Volume 25, Issue 4 (7-2021)                   IBJ 2021, 25(4): 297-302 | Back to browse issues page

PMID: 34217160


XML Print


Abstract:  
Background: Pathogenic variants of RUNX2, a gene that encodes an osteoblast-specific transcription factor, have been shown as the cause of Cleidocranial dysplasia (CCD), which is a rare hereditary skeletal and dental disorder with dominant mode of inheritance and a broad range of clinical variability. Due to the relative lack of clinical complications resulting in CCD, the medical diagnosis of this disorder is challenging, which leaves it underdiagnosed. Methods: In this study, nine healthy and affected members of an Iranian family were investigated. PCR and sequencing of all exons and exon-intron boundaries of runt-related transcription factor 2 (RUNX2; NM_001024630) gene was performed on proband. Co-segregation analysis was conducted in the other family members for the identified variant. Additionally, a cohort of 100 Iranian ethnicity-matched healthy controls was screened by Amplification Refractory Mutation System PCR method. Results: The novel splice site variant (c.860-2A>G), which was identified in the intron 6 of RUNX2 gene, co-segregated with the disease in the family, and it was absent in healthy controls. Pathogenicity of this variant was determined by several software, including , human splicing finder, which predicts the formation or disruption of splice donor sites, splice acceptor sites, exonic splicing silencer sites, and exonic splicing enhancer sites. In silico analysis predicted this novel variant to be disease causing. Conclusion: The identified variant is predicted to have an effect on splicing, which leads to exon skipping and producing a truncated protein via introducing a premature stop codon.
Type of Study: Case Report | Subject: Molecular Genetics & Genomics

