Modern classification and molecular-genetic aspects of osteogenesis imperfecta

Osteogenesis imperfecta (imperfect osteogenesis in the Russian literature) is the most common hereditary form of bone fragility, it is a genetically and clinically heterogeneous disease with a wide range of clinical severity, often leading to disability from early childhood. It is based on genetic disorders leading to a violation of the structure of bone tissue, which leads to frequent fractures, impaired growth and posture, with the development of characteristic disabling bone deformities and associated problems, including respiratory, neurological, cardiac, renal impairment, hearing loss. Osteogenesis imperfecta occurs in both men and women, the disease is inherited in both autosomal dominant and autosomal recessive types, there are sporadic cases of the disease due to de novomutations, as well as X-linked forms. The term “osteogenesis imperfecta” was coined by W. Vrolick in the 1840s. The first classification of the disease was made in 1979 and has been repeatedly reviewed due to the identification of the molecular cause of the disease and the discovery of new mechanisms for the development of osteogenesis imperfecta. In the early 1980s, mutations in two genes of collagen type I (COL1A1and COL1A2) were first associated with an autosomal dominant inheritance type of osteogenesis imperfecta. Since then, 18 more genes have been identified whose products are involved in the formation and mineralization of bone tissue.  The degree of genetic heterogeneity of the disease has not yet been determined, researchers continue to identify new genes involved in its pathogenesis, the number of which has reached 20. In the last decade, it has become  known that autosomal recessive, autosomal dominant and X-linked mutations in a wide range of genes, encoding  proteins that are involved in the synthesis of type I collagen, its processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells, cause imperfect  osteogenesis. A large number of causative genes complicated the classical classification of the disease and, due to new advances in the molecular basis of the disease, the classification of the disease is constantly being improved.  In this review, we systematized and summarized information on the results of studies in the field of clinical and genetic aspects of osteogenesis imperfecta and reflected the current state of the classification criteria for diagnosing the disease.

1. Asharani P.V., Keupp K., Semler O., Wang W., Li Y., Thiele H., Yigit G., Pohl E., Becker J., Frommolt P., Sonntag C., Altmüller J., Zimmermann K., Greenspan D.S., Akarsu N.A., Netzer C., Schönau E., Wirth R., Hammerschmidt M., Nürnberg P., Wollnik B., Carney T.J. Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish. Am. J. Hum. Genet. 2012;90(4):661-674. DOI 10.1016/j.ajhg.2012.02.026.

2. Barnes A.M., Cabral W.A., Weis M., Makareeva E., Merta E.L., Leikin S., Eyre D., Trujillo C., Marini J.C. Absence of FKBP10in recessive type XI OI leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix. Hum. Mutat. 2012;33(11):1589-1598. DOI 10.1002/humu.22139.

3. Becker J., Semler O., Gilissen C., Li Y., Bolz H.J., Giunta C., Bergmann C., Rohrbach M., Koerber F., Zimmermann K. Exome sequencing identifies truncating mutations in human SERPINF1in autosomal-recessive osteogenesis imperfecta. Am. J. Hum. Genet. 2011;88(3):362-371. DOI 10.1016/j.ajhg.2011.01.015. Belgian Bone Club. 2019. Available at: http://www.bbcbonehealth.org/osteogenesisimperfecta.

4. Cabral W.A., Chang W., Barnes A.M., Weis M.A., Scott M.A., Leikin S., Makareeva E., Kuznetsova N.V., Rosenbaum K.N., Tifft C.J., Bulas D.I., Kozma C., Smith P.A., Eyre D.R., Marini J.C. Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat. Genet. 2007;39(3):359-365. DOI 10.1038/ng1968.

5. Christiansen H.E., Schwarze U., Pyott S.M., AlSwaid A., Al Balwi M., Alrasheed S., Pepin M.G., Weis M.A., Eyre D.R., Byers P.H. Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta. Am. J. Hum. Genet.2010;86(3):389-398. DOI 10.1016/j.ajhg.2010.01.034.

