Calcified Tissue International

, Volume 102, Issue 3, pp 296–309 | Cite as

Novel Mutations in PLOD2 Cause Rare Bruck Syndrome

  • Fang Lv
  • Xiaojie Xu
  • Yuwen Song
  • Lujiao Li
  • Asan
  • Jian Wang
  • Huanming Yang
  • Ou Wang
  • Yan Jiang
  • Weibo Xia
  • Xiaoping Xing
  • Mei Li
Original Research

Abstract

Bruck syndrome is a rare autosomal recessive form of osteogenesis imperfecta (OI), which is mainly characterized by joint contractures and recurrent fragility fractures. Mutations in FKBP10 and PLOD2 were identified as the underlying genetic defects of Bruck syndrome. Here we investigated the phenotypes and the pathogenic mutations of three unrelated Chinese patients with Bruck syndrome. Clinical fractures, bone mineral density (BMD), bone turnover biomarkers, and skeletal images were evaluated in detail. The pathogenic mutations were identified by targeted next-generation sequencing and subsequently confirmed by Sanger sequencing and cosegregation analysis. We also evaluated the effects of zoledronic acid on bone fracture incidence and BMD of the patients. Three patients had congenital joint contractures, recurrent fragility fractures, camptodactyly, clubfoot, scoliosis, but without dentinogenesis imperfecta and hearing loss. Five novel heterozygous mutations were detected in PLOD2, including three heterozygous missense mutations (c.1138C>T, p.Arg380Cys; c.1153T>C, p.Cys385Arg; and c.1982G>A, p.Gly661Asp), one heterozygous nonsense mutation (c.2038C>T, p.Arg680X), and one heterozygous splice-site mutation (c.503-2A>G). Their parents were all heterozygous carriers of these mutations in PLOD2. No clear genotype–phenotype correlations were found in these patients with PLOD2 mutations. Z-score of BMD was significantly increased, but scoliosis progressed and new bone fractures occurred during the treatment of zoledronic acid. Our findings expanded the spectrum of gene mutations of Bruck syndrome.

Keywords

Bruck syndrome Osteogenesis imperfecta PLOD2 mutations 

Notes

Acknowledgements

We thank the staff at the radiology department, Peking Union Medical College Hospital for measurement of bone mineral density and interpretation of radiographs. We also thank the patients with PLOD2 mutations and their families for participation in this research and thank all unaffected, unrelated individuals for providing control DNA samples.

Compliance with Ethical Standards

Conflict of interest

Fang Lv, Xiaojie Xu, Yuwen Song, Lujiao Li, Asan, Jian Wang, Huanming Yang, Ou Wang, Yan Jiang, Weibo Xia, Xiaoping Xing, and Mei Li state that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

The study was approved by the Medical Ethics Committee of the PUMCH and written consent was obtained from all patients who responded and were included in the study.

Supplementary material

223_2017_360_MOESM1_ESM.ppt (173 kb)
Supplementary material 1 (PPT 173 kb)
223_2017_360_MOESM2_ESM.doc (26 kb)
Supplementary material 2 (DOC 26 kb)