References
1. Marie P, Sainton P. Sur la dysostose cleido-clanienne hereditaire. Revista de Neurología 1898; 6: 835-838.
2. Patil PP, Barpande SR, Bhavthankar JD, Humbe JG. Cleidocranial dysplasia: A clinico-radiographic spectrum with differential diagnosis. Journal of orthopaedic case reports 2015; 5(2): 21-24.
3. Keats TE. Cleidocranial dysostosis: some atypical roentgen manifestations. The American journal of roentgenology radium therapy and nuclear medicine 1967; 100(1): 71-74. [DOI:10.2214/ajr.100.1.71]
4. Jarvis JL, KEATS TE. Cleidocranial dysostosis: A review of 40 new cases. American journal of roentgenology. 1974; 121(1): 5-16. [DOI:10.2214/ajr.121.1.5]
5. Mundlos S. Cleidocranial dysplasia: clinical and molecular genetics. Journal of medical genetics 1999; 36(3): 177-182.
6. Rezani Toptancı İ, Çolak H, Köseoğlu S. Cleidocranial dysplasia: Etiology, clinicoradiological presentation and management. Journal of clinical and experimental investigations 2012; 3: 133-136. [DOI:10.5799/ahinjs.01.2012.01.0131]
7. Garg RK, Agrawal P. Clinical spectrum of cleidocranial dysplasia: a case report. Cases journal 2008; 1(1): 377. [DOI:10.1186/1757-1626-1-377]
8. Chelvan HT, Malathi N, Kailasam V, Ponnudurai A. Cleidocranial dysplasia: a family report. Journal of the Indian society of pedodontics and preventive dentistry 2009; 27(4): 249-252. [DOI:10.4103/0970-4388.57661]
9. Li YL, Xiao ZS. Advances in Runx2 regulation and its isoforms. Medical hypotheses 2007; 68(1): 169-175. [DOI:10.1016/j.mehy.2006.06.006]
10. Golan I, Preising M, Wagener H, Baumert U, Niederdellmann H, Lorenz B, Müssig D. A novel missense mutation of the CBFA1 gene in a family with cleidocranial dysplasia (CCD) and variable expressivity. Journal of craniofacial genetics and developmental biology 2000; 20(3): 113-120.
11. Brueton LA, Reeve A, Ellis R, Husband P, Thompson EM, Kingston HM. Apparent cleidocranial dysplasia associated with abnormalities of 8q22 in three individuals. American journal of medical genetics 1992; 43(3): 612-618. [DOI:10.1002/ajmg.1320430322]
12. Francke U, Weber F, Sparkes RS, Mattson PD, Mann J. Duplication 11 (q21 to 23 leads to qter) syndrome. Birth defects original article series 1977; 13(3b): 167-186.
13. Nakai H, Yamamoto Y, Kuroki Y. Partial trisomy of 11 and 22 due to familial translocation t(11;22)(q23;q11), inherited in three generations. Human genetics 1979; 51(3): 349-355. [DOI:10.1007/BF00283408]
14. Schinzel A. Trisomy 20pter = to q11 in a malformed boy from a t(13;20)(p11;q11) translocation-carrier mother. Human genetics 1980; 53(2): 169-172. [DOI:10.1007/BF00273490]
15. Gelb BD, Cooper E, Shevell M, Desnick RJ. Genetic mapping of the cleidocranial dysplasia (CCD) locus on chromosome band 6p21 to include a microdeletion. American journal of medical genetics 1995; 58(2): 200-205. [DOI:10.1002/ajmg.1320580222]
16. Mundlos S, Mulliken JB, Abramson DL, Warman ML, Knoll JH, Olsen BR. Genetic mapping of cleidocranial dysplasia and evidence of a microdeletion in one family. Human molecular genetics 1995; 4(1): 71-75. [DOI:10.1093/hmg/4.1.71]
17. Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, GaoYH, Inada M, Sato M, Okamoto R, Kitamura Y, Yoshiki S, Kishimoto T. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 1997; 89(5): 755-764. [DOI:10.1016/S0092-8674(00)80258-5]
18. Napierala D, Garcia-Rojas X, Sam K, Wakui K, Chen C, Mendoza-Londono R, Zhou G, Zheng Q, Lee B. Mutations and promoter SNPs in RUNX2, a transcriptional regulator of bone formation. Molecular genetics and metabolism 2005; 86(1-2): 257-268. [DOI:10.1016/j.ymgme.2005.07.012]
19. Ercan Sekerci A, Balta B, Bahadır O, Sisman Y, Dundar M, Tursem Tokmak T, Mundlos S. Cleidocranial dysplasia with a rare mutation: Study of a family with review of literature. Open journal of stomatology 2013; (03): 402-410. [DOI:10.4236/ojst.2013.38068]
20. Machuca-Tzili L, Monroy-Jaramillo N, Gonzalez-del Angel A, Kofman-Alfaro S. New mutations in the CBFA1 gene in two Mexican patients with cleidocranial dysplasia. Clinical genetics 2002; 61(5): 349-353. [DOI:10.1034/j.1399-0004.2002.610505.x]
21. Otto F, Kanegane H, Mundlos S. Mutations in the RUNX2 gene in patients with cleidocranial dysplasia. Human mutation 2002; 19(3): 209-216. [DOI:10.1002/humu.10043]
22. Yoshida T, Kanegane H, Osato M, Yanagida M, Miyawaki T, Ito Y, Shigesada K. Functional analysis of RUNX2 mutations in Japanese patients with cleidocranial dysplasia demonstrates novel genotype-phenotype correlations. American journal of human genetics 2002; 71(4): 724-738. [DOI:10.1086/342717]
23. Zhang YW, Yasui N, Kakazu N, Abe T, Takada K, Imai S, Sato M, Nomura S, Ochi T, Okuzumi S, Nogami H, Nagai T, Ohashi H, Ito Y. PEBP2alphaA/CBFA1 mutations in Japanese cleidocranial dysplasia patients. Gene 2000; 244(1-2): 21-28. [DOI:10.1016/S0378-1119(99)00558-2]
24. Geoffroy V, Corral DA, Zhou L, Lee B, Karsenty G. Genomic organization, expression of the human CBFA1 gene, and evidence for an alternative splicing event affecting protein function. Mammalian genome 1998; 9(1): 54-57. [DOI:10.1007/s003359900679]
25. Mundlos S, Otto F, Mundlos C, Mulliken JB, Aylsworth AS, Albright S, Lindhout D, Cole WG, Knoll JH, Owen MJ, Mertelsmann R, Zabel BU, Oslen BR. Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 1997; 89(5): 773-779. [DOI:10.1016/S0092-8674(00)80260-3]
26. Thirunavukkarasu K, Mahajan M, McLarren KW, Stifani S, Karsenty G. Two domains unique to osteoblast-specific transcription factor Osf2/Cbfa1 contribute to its transactivation function and its inability to heterodimerize with Cbfbeta. Molecular and cellular biology 1998; 18(7): 4197-4208. [DOI:10.1128/MCB.18.7.4197]
27. Wang S, Zhang S, Wang Y, Chen Y, Zhou L. Cleidocranial dysplasia syndrome: clinical characteristics and mutation study of a Chinese family. International journal of clinical and experimental medicine 2013; 6(10): 900-907.

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.