ANALYSIS OF MICROSATELLITE POLYMORPHISMS IN SOUTH INDIAN PATIENTS WITH NON SYNDROMIC CLEFT LIP AND PALATE
Xavier DL1,* Arif YA1, Murali RV1, Kishore Kumar S1, Vipin Kumar S2, Tamang R2, Thangaraj K2, Bhaskar LVKS3
*Corresponding Author: Dr. Dhayananth L. Xavier, Department of Orthodontics, Sree Balaji Dental College, Pallikaranai, Chennai, India; Tel.: +91-44-22461883; E-mail: drxavy@gmail.com
page: 49

DISCUSSION

The present study investigated possible associations between NSCLP and microsatellite markers from five dif-ferent genes. We demonstrated the distribution of micro-satellite markers in the NSCLP and control groups in the South Indian samples. The differences in the frequency of different alleles were statistically significant between NSCLP and controls for only the RARA gene microsatel-lite. Retinoic acid (RA) and its signaling pathway was in-volved in normal development of the frontonasal and maxillary structures [8]. Retinoic acid appeared to cause G1 arrest in palatal mesenchymal cells in a similar manner as in various cancer and embryonic cells. It is likely that apoptotic cell death and cell cycle disruption are involved in cleft palate formation induced by RA [9]. The RARA gene that had been studied using case-control association and linkage parameters, yielded contradictory results [10,11]. Other authors, using non parametric methods, reported negative results of association [12] as well as positive results for linkage [13]. Another microsatellite marker of RA receptor-a (RARA), D17S579 was also investigated to test the relationship between the genetic susceptibility to NSCLP in Hunan Hans [14]. Endothelin-1 is synthesized by vascular endothelial cells and is found in plasma. Endothelin-1 is released from an inactive transitional form in a step catalyzed by endothelin-converting enzyme (ECE). The EDN1 knockout mice have shown craniofacial abnormalities, including cleft palate [15]. The mouse deficient in ECE or endo-thelin-A receptor genes has also shown almost identical abnormalities to those of EDN1-deficient mice [16]. In zebra fish, EDN1 is expressed ventrally in the primordia of the pharyngeal arches and helps in patterning of pharyngeal cartilage development. By injecting the morpholino, Kimmel et al. [17], demonstrated the role of EDN1 in the sizing of pharyngeal skeletal elements of the jaw and oper-cular regions in zebra fish. But genes involved in the endothelin pathway (EDN1, ECE1, EDNRA and EDNRB) have not shown linkage with orofacial clefts [18]. The MSX1 homeobox gene is expressed at diverse sites of epithelial-mesenchymal interaction during vertebrate embryogenesis, and has been implicated in signalling processes between tissue layers. Mice lacking the MSX1 function manifest a cleft secondary palate, a deficiency of alveolar mandible and maxilla and a failure of tooth development [19,20]. Analysis of a Dutch family with CL/P, CP and selective tooth agenesis, revealed a heterozygous nonsense mutation in the MSX1 gene. Furthermore, complete sequencing of the MSX1 gene in 1000 unrelated CL/P individuals showed that mutations on the MSX1 gene alone could account for 2.0% of isolated CL/P [21]. Members of the Dlx gene family contain a homeobox that is related to that of distal-less (Dll), a gene expressed in the head and limbs of the developing fruit fly. Mutations in this gene have been associated with the autosomal dominant conditions like trichodentoosseous syndrome and amelogenesis imperfecta with taurodontism [22]. In the Japanese the DLX3 gene failed to show positive association [23]. The present study also failed to demonstrate statistically significant difference in the frequency of different alleles between NSCLP and controls for the DLX3 microsatellite. The proto-oncogene BCL3 has a role in the transcriptional regulation of genes involved in cell cycles [24]. Analysis of three ethnic populations using a variety of parametric and non parametric techniques showed linkage between NSCLP and the BCL3 microsatellite [25]. Moreover, the present study also failed to show statistically significant association between CL/P and controls using the BCL3 microsatellite. The association study design may determine whether alleles occur together with a specific phenotype more often than in a control group. There were several limitations to this study. First, we ascertained subjects without considering the smoking status and drug usage, which prevented us analyzing gene environment interactions and second, our relatively small total samples as well as markers, would have allowed the population stratification and influenced the ability to identify association between CL/P and micro-satellite polymorphisms. Large-scale association studies may provide a powerful tool for identifying alleles associated with complex phenotypes such as orofacial clefts. Declaration of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.



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