A novel gene mutation of Runx2 in cleidocranial dysplasia

Abstract

Haploinsufficiency of the runt-related transcription factor 2 (Runx2) gene is widely known to be responsible for cleidocranial dysplasia (CCD). To date, more than 190 mutations in Runx2 gene have been reported to be related to CCD. In this study, a novel mutation of Runx2 gene was observed in a female with CCD. Genomic DNA was extracted from peripheral venous blood of the proband and eleven members of her family. Genetic testing on these twelve people identified a novel missense mutation (c.895 T>C, Y299H) in exon 5 of the RUNX2 gene in the proband. This mutation results in an amino acid change at codon 895 (P.Tyr 299 His.) from a tryptophan codon (TAT) to a histidine codon (CAT). Our finding may further extend the known mutation spectrum of the RUNX2 gene, and facilitate prenatal genetic diagnosis of CCD in the future.

Keywords

cleidocranial dysplasia / RUNX2 / genetic testing / mutation

References

[1] MundlosS, OttoF, MundlosC, et al. . Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell, 1997, 89(5): 773-779 PMID: 9182765

[2] Dinçsoy BirF, DinçkanN, GüvenY, et al. . Cleidocranial dysplasia: Clinical, endocrinologic and molecular findings in 15 patients from 11 families. Eur J Med Genet, 2017, 60(3): 163-168 PMID: 28027977

[3] PaulSA, SimonSS, KarthikAK, et al. . A review of clinical and radiological features of cleidocranial dysplasia with a report of two cases and a dental treatment protocol. J Pharm Bioallied Sci, 2015, 7(2): S428-S432 PMID: 26538892 PMCID: 4606634

[4] HsuehSJ, LeeNC, YangSH, et al. . A limb-girdle myopathy phenotype of RUNX2 mutation in a patient with cleidocranial dysplasia: a case study and literature review. BMC Neurol, 2017, 17(1): 2 PMID: 28056872 PMCID: 5216594

[5] TangS, XuQ, XuX, et al. . A novel RUNX2 missense mutation predicted to disrupt DNA binding causes cleidocranial dysplasia in a large Chinese family with hyperplastic nails. BMC Med Genet, 2007, 8: 82 PMID: 18166138 PMCID: 2241583

[6] TakenouchiT, SatoW, ToriiC, et al. . Progressive cognitive decline in an adult patient with cleidocranial dysplasia. Eur J Med Genet, 2014, 57(7): 319-321 PMID: 24797831

[7] ChangJL, BrauerDS, JohnsonJ, et al. . Tissue-specific calibration of extracellular matrix material properties by transforming growth factor-beta and Runx2 in bone is required for hearing. EMBO Rep, 2010, 11(10): 765-771 PMID: 20847738 PMCID: 2948188

[8] BlumenthalE, GreenblattS, HuangG, et al. . Covalent modifications of RUNX proteins: structure affects function. Adv Exp Med Biol, 2017, 962: 33-44 PMID: 28299649

[9] LeeKE, SeymenF, KoJ, et al. . RUNX2 mutations in cleidocranial dysplasia. Genet Mol Res, 2013, 12(4): 4567-4574 PMID: 24222232

[10] AnthonappaRP, Yan-HuiF, KingNM, et al. . Novel complex disease allele mutations in cleidocranial dysplasia patients. J Oral Pathol Med, 2014, 43(10): 798-800 PMID: 24935264

[11] GuoYW, ChiuCY, LiuCL, et al. . Novel mutation of RUNX2 gene in a patient with cleidocranial dysplasia. Int J Clin Exp Pathol, 2015, 8(1): 1057-1062 PMID: 25755819 PMCID: 4348862

[12] BhargavaP, KhanS, SharmaR, et al. . Cleidocranial dysplasia with autosomal dominant inheritance pattern. Ann Med Health Sci Res, 2014, 4(2): S152-S154 PMID: 25184084 PMCID: 4145514

[13] LouY, JavedA, HussainS, et al. . A Runx2 threshold for the cleidocranial dysplasia phenotype. Hum Mol Genet, 2009, 18(3): 556-568 PMID: 19028669

[14] JarugaA, HordyjewskaE, KandzierskiG, et al. . Cleidocranial dysplasia and RUNX2-clinical phenotype-genotype correlation. Clin Genet, 2016, 90(5): 393-402 PMID: 27272193

[15] RyooHM, KangHY, LeeSK, et al. . RUNX2 mutations in cleidocranial dysplasia patients. Oral Dis, 2010, 16(1): 55-60 PMID: 19744171

[16] PawlowskaE W K A, SynowiecE, et al. . Expression of RUNX2 and its signaling partners TCF7, FGFR1/2 in cleidocranial dysplasia. Acta Biochim Pol, 2015, 62(1): 123-126 PMID: 25738174

[17] WuLZ, SuWQ, LiuYF, et al. . Role of the RUNX2 p.R225Q mutation in cleidocranial dysplasia: a rare presentation and an analysis of the RUNX2 protein structure. Genet Mol Res, 2014, 13(1): 1187-1194 PMID: 24634175

[18] GonzalezGE, CarusoPA, SmallJE, et al. . Craniofacial and temporal bone CT findings in cleidocranial dysplasia. Pediatr Radiol, 2008, 38(8): 892-897 PMID: 18446333

[19] TongYQ, LiuB, FuCH, et al. . Genetic Analysis of the PKHD1 Gene with Long-rang PCR Sequencing. J Huazhong Univ Sci Technol Med Sci, 2016, 36(5): 758-766 PMID: 27752906

[20] LeeB, ThirunavukkarasuK, ZhouL, et al. . Missense mutations abolishing DNA binding of the osteoblast-specific transcription factor OSF2/CBFA1 in cleidocranial dysplasia. Nat Genet, 1997, 16(3): 307-310 PMID: 9207800

[21] SudaN, HamadaT, HattoriM, et al. . Diversity of supernumerary tooth formation in siblings with cleidocranial dysplasia having identical mutation in RUNX2: possible involvement of non-genetic or epigenetic regulation. Orthod Craniofac Res, 2007, 10(4): 222-225 PMID: 17973689

[22] WangXZ, SunXY, ZhangCY, et al. . RUNX2 mutation impairs 1a, 25-dihydroxyvitamin D3 mediated osteoclastogenesis in dental follicle cells. Sci Rep, 2016, 6: 24225 PMID: 27068678 PMCID: 4828645

[23] VijR, BatraP, VijH. Cleidocranial dysplasia: complete clinical, radiological and histological profiles. BMJ Case Rep, 2013, 2013: 2013009015

[24] BufalinoA, ParanaibaLM, GouveaAF, et al. . Cleidocranial dysplasia: oral features and genetic analysis of 11 patients. Oral Dis, 2012, 18(2): 184-190 PMID: 22023169

[25] CunninghamML, SetoML, HingAV, et al. . Cleidocranial dysplasia with severe parietal bone dysplasia: C-terminal RUNX2 mutations. Birth Defects Res A Clin Mol Teratol, 2006, 76(2): 78-85 PMID: 16463420

[26] LiuZM, PengYJ, LongX, et al. . Mutual effect between neuropeptides and inflammatory cytokines in neurogenic SMSCs of human temporomandibular joint. J Huazhong Univ Sci and Technology Med Sci, 2014, 34(4): 602-607

[27] YoshidaT, KaneganeH, OsatoM, et al. . Functional analysis of RUNX2 mutations in Japanese patients with cleidocranial dysplasia demonstrates novel genotype-phenotype correlations. Am J Hum Genet, 2002, 71(4): 724-738 PMID: 12196916 PMCID: 378531