Статья

Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen

U. SchwarzeDepartment of Pathology, University of Washington, Seattle, WA 98195-7470, USATim CundyDepartment of Medicine, University of Auckland, Auckland, NZ, USAShawna M. PyottH. E. ChristiansenMadhuri HegdeDepartment of Human Genetics, Emory University, Atlanta, GA, USARuud A. BankDepartment of Medical Biology, University Medical Center Groningen, Groningen, Netherlands,Gerard PalsDepartment of Clinical Genetics, VU Medical Center, Amsterdam, Netherlands,Arunkanth AnkalaDepartment of Human Genetics, Emory University, Atlanta, GA, USAKaren N. ConneelyDepartment of Human Genetics, Emory University, Atlanta, GA, USALaurie H. SeaverDepartment of Pediatrics, John A. Burns School of Medicine, Honolulu, HI, USASuzanne M. YandowDepartment of Pediatrics, John A. Burns School of Medicine, Honolulu, HI, USAEllen M. RaneyDepartment of Pediatrics, John A. Burns School of Medicine, Honolulu, HI, USADusica Babovic‐VuksanovicDivision of Medical Genetics, Mayo Clinic, Rochester, MN, USA,Joan M. StolerDivision of Genetics, Children's Hospital, Boston, MA, USA,Ziva Ben‐NeriahHadassah University Hospital, Jerusalem, Israel,Reeval SegelHadassah University Hospital, Jerusalem, Israel,Sari LiebermanMedical Genetics Institute, Shaare Zedek Medical Center and Hebrew University, Jerusalem, Israel,Liesbeth SideriusYouth Health Care, Meppel, Netherlands,Aida I. Al‐AqeelDepartment of Pediatrics, Riyadh Armed Forces Hospital, Riyadh, Saudi Arabia,Mark HannibalDepartment of Pediatrics, University of Washington, Seattle, WA, USALucas HudginsDepartment of Pediatrics, University of Washington, Seattle, WA, USAElizabeth McPhersonWest Penn Hospital, Pittsburgh, PA, USA,Michele ClemensWest Penn Hospital, Pittsburgh, PA, USA,Michael D. SussmanShriners Hospital, Portland, OR, USA,Robert D. SteinerDepartment of Pediatrics, Oregon Health and Sciences University, Portland, OR, USA,John D. MahanNationwide Children's Hospital, Columbus, OH, USA,Rosemarie SmithDivision of Genetics, Department of Pediatrics, Maine Medical Center, Portland, ME, USA,Kwame Anyane‐YeboaDepartment of Pediatrics, Columbia University Medical Center, New York, NY, USA,Julia WynnDepartment of Pediatrics, Columbia University Medical Center, New York, NY, USA,Karen ChongMt. Sinai Hospital, Toronto, Ontario, Canada,Tami UsterMt. Sinai Hospital, Toronto, Ontario, Canada,Salim AftimosV. Reid SuttonDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA andElise DavisDepartment of Cell Biology, McGill University, Montreal, Quebec, CanadaIn S. KimMary Ann WeisDavid R. EyrePeter H. Byers

2012en

ABI

Аннотация

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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Идентификаторы

DOI: 10.1093/hmg/dds371

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Цитирований: 2Использованных источников: 0

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