Journal of Bone and Mineral Metabolism

, Volume 30, Issue 1, pp 69–77

The identification of novel mutations in COL1A1, COL1A2, and LEPRE1 genes in Chinese patients with osteogenesis imperfecta

  • Zhen-Lin Zhang
  • Hao Zhang
  • Yao-hua Ke
  • Hua Yue
  • Wen-Jin Xiao
  • Jin-Bo Yu
  • Jie-Mei Gu
  • Wei-Wei Hu
  • Chun Wang
  • Jin-Wei He
  • Wen-Zhen Fu
Original Article

Abstract

Dominant inheritance of osteogenesis imperfecta (OI) is caused by mutations in COL1A1 or COL1A2, the genes that encode type I collagen, and CRTAP, LEPRE1, PPIB, FKBP10, SERPINH1, and SP7 mutations were recently detected in a minority of patients with autosomal recessive OI. However, these findings have been mostly restricted to Western populations. The proportion of mutations and the correlations between genotype and phenotype in Chinese patients with OI are completely unknown. In this study, mutation analyses were performed for COL1A1, COL1A2, CRTAP, and LEPRE1 in a cohort of 58 unrelated Chinese patients with OI; the relationship between collagen type I mutations and clinical features was examined. A total of 56 heterozygous mutations were identified in COL1A1 and COL1A2, including 43 mutations in COL1A1 and 13 mutations in COL1A2. Among the 56 causative COL1A1 and COL1A2 mutations, 24 novel mutations were found, and 25 (44.6%) resulted in the substitution of a glycine within the Gly-X-Y triplet domain of the triple helix. Compared with COL1A1 haploinsufficiency (n = 23), patients with mutations affecting glycine residues had a severe skeletal phenotype. In patients 18 years of age or older, on average patients with COL1A1 haploinsufficiency were taller and had higher femoral neck bone mineral density than with patients with helical mutations. Interestingly, we found two novel compound heterozygous mutations in the LEPRE1 gene in two unrelated families with autosomal recessive OI. Although the genotype–phenotype correlation is still unclear, our findings are useful to understand the genetic basis of Chinese patients with OI.

