Non syndromic cleft lip and/or palate (NSCLP) is a complex congenital anomaly with varying incidence among patients of different geographical origins. Multiple contributing factors are known to trigger the cleft formation. There are several genes involved in the aetiology of NSCLP and they are different in different populations. The genetic components of clefts that underlie the susceptibility to respond to the environment still remain unclear. In this study, five microsatellite polymorphisms from five candidate genes were employed to analyze the association between these genes and NSCLP in 83 patients and 90 controls. Genotyping was performed by separating and visualizing the fluorescently-labeled polymerase chain reaction (PCR) products. The association of the five microsatellite polymorphisms with NSCLP was tested by using the CLUMP v1.9 program that uses the Monte Carlo method. The genotypic distribution is in Hardy-Weinberg equilibrium in the control group for only the MSX1 and DLX3 genes. The RARA microsatellite was significantly associated with NSCLP. Our results suggest that the RARA gene is involved in pathogenesis of cleft lip and palate in South Indians.
If the inline PDF is not rendering correctly, you can download the PDF file here.
1. Schutte BC, Murray JC. The many faces and factors of orofacial clefts. Hum Mol Genet. 1999; 8(10): 1853-1859.
2. Mitchell LE, Murray JC, O’Brien S, Christensen K. Retinoic acid receptor a gene variants, multivitamin use, and liver intake as risk factors for oral clefts: a population-based case-control study in Denmark, 1991-1994. Am J Epidemiol. 2003; 158(1): 69-76.
3. Lammer EJ, Shaw GM, Iovannisci DM, Finnell RH. Periconceptional multivitamin intake during early pregnancy, genetic variation of acetyl- N-transferase 1 (NAT1), and risk for orofacial clefts. Birth Defects Res A Clin Mol Teratol. 2004; 70(11): 846-852.
4. Murray JC. Face facts: genes, environment, and clefts. Am J Hum Genet. 1995; 57(2): 227-232.
5. Murthy J, Bhaskar L. Current concepts in genetics of nonsyndromic clefts. Indian J Plast Surg. 2009; 42(1): 68-81.
6. Thangaraj K, Joshi MB, Reddy AG, Gupta NJ, Chakravarty B, Singh L. CAG repeat expansion in the an-drogen receptor gene is not associated with male infertility in Indian populations. J Androl. 2002; 23(6): 815-818.
7. Sham PC, Curtis D. Monte Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann Hum Genet. 1995; 59(Pt 1): 97-105.
8. Helms JA, Kim CH, Hu D, Minkoff R, Thaller C, Eichele G. Sonic hedgehog participates in craniofacial morphogenesis and is down-regulated by teratogenic doses of retinoic acid. Dev Biol. 1997; 187(1): 25-35.
9. Okano J, Suzuki S, Shiota K. Involvement of apoptotic cell death and cell cycle perturbation in retinoic acid-induced cleft palate in mice. Toxicol Appl Pharmacol. 2007; 221(1): 42-56.
10. Chenevix-Trench G, Jones K, Green AC, Duffy DL, Martin NG. Cleft lip with or without cleft palate: associations with transforming growth factor alpha and retinoic acid receptor loci. Am J Hum Genet. 1992; 51(6): 1377-1385.
11. Shaw D, Ray A, Marazita M, Field L. Further evidence of a relationship between the retinoic acid receptor a locus and nonsyndromic cleft lip with or without cleft palate (CL ± P). Am J Hum Genet. 1993; 53(5): 1156-1157.
12. Kanno K, Suzuki Y, Yang X, Yamada A, Aoki Y, Kure S, et al. Lack of evidence for a significant association between nonsyndromic cleft lip with or without cleft palate and the retinoic acid receptor a gene in the Japanese population. J Hum Genet. 2002; 47(6): 269-274.
13. Peanchitlertkajorn S, Cooper ME, Liu YE, Field LL, Marazita ML. Chromosome 17: gene mapping studies of cleft lip with or without cleft palate in Chinese families. Cleft Palate Craniofac J. 2003; 40(1): 71-79.
14. Fan GZ, Li YL, Wu PA. [Association between retinoic acid receptor a gene polymorphisms and nonsyndromic cleft lip with or without cleft palate susceptibility]. Zhonghua Yi Xue Za Zhi. 2007; 87(6): 396-398.
15. Kurihara Y, Kurihara H, Suzuki H, Kodama T, Maemura K, Nagai R, et al. Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature. 1994; 368(6473): 703-710.
16. Yanagisawa H, Yanagisawa M, Kapur RP, Richardson JA, Williams SC, Clouthier DE, et al. Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene. Development. 1998; 125(5): 825-836.
17. Kimmel CB, Ullmann B, Walker M, Miller CT, Crump JG. Endothelin 1-mediated regulation of pharyngeal bone development in zebrafish. Development. 2003; 130(7): 1339-1351.
18. Pezzetti F, Scapoli L, Martinelli M, Carinci F, Brunelli G, Carls FP, et al. Linkage analysis of candidate endothelin pathway genes in nonsyndromic familial orofacial cleft. Ann Hum Genet. 2000; 64(Pt 4): 341-347.
19. Lu MF, Cheng HT, Lacy AR, Kern MJ, Argao EA, Potter SS, et al. Paired-related homeobox genes cooperate in handplate and hindlimb zeugopod morphogenesis. Dev Biol. 1999; 205(1): 145-157.
20. 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(17): 4135-4146.
21. Jezewski PA, Vieira AR, Nishimura C, Ludwig B, Johnson M, O’Brien SE, et al. Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate. J Med Genet. 2003; 40(6): 399-407.
22. Wright JT, Hong SP, Simmons D, Daly B, Uebelhart D, Luder HU. DLX3 c.561_562delCT mutation causes attenuated phenotype of trichodento- osseous syndrome. Am J Med Genet A. 2008; 146(3): 343-349.
23. Ichikawa E, Watanabe A, Nakano Y, Akita S, Hirano A, Kinoshita A, et al. PAX9 and TGFB3 are linked to susceptibility to nonsyndromic cleft lip with or without cleft palate in the Japanese: population-based and family-based candidate gene analyses. J Hum Genet. 2006; 51(1): 38-46.
24. Fujita H, Nagata M, Ono K, Okubo H, Takagi R. Linkage analysis between BCL3 and nearby genes on 19q13.2 and non-syndromic cleft lip with or without cleft palate in multigenerational Japanese families. Oral Dis. 2004; 10(6): 353-359.
25. Amos C, Gasser D, Hecht JT. Nonsyndromic cleft lip with or without cleft palate: new BCL3 information. Am J Hum Genet. 1996; 59(3): 743-744.