Deniz AŞLAR ÖNER, Hakki TASTAN

DUDAK DAMAK YARIKLARINA MOLEKÜLER YAKLAŞIM

Dudak damak yarıkları, dünya genelinde görülen en yaygın doğum anomalilerinden birisidir. Görülme sıklığı, etnik geçmiş, coğrafi köken ve sosyo-ekonomik duruma göre değişkenlik göstermektedir. Hamilelik sırasında annenin sigara içmesi, alkol tüketmesi, folik asit, B6 ve B12 vitaminlerince yetersiz beslenmesi gibi çevresel faktörler ile beraber genetik faktörlerin etkileşimi, yarık dudak damak oluşumuna sebep olabilmektedir. Dudak damak yarıklarının genetik açıdan incelenmesi için birçok aday gen araştırılmıştır. MTHFR, MTR, MTRR, TGFβ ve PVRL1 genleri dudak damak yarıklarının oluşumuna sebep olan önemli genlerdir. Yarık dudak ve damak oluşumunun erken teşhis edilememesi, embriyogenez sırasında dudak ve damak gelişimini düzenleyen gen ekspresyon kalıplarının ve etkili sinyal moleküllerinin etki mekanizmalarının yeterli bilinmemesinden kaynaklanmaktadır. Yarık dudak ve damak etiyolojisine sebep olan faktörlerin belirlenmesi, yarık dudak damak oluşumunun önlenmesi ve gerekli tedbirlerin alınması açısından çok büyük önem taşımaktadır. Bu derlemede yarık dudak damak hastalığının genetik faktörler ile ilişkisinin belirlenmesi amaçlanmıştır.

Anahtar Kelimeler:

Yarık dudak-damak sendromu, Polimorfizm, Folik asit, MTHFR eksikliği

MOLECULAR APPROACH TO CLEFT LIP AND PALATE

Cleft lip and palate is one of the most common birth anomalies world wide although its prevalence rate varies based on geographical origin, ethnic background, and socioeconomic status. The interaction of genetic factors and environmental factors such as maternal smoking, alcohol consumption, inadequate intake of folic acid, B6 and B12 vitamins during pregnancy can cause cleft lip and palate formation. Genetic studies on this disorder have investigated numerous candidate genes. MTHFR, MTR, MTRR, TGFβ and PVRL1 genes are important genes that cause cleft lip and palate. The inability to detect cleft lip and palate formation early is probably due to lack of knowledge of the mechanisms of gene expression patterns and action of effective signaling molecules that regulate lip and palate development during embryogenesis. Determination of the factors causing the cleft lip and palate etiology is very important in terms of prevention of cleft lip and palate formation and taking necessary precautions. In this review, it is aimed to determine the relationship between cleft lip palate disease and genetic factors.

Keywords:

