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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
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, Volume 22, No. 1, Article dds371, Year 2013
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Description
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. © The Author 2012. Published by Oxford University Press. All rights reserved.
Authors & Co-Authors
Schwarze, Ulrike
Unknown Affiliation
Cundy, Tim F.
Unknown Affiliation
Pyott, Shawna M.
Unknown Affiliation
Christiansen, Helena E.
Unknown Affiliation
Hegde, Madhuri R.
Unknown Affiliation
Bank, Ruud A.
Unknown Affiliation
Pals, Gerard
Unknown Affiliation
Ankala, Arunkanth
Unknown Affiliation
Conneely, K. N.
Unknown Affiliation
Seaver, Laurie H.
Unknown Affiliation
Yandow, Suzanne M.
Unknown Affiliation
Raney, Ellen
Unknown Affiliation
Babović-Vuksanović, Dusica
Unknown Affiliation
Stoler, Joan Marilyn
Unknown Affiliation
Ben-Neriah, Ziva
Unknown Affiliation
Segel, Reeval
Unknown Affiliation
Lieberman, Sari
Unknown Affiliation
Siderius, Liesbeth
Unknown Affiliation
Al-Aqeel, Aida Imbrahim
Unknown Affiliation
Hannibal, Mark
Unknown Affiliation
Hudgins, Louanne M.
Unknown Affiliation
Mcpherson, Elizabeth
Unknown Affiliation
Clemens, Michele
Unknown Affiliation
Sussman, Michael D.
Unknown Affiliation
Steiner, Robert
Unknown Affiliation
Mahan, John D.
Unknown Affiliation
Smith, Rosemarie
Unknown Affiliation
Anyane-Yeboa, Kwame
Unknown Affiliation
Wynn, Julia
Unknown Affiliation
Chong, Karen
Unknown Affiliation
Uster, Tami
Unknown Affiliation
Aftimos, Salim
Unknown Affiliation
Sutton, Vernon Reid
Unknown Affiliation
Davis, Elaine C.
Unknown Affiliation
Kim, Lammy S.
Unknown Affiliation
Weis, Mary Ann
Unknown Affiliation
Eyre, David
Unknown Affiliation
Byers, Peter H.
Unknown Affiliation
Statistics
Citations: 123
Authors: 38
Affiliations: 23
Identifiers
Doi:
10.1093/hmg/dds371
ISSN:
09646906
e-ISSN:
14602083
Research Areas
Cancer
Maternal And Child Health
Violence And Injury
Study Design
Cohort Study