Schwarze U, Cundy T, Pyott SM, et al. Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen

Department of Pathology.
Human Molecular Genetics (Impact Factor: 6.39). 09/2012; 22(1). DOI: 10.1093/hmg/dds371
Source: PubMed


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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    • "In order to elucidate the detail mechanism of BS caused by FKBP10 and PLOD2 mutations, we should further analyze the molecular stability and post-translational modification of type I procollagen through culturing fibroblasts or osteoblasts of the patients with BS using Western blot analysis or immunocytochemical analysis of proteins. The C18 reverse-phase HPLC is helpful to complete quantitative analysis of the cross-link of type I collagen [15]. "
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    ABSTRACT: Bruck syndrome (BS) is an extremely rare form of osteogenesis imperfecta characterized by congenital joint contracture, multiple fractures and short stature. We described the phenotypes of BS in two Chinese patients for the first time. The novel compound heterozygous mutations c.764_772dupACGTCCTCC (p.255_257dupHisValLeu) in exon 5 and c.1405G>T (p.Gly469X) in exon 9 of FKBP10 were identified in one proband. The novel compound heterozygous mutations c.1624delT (p.Tyr542Thrfs*18) in exon 14 and c.1880T>C (p.Val627Ala) in exon 17 of PLOD2 were identified in another probrand. Intravenous zoledronate was a potent agent for these patients, confirmed the efficacy of bisphosphonates on this disease. In conclusion, the novel causative mutations identified in the patients expand the genotypic spectrum of BS.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "As such, these latter usually have a milder bone disorder than patients with osteoporosis pseudoglioma who have homozygous or compound heterozygous mutations in LRP5 and severe osteoporosis with visual disability [Hartikka et al., 2005]. b Recently, recessive mutations in FKBP10 have been described to cause (a) recessive OI most closely resembling OI type III or (b) Bruck syndrome type I [Schwarze et al., 2013]. "
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    ABSTRACT: Recently, the genetic heterogeneity in osteogenesis imperfecta (OI), proposed in 1979 by Sillence et al., has been confirmed with molecular genetic studies. At present, 17 genetic causes of OI and closely related disorders have been identified and it is expected that more will follow. Unlike most reviews that have been published in the last decade on the genetic causes and biochemical processes leading to OI, this review focuses on the clinical classification of OI and elaborates on the newly proposed OI classification from 2010, which returned to a descriptive and numerical grouping of five OI syndromic groups. The new OI nomenclature and the pre-and postnatal severity assessment introduced in this review, emphasize the importance of phenotyping in order to diagnose, classify, and assess severity of OI. This will provide patients and their families with insight into the probable course of the disorder and it will allow physicians to evaluate the effect of therapy. A careful clinical description in combination with knowledge of the specific molecular genetic cause is the starting point for development and assessment of therapy in patients with heritable disorders including OI. © 2014 The Authors. American Journal of Medical Genetics Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution–NonCommercial–NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
    Full-text · Article · Jun 2014 · American Journal of Medical Genetics Part A
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    • "PLOD2 and FKBP10 are also responsible for Bruck syndrome (BS; MIMs 259450, 609220), a recessive condition that in addition to bone fragility is also associated with congenital joint contractures [van der Slot et al., 2003; Ha-Vinh et al., 2004; Shaheen et al., 2010, 2011; Kelley et al., 2011]. As FKBP10 inactivation has been demonstrated to cause diminished collagen telopeptide lysyl hydroxylation, which is the function of PLOD2, it seems clear that defects in this biochemical process are tightly connected to the BS phenotype [Barnes et al., 2012; Schwarze et al., 2013]. "
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    ABSTRACT: Autosomal recessive osteogenesis imperfecta (AR-OI) is an inherited condition which in recent years has been shown with increasing genetic and clinical heterogeneity. In this article, we performed clinical assessment and sought mutations in patients from 10 unrelated families with AR-OI, one of whom was presented with the additional features of Bruck syndrome (BS). Pathogenic changes were identified in five different genes: three families had mutations in FKBP10, three in SERPINF1, two in LEPRE1, one in CRTAP, and one in PPIB. With the exception of a FKBP10 mutation in the BS case, all changes are novel. Of note, insertion of an AluYb8 repetitive element was detected in exon 6 of SERPINF1. Since the studied patients had variable manifestations and some distinctive features, genotype/phenotype correlations are suggested. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · Jun 2013 · American Journal of Medical Genetics Part A
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