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 Hannibal & 18 others Louanne 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

Research output: Contribution to journalArticle

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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 1 2013

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Osteogenesis Imperfecta
Hydroxylation
Lysine
Collagen
Bone and Bones
Mutation
Collagen Type I
Contracture
Missense Mutation
Genes
Samoa
cis-trans-Isomerases
Peptidylprolyl Isomerase
Phenotype
Procollagen
Nonsense Codon
RNA Stability
Scoliosis
Post Translational Protein Processing
Osteogenesis

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Mutations in FKBp10, which result in bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen. / Schwarze, Ulrike; Cundy, Tim; Pyott, Shawna M.; Christiansen, Helena E.; Hegde, Madhuri R.; Bank, Ruud A.; Pals, Gerard; Ankala, Arunkanth; Conneely, Karen; Seaver, Laurie; Yandow, Suzanne M.; Raney, Ellen; Babovic-Vuksanovic, Dusica; Stoler, Joan; Ben-Neriah, Ziva; Segel, Reeval; Lieberman, Sari; Siderius, Liesbeth; Al-Aqeel, Aida; Hannibal, Mark; Hudgins, Louanne; Mcpherson, Elizabeth; Clemens, Michele; Sussman, Michael D.; Steiner, Robert D.; Mahan, John; Smith, Rosemarie; Anyane-Yeboa, Kwame; Wynn, Julia; Chong, Karen; Uster, Tami; Aftimos, Salim; Sutton, V. Reid; Davis, Elaine C.; Kim, Lammy S.; Weis, Mary Ann; Eyre, David; Byers, Peter H.

In: Human Molecular Genetics, Vol. 22, No. 1, dds371, 01.01.2013, p. 1-17.

Research output: Contribution to journalArticle

Schwarze, U, Cundy, T, Pyott, SM, Christiansen, HE, Hegde, MR, Bank, RA, Pals, G, Ankala, A, Conneely, K, Seaver, L, Yandow, SM, Raney, E, Babovic-Vuksanovic, D, Stoler, J, Ben-Neriah, Z, Segel, R, Lieberman, S, Siderius, L, Al-Aqeel, A, Hannibal, M, Hudgins, L, Mcpherson, E, Clemens, M, Sussman, MD, Steiner, RD, Mahan, J, Smith, R, Anyane-Yeboa, K, Wynn, J, Chong, K, Uster, T, Aftimos, S, Sutton, VR, Davis, EC, Kim, LS, Weis, MA, Eyre, D & Byers, PH 2013, 'Mutations in FKBp10, which result in bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen', Human Molecular Genetics, vol. 22, no. 1, dds371, pp. 1-17. https://doi.org/10.1093/hmg/dds371
Schwarze, Ulrike ; Cundy, Tim ; Pyott, Shawna M. ; Christiansen, Helena E. ; Hegde, Madhuri R. ; Bank, Ruud A. ; Pals, Gerard ; Ankala, Arunkanth ; Conneely, Karen ; Seaver, Laurie ; Yandow, Suzanne M. ; Raney, Ellen ; Babovic-Vuksanovic, Dusica ; Stoler, Joan ; Ben-Neriah, Ziva ; Segel, Reeval ; Lieberman, Sari ; Siderius, Liesbeth ; Al-Aqeel, Aida ; Hannibal, Mark ; Hudgins, Louanne ; Mcpherson, Elizabeth ; Clemens, Michele ; Sussman, Michael D. ; Steiner, Robert D. ; Mahan, John ; Smith, Rosemarie ; Anyane-Yeboa, Kwame ; Wynn, Julia ; Chong, Karen ; Uster, Tami ; Aftimos, Salim ; Sutton, V. Reid ; Davis, Elaine C. ; Kim, Lammy S. ; Weis, Mary Ann ; Eyre, David ; Byers, Peter H. / Mutations in FKBp10, which result in bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen. In: Human Molecular Genetics. 2013 ; Vol. 22, No. 1. pp. 1-17.
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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.",
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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.

PY - 2013/1/1

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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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