lastname: Seaver
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Yandow
authors.forename: Ellen
authors.initials: E
authors.lastname: Raney
authors.forename: Dusica
authors.initials: D
authors.lastname: Babovic-Vuksanovic
authors.forename: Joan
authors.initials: J
authors.lastname: Stoler
authors.forename: Ziva
authors.initials: Z
authors.lastname: Ben-Neriah
authors.forename: Reeval
authors.initials: R
authors.lastname: Segel
authors.forename: Sari
authors.initials: S
authors.lastname: Lieberman
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Siderius
authors.forename: Aida
authors.initials: A
authors.lastname: Al-Aqeel
authors.forename: Mark
authors.initials: M
authors.lastname: Hannibal
authors.forename: Louanne
authors.initials: L
authors.lastname: Hudgins
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McPherson
authors.forename: Michele
authors.initials: M
authors.lastname: Clemens
authors.forename: Michael D
authors.initials: MD
authors.lastname: Sussman
authors.forename: Robert D
authors.initials: RD
authors.lastname: Steiner
authors.forename: John
authors.initials: J
authors.lastname: Mahan
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Smith
authors.forename: Kwame
authors.initials: K
authors.lastname: Anyane-Yeboa
authors.forename: Julia
authors.initials: J
authors.lastname: Wynn
authors.forename: Karen
authors.initials: K
authors.lastname: Chong
authors.forename: Tami
authors.initials: T
authors.lastname: Uster
authors.forename: Salim
authors.initials: S
authors.lastname: Aftimos
authors.forename: V Reid
authors.initials: VR
authors.lastname: Sutton
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Davis
authors.forename: Lammy S
authors.initials: LS
authors.lastname: Kim
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Weis
authors.forename: David
authors.initials: D
authors.lastname: Eyre
authors.forename: Peter H
authors.initials: PH
authors.lastname: Byers
mesh_terms: D001176:Arthrogryposis / Q000235:genetics*; D024042:Collagen Type I / Q000378:metabolism*; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D006900:Hydroxylation; D008239:Lysine / Q000378:metabolism*; D008297:Male; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D011499:Protein Processing, Post-Translational; D022021:Tacrolimus Binding Proteins / Q000235:genetics*
chemical_list: D024042:Collagen Type I; D022021:Tacrolimus Binding Proteins; C110054:FKBP10 protein, human; D008239:Lysine