Cleft lip-palate syndrome, Polymorphism, Folic Acid, MTHFR deficiency,

PDF

___

1. Pezzetti F, Martinelli M, Scapoli L, et al. Maternal MTHFR Variant Forms Increase the Risk in Offspring of Isolated Nonsyndromic Cleft Lip With or Without Cleft Palate. Hum Mutat. 2004; 24(1): 104-5.
2. Güvenç TN, Aksu M, Kocadereli I. The role of orthodontics in the treatment of cleft lip-palate patients. Dental Journal of Dicle. 2010; 11(1): 57-65.
3. Dixon MJ, Marazita ML, Beaty TH, et al. Cleft lip and palate:understanding genetic and environmental influences. Nat Rev Genet. 2011; 12(3): 167-78.
4. Goyette P, Pai A, Milos R, et al. Gene structure of human and mouse methylenetetrahydrofolate. Mamm Genome. 1998; 9(8): 652–6.
5. Goyette P, Sumner JS, Milos R, et al. Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet. 1994; 7(2): 195-200.
6. Blanton SH, Henry RR, Yuan Q, et al. Folate Pathway and Nonsyndromic Cleft Lip and Palate. Birth Defects Res Part A. 2011; 91(1): 50-60.
7. Bhaskara LV, Murthy J, Venkatesh Babu G. Polymorphisms in genes involved in folate metabolism and orofacial clefts. Arch Oral Biol. 2011; 56: 723-37.
8. Vaughn JD, Bailey LB, Shelnutt KP, et al. Methionine synthase reductase 66A->G polymorphism is associated with increased plasma homocysteine concentration when combined with the homozygous methylenetetrahydrofolate reductase 677C->T variant. J Nutr. 2004; 134(11): 2985-90.
9. Barbosa PR, Stabler SP, Machado AL, et al. Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphisms as determinants for elevated total homocysteine concentrations in pregnant women. Eur J Clin Nutr. 2008; 62: 1010-21.
10. Refsum H. Folate, vitamin B12 and homocysteine in relation to birth defects and pregnancy outcome. Br J Nutr. 2001; 85(2): 109-13.
11. Dikmen M. Molecular Biology of Methylenetetrahydrofolate Reductase (MTHFR) Enzyme and Its Association with Diseases. Kocatepe Medical Journal. 2004; 5: 9- 16.
12. Lamprecht SA, Lipkin M. Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms. Nat Rev Cancer. 2003; 3(8): 601-14.
13. Evans JC, Huddler DP, Hilgers MT, et al. Structures of the N-terminal modules imply large domain motions during catalysis by methionine synthase. Proc Natl Acad Sci USA. 2004; 101(11): 3729-36.
14. Yi P, Melnyk S, Pogribna M, Pogribny IP, et al. Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation. The Journal of Biological Chemistry. 2000; 275(38), 29318-23.
15. Bezerra JF, Oliveira GH, Soares CD, et al. Genetic and non-genetic factors that increase the risk of non-syndromic cleft lip and/or palate development. Oral Dis. 2015; 21(3): 393-9.
16. Weiner AS, Boyarskikh UA, Voronina EN, Mishukova OV, Filipenko ML. Methylenetetrahydrofolate reductase C677T and methionine synthase A2756G polymorphisms influence on leukocyte genomic DNA methylation level. Gene. 2014;533(1):168-72.
17. James SJ, Melnyk S, Pogribna M, et al. Elevation in S-adenosylhomocysteine and DNA hypomethylation: potential epigenetic mechanism for homocysteine-related pathology. J Nutr. 2002; 132(8): 2361-6.
18. Leclerc D, Wilson A, Dumas R, et al. Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria. Proc Natl Acad Sci USA. 1998; 95: 3059-64.
19. Wolthers KR, Scrutton NS. Protein interactions in the human methionine synthase-methionine synthase reductase complex and implications for the mechanism of enzyme reactivation. Biochemistry. 2007; 46(23): 6696-709.
20. Chorna LB, Akopyan HR, Makukh HV, Fedoryk IM. Allelic polymorphisms in the MTHFR, MTR and MTRR genes in patients with cleft lip and/or palate and their mothers. Cytology and Genetics. 2011; 45(3):177-81.
21. Brandalize AP, Bandinelli E, Borba JB, et al.Polymorphisms in genes MTHFR, MTR and MTRR are not risk factors for cleft lip/palate in South Brazil. Braz J Med Biol Res. 2007; 40(6): 787-91.
22. Gaughan DJ, Kluijtmans LA, Barbaux S, et al. The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations. Atherosclerosis. 2001; 157(2): 451-6.
23. Cheng HQ, Huang EM, Xu MY, et al. PVRL1 as a Candidate Gene for Nonsyndromic Cleft Lip With or Without Cleft Palate: No Evidence for the Involvement of Common or Rare Variants in Southern Han Chinese Patients. DNA Cell Biol. 2012;31(7): 1321-7.
24. Sakisaka T, Ikeda W, Ogita H, et al. The roles of nectins in cell adhesions: cooperation with other cell adhesion molecules and growth factor receptors. Curr Opin Cell Biol. 2007;19(5): 593-602.