6. Costantini A., Krallis P.Ν., Kämpe A., Karavitakis E.M., Taylan F., Mäkitie O., Doulgeraki A. A novel frameshift deletion in PLS3 causing severe primary osteoporosis. J. Hum. Genet.2018;63(8): 923-926. DOI 10.1038/s10038-018-0472-5.

7. Doyard M., Bacrot S., Huber C., Di Rocco M. FAM46Amutations are responsible for autosomal recessive osteogenesis imperfecta. J. Med. Genet.2018;55(4):278-284. DOI 10.1136/jmedgenet-2017-104999. Epub 2018. Jan 22.

8. Dwan K., Phillipi C.A., Steiner R.D. Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database Syst. Rev. 2014;7:Cd005088.

9. Fratzl-ZelmanN., Barnes A.M., Weis M., Carter E., Hefferan T.E., Perino G., Chang W., Smith P.A., Roschger P., Klaushofer K., Glorieux F.H., Eyre D.R., Raggio C., Rauch F., Marini J.C. Non-lethal type VIII osteogenesis imperfecta has elevated bone matrix mineralization. J. Clin. Endocrinol. Metab. 2016;101(9):3516-3525. DOI 10.1210/jc.2016-1334.

10. Glorieux F.H., Rauch F., Plotkin H., Ward L., Travers R., Roughley P., Lalic L., Glorieux D.F., Fassier F., Bishop N.J. Type V osteogenesis imperfecta: a new form of brittle bone disease. J. Bone Miner. Res. 2000;15(9):1650-1658. DOI 10.1359/jbmr.2000.15.9.1650.

11. Glorieux F.H., Ward L.M., Rauch F., Lalic L., Roughley P.J., Travers R. Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect. J. Bone Miner. Res. 2002;17(1):30-38. DOI 10.1359/jbmr.2002.17.1.30.

12. Grafe I., Alexander S., Yang T., Lietman C., Homan E.P., Munivez E., Chen Y., Jiang M.M., Bertin T., Dawson B., Asuncion F., Ke H.Z., Ominsky M.S., Lee B. Sclerostin antibody treatment improves the bone phenotype of Crtap (–/–) mice, a model of recessive Osteogenesis Imperfecta. J. Bone Miner. Res. 2016;31(5):1030-1040.

13. Hoyer-Kuhn H., Franklin J., Allo G., Kron M., Netzer C., Eysel P., Hero B., Schoenau E., Semler O. Safety and efficacy of denosumab in children with osteogenesis imperfect – a first prospective trial. J. Musculoskelet Neuronal. Interact.2016;16(1):24-32.

14. Ignatovich O.N., Namazova-Baranova L.S., Margieva T.V., Yakhyaeva G.T., Zhurkova N.V., Savostyanov K.V., Pushkov A.A., Krotov I.A. Osteogenesis imperfecta: diagnostic feature. Pediatricheskaya Pharmacologiya = Pediatric Pharmacology. 2018;15(3): 224-232. DOI 10.15690/pf.v15i3.1902. (in Russian)

15. Kruchkova O.A., Kruglov S.V. Treatment of osteogenesis imperfecta. Symptoms of osteogenesis imperfecta. 2014. Available at: https://ymkababy.ru/pregnancy/nesovershennyi-osteogenez-lechenie-nesovershennyi-osteogenez-simptomy.html. (in Russian)

16. Laine C.M., Joeng K.S., Campeau P.M., Kiviranta R., Tarkkonen K., Grover M., Lu J.T., Pekkinen M., Wessman M., Heino T.J., Nieminen-Pihala V., Aronen M., Laine T., Kröger H., Cole W.G., Lehesjoki A.E., Nevarez L., Krakow D., Curry C.J., Cohn D.H., Gibbs R.A., Lee B.H., Mäkitie O. WNT1mutations in early-onset osteoporosis and osteogenesis imperfecta. N. Engl. J. Med. 2013; 368:1809-1816. DOI 10.1056/NEJMoa1215458.