References

  1. 1.
    Breslau-Siderius EJ, Engelbert RH, Pals G, van der Sluijs JA (1998) Bruck syndrome: a rare combination of bone fragility and multiple congenital joint contractures. J Pediatr Orthop B 7:35–38CrossRefPubMedGoogle Scholar
  2. 2.
    Caparros-Martin JA, Aglan MS, Temtamy S, Otaify GA, Valencia M, Nevado J, Vallespin E, Del Pozo A, Prior de Castro C, Calatrava-Ferreras L, Gutierrez P, Bueno AM, Sagastizabal B, Guillen-Navarro E, Ballesta-Martinez M, Gonzalez V, Basaran SY, Buyukoglan R, Sarikepe B, Espinoza-Valdez C, Cammarata-Scalisi F, Martinez-Glez V, Heath KE, Lapunzina P, Ruiz-Perez VL (2016) Molecular spectrum and differential diagnosis in patients referred with sporadic or autosomal recessive osteogenesis imperfecta. Mol Genet Genom Med 5:28–39CrossRefGoogle Scholar
  3. 3.
    Ha-Vinh R, Alanay Y, Bank RA, Campos-Xavier AB, Zankl A, Superti-Furga A, Bonafé L (2004) Phenotypic and molecular characterization of Bruck syndrome (osteogenesis imperfecta with contractures of the large joints) caused by a recessive mutation in PLOD2. Am J Med Genet A 131:115–120CrossRefPubMedGoogle Scholar
  4. 4.
    Zhou P, Liu Y, Lv F, Nie M, Jiang Y, Wang O, Xia W, Xing X, Li M (2014) Novel mutations in FKBP10 and PLOD2 cause rare Bruck syndrome in Chinese patients. PLoS ONE 9:e107594CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Hyry M, Lantto J, Myllyharju J (2009) Missense mutations that cause Bruck syndrome affect enzymatic activity, folding, and oligomerization of lysyl hydroxylase 2. J Biol Chem 284:30917–30924CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    van der Slot AJ, Zuurmond AM, Bardoel AF, Wijmenga C, Pruijs HE, Sillence DO, Brinckmann J, Abraham DJ, Black CM, Verzijl N, DeGroot J, Hanemaaijer R, TeKoppele JM, Huizinga TW, Bank RA (2003) Identification of PLOD2 as telopeptide lysyl hydroxylase, an important enzyme in fibrosis. J Biol Chem 278:40967–40972CrossRefPubMedGoogle Scholar
  7. 7.
    Puig-Hervás MT, Temtamy S, Aglan M, Valencia M, Martínez-Glez V, Ballesta-Martínez MJ, López-González V, Ashour AM, Amr K, Pulido V, Guillén-Navarro E, Lapunzina P, Caparrós-Martín JA, Ruiz-Perez VL (2012) Mutations in PLOD2 cause autosomal-recessive connective tissue disorders within the Bruck syndrome–osteogenesis imperfecta phenotypic spectrum. Hum Mutat 33:1444–1449CrossRefPubMedGoogle Scholar
  8. 8.
    Bank RA, Robins SP, Wijmenga C, Breslau-Siderius LJ, Bardoel AF, van der Sluijs HA, Pruijs HE, TeKoppele JM (1999) Defective collagen crosslinking in bone, but not in ligament or cartilage, in Bruck syndrome: indications for a bone-specific telopeptide lysyl hydroxylase on chromosome 17. Proc Natl Acad Sci U S A 96:1054–1058CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    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. Hum Mol Genet 22:1–17CrossRefPubMedGoogle Scholar
  10. 10.
    Alanay Y, Avaygan H, Camacho N, Utine GE, Boduroglu K, Aktas D, Alikasifoglu M, Tuncbilek E, Orhan D, Bakar FT, Zabel B, Superti-Furga A, Bruckner-Tuderman L, Curry CJ, Pyott S, Byers PH, Eyre DR, Baldridge D, Lee B, Merrill AE, Davis EC, Cohn DH, Akarsu N, Krakow D (2010) Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta. Am J Hum Genet 86:551–559CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Duran I, Martin JH, Weis MA, Krejci P, Konik P, Li B, Alanay Y, Lietman C, Lee B, Eyre D, Cohn DH, Krakow D (2017) A chaperone complex formed by HSP47, FKBP65, and BiP modulates telopeptide lysyl hydroxylation of Type I procollagen. J Bone Miner Res.  https://doi.org/10.1002/jbmr.3095 PubMedGoogle Scholar
