TY - JOUR
T1 - Mutations in FKBp10, which result in bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen
AU - Schwarze, Ulrike
AU - Cundy, Tim
AU - Pyott, Shawna M.
AU - Christiansen, Helena E.
AU - Hegde, Madhuri R.
AU - Bank, Ruud A.
AU - Pals, Gerard
AU - Ankala, Arunkanth
AU - Conneely, Karen
AU - Seaver, Laurie
AU - Yandow, Suzanne M.
AU - Raney, Ellen
AU - Babovic-Vuksanovic, Dusica
AU - Stoler, Joan
AU - Ben-Neriah, Ziva
AU - Segel, Reeval
AU - Lieberman, Sari
AU - Siderius, Liesbeth
AU - Al-Aqeel, Aida
AU - Hannibal, Mark
AU - Hudgins, Louanne
AU - Mcpherson, Elizabeth
AU - Clemens, Michele
AU - Sussman, Michael D.
AU - Steiner, Robert D.
AU - Mahan, John
AU - Smith, Rosemarie
AU - Anyane-Yeboa, Kwame
AU - Wynn, Julia
AU - Chong, Karen
AU - Uster, Tami
AU - Aftimos, Salim
AU - Sutton, V. Reid
AU - Davis, Elaine C.
AU - Kim, Lammy S.
AU - Weis, Mary Ann
AU - Eyre, David
AU - Byers, Peter H.
N1 - Funding Information:
The studies on collagen cross-linking and mass spectral analyses were supported by NIH grants AR37694, AR37318 and HD22657 (to D.R.E.) and the Ernest M Burgess endowment of the University of Washington.
Funding Information:
We are grateful to all the families who took part and to the staff at the Molecular Genetics Laboratory and National Testing Centre at LabPlus, Auckland City Hospital, and to Dr Viali Lameko, the Tupua Tamasese Meaole National and Teaching Hospital, Samoa, and to Dr Rebecca Shine for their invaluable assistance. Partial support for the activities described here is derived from the Health Research Council of New Zealand, the Osteogenesis Imperfecta Foundation and the Freudmann Fund at the University of Washington.
PY - 2013/1
Y1 - 2013/1
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/dds371
DO - 10.1093/hmg/dds371
M3 - Article
C2 - 22949511
AN - SCOPUS:84871243967
SN - 0964-6906
VL - 22
SP - 1
EP - 17
JO - Human molecular genetics
JF - Human molecular genetics
IS - 1
M1 - dds371
ER -