17. Lapunzina P., Aglan M., Temtamy S., Caparrós-Martin J.A., Valencia M., Letón R., Martinez-Glez V., Elhossini R., Arm K., Vilaboa N., Ruiz-Perez V.L. Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta. Am. J. Hum. Genet.2010;87(1):110-114. DOI 10.1016/j.ajhg.2010.05.016.

18. Li L., Zhao D., Zheng W., Wang O., Jiang Y., Xia W., Xing X., Li M. A novel missense mutation in P4HB causes mild osteogenesis imperfecta. Biosci. Rep. 2019;39(4). DOI 10.1042/BSR20182118.

19. Lindahl K., Langdahl B., Ljunggren O., Kindmark A. Treatment of osteogenesis imperfecta in adults. Eur. J. Endocrinol.2014;171(2): R79-R90. DOI 10.1530/EJE-14-0017.

20. Lindert U., Cabral W.A., Ausavarat S., Tongkobpetch S. MBTPS2 mutations cause defective regulated intramembrane proteolysis in X linked osteogenesis imperfecta. Nat. Commun. 2016;7:11920. DOI 10.1038/ncomms11920.

21. Lowenstein E.J. Osteogenesis imperfecta in a 3,000-year-old mummy. Childs Nerv. Syst.2009;25(5):515-516. DOI 10.1007/s00381-009-0817-7.

22. Mahoney M.Ivar the Boneless.2017. Available at: www.englishmonarchs.co.uk/vikings_10.html.

23. Marini J.C., Forlino A., Bächinger H.P., Bishop N.J., Byers P.H., De Paepe A., Fassier F., Fratzl-Zelman N., Kozloff K.M., Krakow D., Montpetit K., Semler O. Osteogenesis imperfecta. Nat. Rev. Dis. Primers. 2017;3:1-19. DOI 10.1038/nrdp.2017.52.

24. Mendoza-Londono R., Fahiminiya S., Majewski J. Care4Rare Canada Consortium; Tétreault M., Nadaf J., Kannu P., Sochett E., Howard A., Stimec J., Dupuis L., Roschger P., Klaushofer K., Palomo T., Ouellet J., Al-Jallad H., Mort J.S., Moffatt P., Boudko S., Bächinger H.P., Rauch F. Recessive osteogenesis imperfecta caused by missense mutations in SPARC. Am. J. Hum. Genet.2015;96(6): 979-985. DOI 10.1016/j.ajhg.2015.04.021.

25. Morello R., Bertin T.K., Chen Y., Hicks J., Tonachini L., Monticone M., Castagnola P., Rauch F., Glorieux F.H., Vranka J., Bachinger H.P., Pace J.M., Schwarze U., Byers P.H., Weis M.A., Fernandes R.J., Eyre D.R., Yao Z., Boyce B.F., Lee B. CRTAPis required for prolyl 3-hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell. 2006;127(2):291-304. DOI 10.1016/j.cell.2006.08.039.

26. Nadyrshina D.D., Khusainova R.I., Khusnutdinova E.K. Studies of type I collagen (COL1A1) α1 chain in patients with osteogenesis imperfecta. Russ. J. Genet. 2012;48(3):321-328.

27. Pigarova E.A., Sheremeta M.S., Kulikova K.S., Belovalova I.M., Tulpakov A.N., Rumiantsev P.O. Osteogenesis imperfecta in combination with Graves disease. Ozhirenie i Metabolism = Obesity and Metabolism. 2017;14(4):77-82. DOI 10.14341/OMET2017477-82. (in Russian)

28. Puig-Hervás M.T., Temtamy S., Aglan M., Valencia M., MartínezGlez V., Ballesta-Martínez M.J., López-González V., Ashour A.M., Amr K., Pulido V., Guillén-Navarro E., Lapunzina P., CaparrósMartín J.A., Ruiz-Perez V.L. Mutations in PLOD2 cause autosomal-recessive connective tissue disorders within the Bruck syndrome-osteogenesis imperfecta phenotypic spectrum. Hum. Mutat. 2012;33(10):1444-1449. DOI 10.1002/humu.22133.