  12. 12.
    Lietman CD, Lim J, Grafe I, Chen Y, Ding H, Bi X, Ambrose CG, Fratzl-Zelman N, Roschger P, Klaushofer K, Wagermaier W, Schmidt I, Fratzl P, Rai J, Weis M, Eyre D, Keene DR, Krakow D, Lee BH (2017) Fkbp10 deletion in osteoblasts leads to qualitative defects in bone. J Bone Miner Res.  https://doi.org/10.1002/jbmr.3108 Google Scholar
  13. 13.
    Li H, Ji CY, Zong XN, Zhang YQ (2009) Height and weight standardized growth charts for Chinese children and adolescents aged 0 to 18 years. Zhonghua Er Ke Za Zhi 47:487–492PubMedGoogle Scholar
  14. 14.
    Khadilkar AV, Sanwalka NJ, Chiplonkar SA, Khadilkar VV, Mughal MZ (2011) Normative data and percentile curves for dual energy X-ray absorptiometry in healthy Indian girls and boys aged 5–17 years. Bone 48:810–819CrossRefPubMedGoogle Scholar
  15. 15.
    Li M, Lv F, Zhang Z, Deng W, Li Y, Deng Z, Jiang Y, Wang O, Xing X, Xu L, Xia W (2016) Establishment of a normal reference value of parathyroid hormone in a large healthy Chinese population and evaluation of its relation to bone turnover and bone mineral density. Osteoporos Int 27:1907–1916CrossRefPubMedGoogle Scholar
  16. 16.
    Liu Y, Ma D, Asan, Lv F, Xu X, Wang J, Xia W, Jiang Y, Wang O, Xing X, Yu W, Wang J, Sun J, Song L, Zhu Y, Yang H, Wang J, Li M (2017) Gene mutation spectrum and genotype-phenotype correlation in a cohort of Chinese osteogenesis imperfecta patients revealed by targeted next generation sequencing. Osteoporos Int.  https://doi.org/10.1007/s00198-017-4143-8 Google Scholar
  17. 17.
    Sule G, Campeau PM, Zhang VW, Nagamani SC, Dawson BC, Grover M, Bacino CA, Sutton VR, Brunetti-Pierri N, Lu JT, Lemire E, Gibbs RA, Cohn DH, Cui H, Wong LJ, Lee BH (2013) Next-generation sequencing for disorders of low and high bone mineral density. Osteoporos Int 24:2253–2259CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Viljoen D, Versfeld G, Beighton P (1989) Osteogenesis imperfecta with congenital joint contractures (Bruck syndrome). Clin Genet 36:122–126CrossRefPubMedGoogle Scholar
  19. 19.
    Moravej H, Karamifar H, Karamizadeh Z, Amirhakimi G, Atashi S, Nasirabadi S (2015) Bruck syndrome—a rare syndrome of bone fragility and joint contracture and novel homozygous FKBP10 mutation. Endokrynol Pol 66:170–174CrossRefPubMedGoogle Scholar
  20. 20.
    Setijowati ED, van Dijk FS, Cobben JM, van Rijn RR, Sistermans EA, Faradz SM, Kawiyana S, Pals G (2012) A novel homozygous 5 bp deletion in FKBP10 causes clinically Bruck syndrome in an Indonesian patient. Eur J Med Genet 55:17–21CrossRefPubMedGoogle Scholar
  21. 21.
    Takaluoma K, Lantto J, Myllyharju J (2007) Lysyl hydroxylase 2 is a specific telopeptide hydroxylase, while all three isoenzymes hydroxylate collagenous sequences. Matrix Biol 26:396–403CrossRefPubMedGoogle Scholar
  22. 22.
    Walker LC, Overstreet MA, Yeowell HN (2005) Tissue-specific expression and regulation of the alternatively-spliced forms of lysyl hydroxylase 2 (LH2) in human kidney cells and skin fibroblasts. Matrix Biol 23:515–523CrossRefPubMedGoogle Scholar
  23. 23.
