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
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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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