Osteoporosis International

, Volume 29, Issue 6, pp 1389–1396 | Cite as

Novel compound heterozygous mutations in SERPINH1 cause rare autosomal recessive osteogenesis imperfecta type X

  • Y. Song
  • D. Zhao
  • X. Xu
  • F. Lv
  • L. Li
  • Y. Jiang
  • O. Wang
  • W. Xia
  • X. Xing
  • M. LiEmail author
Original Article



We identified novel compound heterozygous mutations in SERPINH1 in a Chinese boy suffering from recurrent fractures, femoral deformities, and growth retardation, which resulted in extremely rare autosomal recessive OI type X. Long-term treatment of BPs was effective in increasing BMD Z-score, reducing fracture incidence and reshaping vertebrae compression.


Osteogenesis imperfecta (OI) is a heritable bone disorder characterized by low bone mineral density, recurrent fractures, and progressive bone deformities. Mutation in serpin peptidase inhibitor clade H, member 1 (SERPINH1), which encodes heat shock protein 47 (HSP47), leads to rare autosomal recessive OI type X. We aimed to detect the phenotype and the pathogenic mutation of OI type X in a boy from a non-consanguineous Chinese family.


We investigated the pathogenic mutations and analyzed their relationship with the phenotype in the patient using next-generation sequencing (NGS) and Sanger sequencing. Moreover, the efficacy of long-term bisphosphonate treatment in this patient was evaluated.


The patient suffered from multiple fractures, low bone mass, and bone deformities in the femur, without dentinogenesis imperfecta or hearing loss. Compound heterozygous variants were found in SERPINH1 as follows: c.149 T>G in exon 2 and c.1214G>A in exon 5. His parents were heterozygous carriers of each of these mutations, respectively. Bisphosphonates could be helpful in increasing BMD Z-score, reducing bone fracture risk and reshaping the compressed vertebral bodies of this patient.


We reported novel compound heterozygous mutations in SERPINH1 in a Chinese OI patient for the first time, which expanded the spectrum of phenotype and genotype of extremely rare OI type X.


Bisphosphonates HSP47 Osteogenesis imperfecta SERPINH1 



This study was supported by National Natural Science Foundation of China (No. 81570802) and CAMS Initiative for Innovative Medicine (2016-I2M-3-003). We sincerely thank the patient with SERPINH1 mutation and his parents for the participation in this research and thank all unaffected, unrelated individuals for providing control DNA samples.

Compliance with ethical standards

The study protocol was approved by the Scientific Research Ethics Committee of PUMCH, and the parents of the patient signed informed consent before they participated in this study.

