Single nucleotide polymorphism of bone morphogenetic protein 4 gene: A risk factor of non-syndromic cleft lip with or without palate

ABSTRACT

Background: The bone morphogenetic protein (BMP) signalling pathway is crucial in a number of developmental processes and is critical in the formation of variety of craniofacial elements including cranial neural crest, facial primordium, tooth, lip and palate. It is an important mediator in regulation of lip and palate fusion, cartilage and bone formation. Aim: To study the role of mutation of BMP4 genes in the aetiology of non-syndromic cleft lip with or without palate (NSCL ± P) and identify it directly from human analyses. Materials and Methods: A case-control study was done to evaluate whether BMP4T538C polymorphism, resulting in an amino acid change of Val=Ala (V152A) in the polypeptide, is associated with NSCL ± P in an Indian paediatric population. Genotypes of 100 patients with NSCL ± P and 100 controls (in whom absence of CL ± P was confirmed in three generations) were detected using a polymerase chain reaction-restriction fragment length polymorphism strategy. Logistic regression was performed to evaluate allele and genotype association with NSCLP. Results: Results showed significant association between homozygous CC genotype with CL ± P (odds ratio [OR]-5.59 and 95% confidence interval [CI] = 2.85-10.99). The 538C allele carriers showed an increased risk of NSCL ± P as compared with 538 T allele (OR - 4.2% CI = 2.75-6.41). Conclusion: This study suggests an association between SNP of BMP4 gene among carriers of the C allele and increased risk for NSCLP in an Indian Population. Further studies on this aspect can scale large heights in preventive strategies for NSCLP that may soon become a reality.

KEY WORDS

Aetiology of non-syndromic cleft lip and palate - bone morphogenetic protein 4 gene - bone morphogenetic protein gene

 

Conflicts of interest

There are no conflicts of interest.