29. Pyott S.M., Tran T.T., Leistritz D.F., Pepin M.G., Mendelsohn N.J., Temme R.T., Fernandez B.A., Elsayed S.M., Elsobky E., Verma I., Nair S., Turner E.H., Smith J.D., Jarvik G.P., Byers P.H. WNT1mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta. Am. J. Hum. Genet.2013;92(4): 590-597. DOI 10.1016/j.ajhg.2013.02.009.

30. Ramachandran M., Jones D. Osteogenesis imperfecta. 2018. Available at: https://emedicine.medscape.com/article/1256726-overview.

31. Rubinato E., Morgan A., D’Eustacchio A., Pecile V., Gortani G., Gasparini P. A novel deletion mutation involving TMEM38Bin a patient with autosomal recessive osteogenesis imperfecta. Gene.2014; 545(2):290-292. DOI 10.1016/j.gene.2014.05.028.

32. Sinder B.P., Salemi J.D., Ominsky M.S., Caird M.S., Marini J.C., Kozloff K.M. Rapidly growing Brtl/+ mouse model of osteogenesis imperfecta improves bone mass and strength with sclerostin antibody treatment. Bone. 2015;71:115-123.

33. Symoens S., Malfait F., D’hondt S., Callewaert B., Dheedene A., Steyaert W. Deficiency for the ER-stress transducer OASIS causes severe recessive osteogenesis imperfecta in humans. Orphanet J. Rare Dis.2013;8:154. DOI 10.1186/1750-1172-8-154.

34. Tournis S., Dede A.D. Osteogenesis imperfecta – a clinical update. Metabolism. 2018;80:27-37. DOI 10.1016/j.metabol.2017.06.001.

35. VanDijk F.S., Nesbitt I.M., Zwikstra E.H., Nikkels P.G.J., Piersma S.R., Fratantoni S.A., Jimenez C.R., Huizer M., Morsman A.C., Cobben J.M., van Roij M.H.H., Elting M.W., Verbeke M.I.J.L., Wijnaendts L.C.D., Shaw N.J., Högler W., McKeown C., Sistermans E.A., Dalton A., Meijers-Jeijboer H., Pals G. PPIB mutations cause severe osteogenesis imperfecta. Am. J. Hum. Genet.2009; 85(4):521-527. DOI 10.1016/j.ajhg.2009.09.001.

36. Ward L.M., Rauch F., Travers R., Chabot G., Azouz E.M., Lalic L., Roughley P.J., Glorieux F.H. Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease. Bone.2002;31(1): 12-18.

37. Weaver C.M., Alexander D.D., Boushey C.J., Dawson-Hughes B., Lappe J.M., LeBoff M.S., Liu S., Looker A.C., Wallace T.C., Wang D.D. Calcium plus vitamin D supplementation and risk of fractures: an updated meta-analysis from the National Osteoporosis Foundation. Osteoporos. Int. 2016;27:367-376.

38. Yakhyayeva G.T., Margieva T.V., Namazova-Baranova L.S., Savostyanov K.V., Pushkov A.А., Zhurkova N.V., Zherdev K.V., Vashakmadze N.D., Gevorkyan A.K. Clinical case of rare type V osteogenesis imperfecta. Pediatricheskaya Pharmakologiya = Pediatric Pharmacology. 2015a;12(1):79-84. (in Russian)

39. Yakhyayeva G.T., Namazova-Baranova L.S., Margieva T.V. New aspects of the genetic basis, classification and treatment of osteoge nesis imperfecta: a literature review. Pediatricheskaya Pharmakolo giya = Pediatric Pharmacology. 2015b;12(5):579-588. DOI 10.15690/pf.v12i5.1461. (in Russian)

40. Zhang H., Yue H., Wang C., Gu J., He J., Fu W., Hu W., Zhang Z. Novel mutations in the SEC24D gene in Chinese families with autosomal recessive osteogenesis imperfecta. Osteoporos. Int. 2017; 28(4):1473-1480. DOI 10.1007/s00198-0163866-2.