Keywords

Osteogenesis imperfecta Collagen type I LEPRE1 Mutation 

References

  1. 1.
    Stoll C, Dott B, Roth MP, Alembik Y (1989) Birth prevalence rates of skeletal dysplasias. Clin Genet 35:88–92PubMedCrossRefGoogle Scholar
  2. 2.
    Sillence DO, Rimoin DL (1978) Classification of osteogenesis imperfecta. Lancet 1:1041–1042PubMedCrossRefGoogle Scholar
  3. 3.
    Hartikka H, Kuurila K, Körkkö J, Heini Hartikka H, Kuurila K, Körkkö J, Kaitila I, Grénman R, Pynnönen S, Hyland JC, Ala-Kokko L (2004) Lack of correlation between the type of COL1A1 or COL1A2 mutation and hearing loss in osteogenesis imperfecta patients. Hum Mutat 24:147–154PubMedCrossRefGoogle Scholar
  4. 4.
    Kamoun-Goldrat A, Pannier S, Huber C, Finidori G, Munnich A, Cormier-Daire V, Le Merrer M (2008) A new osteogenesis imperfecta with improvement over time maps to 11q. Am J Med Genet Part A 146A:1807–1814PubMedCrossRefGoogle Scholar
  5. 5.
    Marini JC, Forlino A, Cabral WA et al (2007) Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans. Hum Mutat 28:209–221PubMedCrossRefGoogle Scholar
  6. 6.
    Rauch F, Lalic L, Roughley P, Glorieux FH (2010) Relationship between genotype and skeletal phenotype in children and adolescents with osteogenesis imperfecta. J Bone Miner Res 25:1367–1374PubMedGoogle Scholar
  7. 7.
    Bodian DL, Chan TF, Poon A, Schwarze U, Yang K, Byers PH, Kwok PY, Klein TE (2009) Mutation and polymorphism spectrum in osteogenesis imperfecta type II: implications for genotype–phenotype relationships. Hum Mol Genet 18:463–471PubMedCrossRefGoogle Scholar
  8. 8.
    Cabral WA, Chang W, Barnes AM, Weis M, Scott MA, Leikin S, Makareeva E, Kuznetsova NV, Rosenbaum KN, Tifft CJ, Bulas DI, Kozma C, Smith PA, Eyre DR, Marini JC (2007) Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat Genet 39:359–365PubMedCrossRefGoogle Scholar
  9. 9.
    Morello R, Bertin TK, Chen Y et al (2007) CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell 127:291–304CrossRefGoogle Scholar
  10. 10.
    Willaert A, Malfait F, Symoens S, Gevaert K, Kayserili H, Megarbane A, Mortier G, Leroy JG, Coucke PJ, De Paepe A (2009) Recessive osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation. J Med Genet 46:233–241PubMedCrossRefGoogle Scholar
  11. 11.
    van Dijk FS, Nesbitt IM, Zwikstra EH et al (2009) PPIB mutations cause severe osteogenesis imperfecta. Am J Hum Genet 85:521–527PubMedCrossRefGoogle Scholar
  12. 12.
    Alanay Y, Avaygan H, Camacho N et al (2010) Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta. Am J Hum Genet 86:551–559PubMedCrossRefGoogle Scholar
  13. 13.
    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 86:389–398PubMedCrossRefGoogle Scholar
  14. 14.
    Lapunzina P, Aglan M, Temtamy S, Caparrós-Martín JA, Valencia M, Letón R, Martínez-Glez V, Elhossini R, Amr K, Vilaboa N, Ruiz-Perez VL (2010) Identification of a frameshift mutation in osterix in a patient with recessive osteogenesis imperfecta. Am J Hum Genet 87:110–114PubMedCrossRefGoogle Scholar
  15. 15.
    Qin W, He JX, Shi J, Xing QH, Gao JJ, He L, Qian XQ, Liu ZJ, Shu AL, He L (2005) Mutation detection of COL1A1 gene in a pedigree with osteogenesis imperfecta. Acta Genet Sin 32:248–252PubMedGoogle Scholar
  16. 16.
    Xia XY, Cui YX, Huang YF, Pan LJ, Yang B, Wang HY, Li XJ, Shi YC, Lu HY, Zhou YC (2008) A novel RNA-splicing mutation in COL1A1 gene causing osteogenesis imperfecta type I in a Chinese family. Clin Chim Acta 398:148–151PubMedCrossRefGoogle Scholar
  17. 17.
    Gao G, Zhang ZL, Zhang H, Hu WW, Huang QR, Lu JH, Hu YQ, Li M, Liu YJ, He JW, Gu JM, Yu JB (2008) The changes of hip axis length in 10544 males and females and the association with femoral neck fracture. J Clin Densitom 11:360–367PubMedCrossRefGoogle Scholar
  18. 18.
    Lee KS, Song HR, Cho TJ, Kim HJ, Lee TM, Jin HS, Park HY, Kang S, Jung SC, Koo SK (2006) Mutational spectrum of type I collagen genes in Korean patients with osteogenesis imperfecta. Hum Mutat 27:599PubMedCrossRefGoogle Scholar
  19. 19.
    Kuuila K, Kaitila I, Johanssion R, Grénman R (2002) Hearing loss in Finnish adults with osteogenesis imperfecta: a nationwide survey. Ann Otol Rhinol Laryngol 111:939–946Google Scholar
  20. 20.
    Ries-Levavi L, Ish-Shalom T, Frydman M, Lev D, Cohen S, Barkai G, Goldman B, Byers P, Friedman E (2004) Genetic and biochemical analyses of Israeli osteogenesis imperfecta patients. Hum Mutat 23:399–400PubMedCrossRefGoogle Scholar
  21. 21.
    Barnes AM, Chang W, Morello R, Cabral WA, Weis M, Eyre DR, Leikin S, Makareeva E, Kuznetsova N, Uveges TE, Ashok A, Flor AW, Mulvihill JJ, Wilson PL, Sundaram UT, Lee B, Marini JC (2006) Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta. N Engl J Med 355:2757–2764PubMedCrossRefGoogle Scholar
  22. 22.
    Baldridge D, Schwarze U, Morello R et al (2008) CRTAP and LEPRE1 mutations in recessive osteogenesis imperfecta. Hum Mutat 29:1435–1442PubMedCrossRefGoogle Scholar
  23. 23.
    Obafemi A, Bulas D, Troendle J, Marini JC (2008) Popcorn calcification in osteogenesis imperfecta: incidence, progression, and molecular correlation. Am J Med Genet Part A 146A:2725–2732PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society for Bone and Mineral Research and Springer 2011

Authors and Affiliations

  • Zhen-Lin Zhang
    • 1
  • Hao Zhang
    • 1
  • Yao-hua Ke
    • 1
  • Hua Yue
    • 1
  • Wen-Jin Xiao
    • 1
  • Jin-Bo Yu
    • 1
  • Jie-Mei Gu
    • 1
  • Wei-Wei Hu
    • 1
  • Chun Wang
    • 1
  • Jin-Wei He
    • 1
  • Wen-Zhen Fu
    • 1
  1. 1.Metabolic Bone Disease and Genetics Research Unit, Department of Osteoporosis and Bone DiseasesShanghai Jiao Tong University Affiliated Sixth People’s Hospital, ShanghaiShanghaiPeople’s Republic of China

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