25. Takai Y, Miyoshi J, Ikeda W,et al. Nectins and nectin-like molecules: roles in contact inhibition of cell movement and proliferation. Nat Rev Mol Cell Biol. 2008; 9(8); 603-15.
26. Suzuki K, Hu D, Bustos T, et al. Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia. Nat Genet. 2000;25(4): 427-30.
27. Sözen MA, Suzuki K, Tolarova MM, Bustos T, Fernandez Iglesias JE, Spritz RA. Mutation of PVRL1 is associated with sporadic, non-syndromic cleft lip/palate in northern Venezuela. Nat Genet. 2001; 2:141-2.
28. Avila JR, Jezewski PA, Vieira AR, et al. PVRL1 variants contribute to non-syndromic cleft lip and palate in multiple populations. Am J Med Genet A. 2006;140(23): 2562-70.
29. Nawshad A, LaGamba D, Hay ED. Transforming growth factor beta (TGFbeta) signalling in palatal growth, apoptosis and epithelial mesenchymal transformation (EMT). Arch Oral Biol. 2004;49(9): 675-89.
30. Khalil N, Parekh TV, O'Connor R, et al. Regulation of the effects of TGF-beta 1 by activation of latent TGF-beta 1 and differential expression of TGF-beta receptors (T beta R-I and T beta R-II) in idiopathic pulmonary fibrosis. BMJ Thorax. 2001; 56(12): 907-15.
31. Wipff PJ, Hinz B. Integrins and the activation of latent transforming growth factor beta1 - an intimate relationship. Eur J Cell Biol. 2008; 87(8-9): 601-15.
32. Gressner OA, Weiskirchen R, Gressner AM. Evolving concepts of liver fibrogenesis provide new diagnostic and therapeutic options. Comp Hepatol. 2007; 6: 7.
33. Barutcuoglu M, Umur AS, Vatansever HS, et al. TGF-βs and Smads activities at the site of failed neural tube in the human embryos. Turkish Neurosurgery. 2013;23(6): 693-9.
34. Vural P. The Suppressing Role of Transforming Growth Factor- B in Cancer. Türk Klinik Biyokimya Dergisi. 2010; 8(1): 35-42.
35. Bodo M, Baroni T, Carinci F, et al. TGFbeta isoforms and decorin gene expression are modified in fibroblasts obtained from non-syndromic cleft lip and palate subjects. J Dent Res. 1999; 78(12): 1783-90.
36. Bush JO, Jiang R. Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development. Development. 2012; 139: 231-43.
37. Cambien F, Ricard S, Troesch, A, et al. Polymorphisms of the transforming growth factor-beta 1 gene in relation to myocardial infarction and blood pressure. The Etude Cas-Témoin de l'Infarctus du Myocarde (ECTIM) Study. Hypertension.1996; 28(5): 881-7.
38. Dunning AM, Ellis PD, McBride S, et al. A transforming growth factorbeta1 signal peptide variant increases secretion in vitro and is associated with increased incidence of invasive breast cancer. Cancer Res. 2003; 63(10): 2610-15.
39. Scapoli L, Palmieri A, Martinelli M, et al. Strong evidence of linkage disequilibrium between polymorphisms at the IRF6 locus and nonsyndromic cleft lip with or without cleft palate, in an Italian population. Am J Hum Genet. 2005; 76(1): 180-3.
40. Iwata J, Parada C, Chai Y. The mechanism of TGF-β signaling during palate development. Oral Dis. 2011; 17(8): 733-44.
41. Zucchero TM, Cooper ME, Maher BS, et al. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med. 2004; 351(8): 769-80.
42. Parada-Sanchez MT, Chu EY, Cox LL, et al. Disrupted IRF6-NME1/2 Complexes as a Cause of Cleft Lip/Palate. J Dent Res. 2017; 96(11): 1330-8.
43. Kondo S, Schutte BC, Richardson RJ, et al. Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nat Genet. 2002; 32(2): 285-9.
44. Little HJ, Rorick NK, Su LI, et al. Missense mutations that cause Van der Woude syndrome and popliteal pterygium syndrome affect the DNA-binding and transcriptional activation functions of IRF6. Hum Mol Genet. 2009; 18(3): 535-45.
45. Schutte BC, Murray JC. The many faces and factors of orafacial clefts. Hum Mol Genet 1999; 8(10): 1853-9.
46. Biri A, Onan A, Kocrucuoğlu Ü, Tıraş B, Himmetoğlu Ö. Bir Üniversite Hastanesinde Konjenital Malformasyonların Görülme Sıklığı ve Dağılımı. Perinatoloji Dergisi. 2005; 13(2): 86-90.
47. Tunçbilek G, Özgür F, Balcı S. 1229 yarık dudak ve damak hastasında görülen ek malformasyonlar ve sendromlar, Çocuk Sağlığı ve Hastalıkları Dergisi. 2004; 47(1): 172-6.
48. Semiç-Jusufagiç A, Bircan R, Çelebiler Ö, et al. Association between C677T and A1298C MTHFR gene polymorphism and nonsyndromic orofacial clefts in the Turkish population: a case-parent study. The Turkish Journal of Pediatrics. 2012; 54(6): 617-25.