• REFERENCES

• 1 Kaartinen V, Cui XM, Heisterkamp N, Groffen J, Shuler CF. Transforming growth factor-beta3 regulates transdifferentiation of medial edge epithelium during palatal fusion and associated degradation of the basement membrane. Dev Dyn 1997; 209: 255-60
• 2 Martínez-Alvarez C, Tudela C, Pérez-Miguelsanz J, O’Kane S, Puerta J, Ferguson MW. Medial edge epithelial cell fate during palatal fusion. Dev Biol 2000; 220: 343-57
• 3 Meng L, Bian Z, Torensma R, Von den Hoff JW. Biological mechanisms in palatogenesis and cleft palate. J Dent Res 2009; 88: 22-33
• 4 Wehby GL, Cassell CH. The impact of orofacial clefts on quality of life and healthcare use and costs. Oral Dis 2010; 16: 3-10
• 5 Marazita ML, Lidral AC, Murray JC, Field LL, Maher BS, Goldstein McHenry T. et al. Genome scan, fine-mapping, and candidate gene analysis of non-syndromic cleft lip with or without cleft palate reveals phenotype-specific differences in linkage and association results. Hum Hered 2009; 68: 151-70
• 6 Birnbaum S, Ludwig KU, Reutter H, Herms S, Steffens M, Rubini M. et al. Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24. Nat Genet 2009; 41: 473-7
• 7 Grant SF, Wang K, Zhang H, Glaberson W, Annaiah K, Kim CE. et al. A genome-wide association study identifies a locus for nonsyndromic cleft lip with or without cleft palate on 8q24. J Pediatr 2009; 155: 909-13
• 8 Mangold E, Ludwig KU, Birnbaum S, Baluardo C, Ferrian M, Herms S. et al. Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate. Nat Genet 2010; 42: 24-6
• 9 Nie X, Luukko K, Kettunen P. BMP signalling in craniofacial development. Int J Dev Biol 2006; 50: 511-21
• 10 Gong SG, Guo C. Bmp4 gene is expressed at the putative site of fusion in the midfacial region. Differentiation 2003; 71: 228-36
• 11 Mangino M, Torrente I, De Luca A, Sanchez O, Dallapiccola B, Novelli G. A single-nucleotide polymorphism in the human bone morphogenetic protein-4 (BMP 4) gene. J Hum Genet 1999; 44: 76-7
• 12 Zhang Z, Song Y, Zhao X, Zhang X, Fermin C, Chen Y. Rescue of cleft palate in Msx1-deficient mice by transgenic Bmp4 reveals a network of BMP and SHH signaling in the regulation of mammalian palatogenesis. Development 2002; 129: 4135-46
• 13 Wall NA, Hogan BL. Expression of bone morphogenetic protein-4 (BMP-4), bone morphogenetic protein-7 (BMP-7), fibroblast growth factor-8 (FGF-8) and sonic hedge hog (SHH) during branchial arch development in the chick. Mech Dev 1995; 53: 383-92
• 14 Liu W, Sun X, Braut A, Mishina Y, Behringer RR, Mina M. et al. Distinct functions for Bmp signaling in lip and palate fusion in mice. Development 2005; 132: 1453-61
• 15 Thomason HA, Dixon MJ, Dixon J. Facial clefting in Tp63 deficient mice results from altered Bmp4, Fgf8 and SHH signaling. Dev Biol 2008; 321: 273-82
• 16 Lin JY, Chen YJ, Huang YL, Tang GP, Zhang L, Deng B. et al. Association of bone morphogenetic protein 4 gene polymorphisms with nonsyndromic cleft lip with or without cleft palate in Chinese children. DNA Cell Biol 2008; 27: 601-5
• 17 Suzuki S, Marazita ML, Cooper ME, Miwa N, Hing A, Jugessur A. et al. Mutations in BMP4 are associated with subepithelial, microform, and overt cleft lip. Am J Hum Genet 2009; 84: 406-11
• 18 Suazo J, Tapia JC, Santos JL, Castro VG, Colombo A, Blanco R. Risk variants in BMP4 promoters for nonsyndromic cleft lip/palate in a Chilean population. BMC Med Genet 2011; 12: 163
• 19 Chen Q, Wang H, Hetmanski JB, Zhang T, Ruczinski I, Schwender H. et al. BMP4 was associated with NSCL/P in an Asian population. PLoS One 2012; 7: e35347
• 20 Barlow AJ, Francis-West PH. Ectopic application of recombinant BMP-2 and BMP-4 can change patterning of developing chick facial primordia. Development 1997; 124: 391-8
• 21 Mossey P, Castillia E. Global Registry and Database on Craniofacial Anomalies. Geneva: World Health Organization; 2003
• 22 Ashique AM, Fu K, Richman JM. Endogenous bone morphogenetic proteins regulate outgrowth and epithelial survival during avian lip fusion. Development 2002; 129: 4647-60
• 23 Sathyaprasad S, Sharma SM, Shetty V. BMP4 gene and pathophysiology of cleft lip and palate. Res Rev J Dent Sci 2014; 2: 10
• 24 Wan M, Cao X. BMP signaling in skeletal development. Biochem Biophys Res Commun 2005; 328: 651-7
• 25 He F, Xiong W, Wang Y, Matsui M, Yu X, Chai Y. et al. Modulation of BMP signaling by Noggin is required for the maintenance of palatal epithelial integrity during palatogenesis. Dev Biol 2010; 347: 109-21
• 26 Araújo TK, Simioni M, Félix TM, de Souza LT, Fontes MÍ, Monlleó IL. et al. Preliminary analysis of the nonsynonymous polymorphism rs17563 in BMP4 gene in brazilian population suggests protection for nonsyndromic cleft lip and palate. Plast Surg Int 2012; 2012: 247104
• 27 Paiva KB, Silva-Valenzuela MD, Massironi SM, Ko GM, Siqueira FM, Nunes FD. Differential SHH, Bmp and Wnt gene expressions during craniofacial development in mice. Acta Histochem 2010; 112: 508-17
• 28 Marazita ML, Murray JC, Lidral AC, Arcos-Burgos M, Cooper ME, Goldstein T. et al. Meta-analysis of 13 genome scans reveals multiple cleft lip/palate genes with novel loci on 9q21 and 2q32-35. Am J Hum Genet 2004; 75: 161-73
• 29 Antunes LS, Küchler EC, Tannure PN, Costa MC, Gouvêa CV, Olej B. et al. BMP4 polymorphism is associated with nonsyndromic oral cleft in a Brazilian population. Cleft Palate Craniofac J 2013; 50: 633-8