Conflict of interests



  1. 1.
    Forlino A, Marini JC (2016) Osteogenesis imperfecta. Lancet 387:1657–1671CrossRefPubMedGoogle Scholar
  2. 2.
    Lim J, Grafe I, Alexander S, Lee B (2017) Genetic causes and mechanisms of osteogenesis imperfecta. Bone 102:40–49CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Marini JC, Reich A, Smith SM (2017) Osteogenesis imperfecta due to mutations in non-collagenous genes: lessons in the biology of bone formation. Curr Opin Pediatr 26:500–507CrossRefGoogle Scholar
  4. 4.
    Lv F, Ma M, Liu W, Xu X, Song Y, Li L, Jiang Y, Wang O, Xia W, Xing X, Qiu Z, Li M (2017) A novel large fragment deletion in PLS3 causes rare X-linked early-onset osteoporosis and response to zoledronic acid. Osteoporos Int 28:2691–2700CrossRefPubMedGoogle Scholar
  5. 5.
    Xu XJ, Lv F, Liu Y, Wang JY, Ma DD, Asan, Wang JW, 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
  6. 6.
    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
  7. 7.
    Barbirato C, Trancozo M, Rebouças MR, Sipolatti V, Nunes VR, Paula F (2016) Analysis of FKBP10, SERPINH1, and SERPINF1 genes in patients with osteogenesis imperfecta. Genet Mol Res 15.
  8. 8.
    Eyre DR, Weis MA (2013) Bone collagen: new clues to its mineralization mechanism from recessive osteogenesis imperfecta. Calcif Tissue Int 93:338–347CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Kojima T, Miyaishi O, Saga S, Ishiguro N, Tsutsui Y, Iwata H (1998) The retention of abnormal type I procollagen and correlated expression of HSP 47 in fibroblasts from a patient with lethal osteogenesis imperfecta. J Pathol 184:212–218CrossRefPubMedGoogle Scholar
  10. 10.
    Ito S, Nagata K (2017) Biology of Hsp47 (serpin H1), a collagen-specific molecular chaperone. Semin Cell Dev Biol 62:142–151CrossRefPubMedGoogle Scholar
  11. 11.
    Shroff B, Smith T, Norris K, Pileggi R, Sauk JJ (1993) Hsp 47 is localized to regions of type I collagen production in developing murine femurs and molars. Connect Tissue Res 29:273–286CrossRefPubMedGoogle Scholar
  12. 12.
    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 32:1309–1319CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Duran I, Nevarez L, Sarukhanov A, Wu S, Lee K, Krejci P, Weis M, Eyre D, Krakow D, Cohn DH (2015) HSP47 and FKBP65 cooperate in the synthesis of type I procollagen. Hum Mol Genet 24:1918–1928CrossRefPubMedGoogle Scholar
  14. 14.
    Christiansen HE, Schwarze U, Pyott SM, AlSwaid A, Al Balwi M, Alrasheed S, Pepin MG, Weis MA, Eyre DR, Byers PH (2010) Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta. Am J Hum Genet 86:389–398CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Marshall C, Lopez J, Crookes L, Pollitt RC, Balasubramanian M (2016) A novel homozygous variant in SERPINH1 associated with a severe, lethal presentation of osteogenesis imperfecta with hydranencephaly. Gene 595:49–52CrossRefPubMedGoogle Scholar
  16. 16.
    Essawi O, Symoens S, Fannana M, Darwish M, Farraj M, Willaert A, Essawi T, Callewaert B, De Paepe A, Malfait F, Coucke PJ (2017) Genetic analysis of osteogenesis imperfecta in the Palestinian population: molecular screening of 49 affected families. Mol Genet Genomic Med 6:15–26. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Li H, Ji CY, Zong XN, Zhang YQ (2009) Height and weight standardized growth charts for Chinese children and adolescents aged 0 to 18 year. Zhonghua Er Ke Za Zhi 47:487–492 [Chinese]PubMedGoogle Scholar
  18. 18.
    Liu Y, Asan MD, 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 28:2985–2995CrossRefPubMedGoogle Scholar
  19. 19.
    Ishida Y, Nagata K (2011) Hsp47 as a collagen-specific molecular chaperone. Methods Enzymol 499:167–182CrossRefPubMedGoogle Scholar
  20. 20.
    Engel J, Prockop DJ (1991) The zipper-like folding of collagen triple helices and the effects of mutations that disrupt the zipper. Annu Rev Biophys Biophys Chem 20:137–152CrossRefPubMedGoogle Scholar
  21. 21.
    Widmer C, Gebauer JM, Brunstein E, Rosenbaum S, Zaucke F, Drögemüller C, Leeb T, Baumann U (2012) Molecular basis for the action of the collagen-specific chaperone Hsp47/SERPINH1 and its structure-specific client recognition. Proc Natl Acad Sci U S A 109:13243–13247CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Lamande SR, Bateman JF (1999) Procollagen folding and assembly: the role of endoplasmic reticulum enzymes and molecular chaperones. Semin Cell Dev Biol 10:455–464CrossRefPubMedGoogle Scholar
  23. 23.
    Lindert U, Weis MA, Rai J, Seeliger F, Hausser I, Leeb T, Eyre D, Rohrbach M, Giunta C (2015) Molecular consequences of the SERPINH1/HSP47 mutation in the dachshund natural model of osteogenesis imperfecta. J Biol Chem 290:17679–17689CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Nagai N, Hosokawa M, Itohara S, Adachi E, Matsushita T, Hosokawa N, Nagata K (2000) Embryonic lethality of molecular chaperone hsp47 knockout mice is associated with defects in collagen biosynthesis. J Cell Biol 150:1499–1506CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Drögemüller C, Becker D, Brunner A, Haase B, Kircher P, Seeliger F, Fehr M, Baumann U, Lindblad-Toh K, Leeb T (2009) A missense mutation in the SERPINH1 gene in dachshunds with osteogenesis imperfecta. PLoS Genet 5:e1000579CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ito S, Nagata K (2016) Mutants of collagen-specific molecular chaperone Hsp47 causing osteogenesis imperfecta are structurally unstable with weak binding affinity to collagen. Biochem Biophys Res Commun 469:437–442CrossRefPubMedGoogle Scholar
  27. 27.
    Bishop N, Adami S, Ahmed SF, Antón J, Arundel P, Burren CP, Devogelaer JP, Hangartner T, Hosszú E, Lane JM, Lorenc R, Mäkitie O, Munns CF, Paredes A, Pavlov H, Plotkin H, Raggio CL, Reyes ML, Schoenau E, Semler O, Sillence DO, Steiner RD (2013) Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebocontrolled trial. Lancet 382:1424–1432CrossRefPubMedGoogle Scholar
  28. 28.
    Baroncelli GI, Vierucci F, Bertelloni S, Erba P, Zampollo E, Giuca MR (2013) Pamidronate treatment stimulates the onset of recovery phase reducing fracture rate and skeletal deformities in patients with idiopathic juvenile osteoporosis: comparison with untreated patients. J Bone Miner Metab 31:533–543CrossRefPubMedGoogle Scholar
  29. 29.
    Dwan K, Phillipi CA, Steiner RD, Basel D (2016) Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database Syst Rev 10:CD005088.
  30. 30.
    Lv F, Liu Y, Xu X, Wang J, Ma D, Jiang Y, Wang O, Xia W, Xing X, Yu W, Li M (2016) Effects of long-term alendronate treatment on a large sample of pediatric patients with osteogenesis imperfecta. Endocr Pract 22:1369–1376CrossRefPubMedGoogle Scholar
  31. 31.
    Palomo T, Fassier F, Ouellet J, Sato A, Montpetit K, Glorieux FH, Rauch F (2015) Intravenous bisphosphonate therapy of young children with osteogenesis imperfecta: skeletal findings during follow up throughout the growing years. J Bone Miner Res 30:2150–2157CrossRefPubMedGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2018

Authors and Affiliations

  • Y. Song
    • 1
  • D. Zhao
    • 1
  • X. Xu
    • 2
  • F. Lv
    • 1
  • L. Li
    • 1
  • Y. Jiang
    • 1
  • O. Wang
    • 1
  • W. Xia
    • 1
  • X. Xing
    • 1
  • M. Li
    • 1
    Email author
  1. 1.Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning CommissionPeking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
  2. 2.Department of Endocrinology, Beijing Jishuitan HospitalThe Fourth Clinical Medical College of Peking UniversityBeijingChina

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