    Yeowell HN, Walker LC (1999) Tissue specificity of a new splice form of the human lysyl hydroxylase 2 gene. Matrix Biol 18:179–187CrossRefPubMedGoogle Scholar
  24. 24.
    Eyre DR, Weis MA (2013) Bone collagen: new clues to its mineralization mechanism from recessive osteogenesis imperfecta. Calcif Tissue Int 93:338–347CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Mercer DK, Nicol PF, Kimbembe C, Robins SP (2003) Identification, expression, and tissue distribution of the three rat lysyl hydroxylase isoforms. Biochem Biophys Res Commun 307:803–809CrossRefPubMedGoogle Scholar
  26. 26.
    Pornprasertsuk S, Duarte WR, Mochida Y, Yamauchi M (2004) Lysyl hydroxylase-2b directs collagen cross-linking pathways in MC3T3-E1 cells. J Bone Miner Res 19:1349–1355CrossRefPubMedGoogle Scholar
  27. 27.
    Gistelinck C, Witten PE, Huysseune A, Symoens S, Malfait F, Larionova D, Simoens P, Dierick M, Van Hoorebeke L, De Paepe A, Kwon RY, Weis M, Eyre DR, Willaert A, Coucke PJ (2016) Loss of type I collagen telopeptide lysyl hydroxylation causes musculoskeletal abnormalities in a zebrafish model of Bruck Syndrome. J Bone Miner Res 31:1930–1942CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Dwan K, Phillipi CA, Steiner RD, Basel D (2016) Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database Syst Rev.  https://doi.org/10.1002/14651858.CD005088.pub2 Google Scholar
  29. 29.
    Trejo P, Rauch F (2016) Osteogenesis imperfecta in children and adolescents-new developments in diagnosis and treatment. Osteoporos Int 27:3427–3437CrossRefPubMedGoogle Scholar
  30. 30.
    Otaify GA, Aglan MS, Ibrahim MM, Elnashar M, El Banna RA, Temtamy SA (2016) Zoledronic acid in children with osteogenesis imperfecta and Bruck syndrome: a 2-year prospective observational study. Osteoporos Int 27:81–92CrossRefPubMedGoogle Scholar
  31. 31.
    Xu XJ, Lv F, Liu Y, Wang JY, Ma DD, Wang JW, Asan, Song LJ, Jiang Y, Wang O, Xia WB, Xing XP, Li M (2017) Novel mutations in FKBP10 in Chinese patients with osteogenesis imperfecta and their treatment with zoledronic acid. J Hum Genet 62:205–211CrossRefPubMedGoogle Scholar
  32. 32.
    Lv F, Xu XJ, Wang JY, Liu Y, Wang JW, Asan, Song LJ, Song YW, Jiang Y, Wang O, Xia WB, Xing XP, Li M (2016) Two novel mutations in TMEM38B result in rare autosomal recessive osteogenesis imperfecta. J Hum Genet 61:539–545CrossRefPubMedGoogle Scholar
  33. 33.
    Liu Y, Song L, Ma D, Lv F, Xu X, Wang J, Xia W, Jiang Y, Wang O, Song Y, Xing X, Li M, Asan (2016) Genotype-phenotype analysis of a rare type of osteogenesis imperfecta in four Chinese families with WNT1 mutations. Clin Chim Acta 461:172–180CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • Fang Lv
    • 1
  • Xiaojie Xu
    • 1
  • Yuwen Song
    • 1
  • Lujiao Li
    • 1
  • Asan
    • 2
    • 3
    • 4
  • Jian Wang
    • 2
    • 3
    • 4
  • Huanming Yang
    • 2
    • 3
    • 4
  • Ou Wang
    • 1
  • Yan Jiang
    • 1
  • Weibo Xia
    • 1
  • Xiaoping Xing
    • 1
  • Mei Li
    • 1
  1. 1.Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical CollegeChinese Academy of Medical ScienceBeijingChina
  2. 2.Binhai Genomics InstituteBGI-Tianjin, BGI-ShenzhenTianjinChina
  3. 3.Tianjin Enterprise Key Laboratory of Clinical Molecular DiagnosticBGI-ShenzhenTianjinChina
  4. 4.BGI-ShenzhenShenzhenChina

Personalised recommendations