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Provide an essay for this summary: The study found that some CNV's within some duplicated segments of the 7q11.23 region can predispose the carriers to the development of WBS.
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##Introduction
Williams-Beuren syndrome (WBS) or Williams’ syndrome is a neuro-developmental genetic disorder affecting the central nervous system and most connective tissues. WBS is caused by hemizygous deletions within the critical region of chromosome 7q11.23 including the GTF2IRD1 gene (Ewart 11).
Moreover, insufficient levels of the dosage-sensitive genes within the 7q11.23 region have also been implicated in the genesis of WBS. Additionally, reduced levels of elastin, which occurs as a result of deletion of ELN, lead to a prominent feature of WBS known to as supravalvular aortic stenosis (SVAS). Accordingly, human genomic studies show that the GTF2IRD1 and GTF2I genes play a pivotal role in the occurrence of certain features of WBS such as craniofacial dysmorphology, visuospatial deficits, and hypersociability among others (Ewart 12).
In this paper, we are going to review three experimental studies regarding WBS to highlight the major DNA, protein, and phenotypic alterations implicated in this genetic disorder. Here, it is expected that the results of the three experimental studies will point out the major predisposing factors in the development of WBS particularly the gene deletions involving the 7q11.23 critical region.
##Method
To identify the most appropriate research materials for this paper, the PubMed internet search engine was used. Therefore, some key words such as Williams’ syndrome, phenotypic alterations, and chromosome 7q11.23 were used to locate scholarly and peer reviewed journal articles published in 2003-2011.
##Results/Observations
Using the above-mentioned approach, three scholarly and peer reviewed articles highlighting different experiments on WBS were identified and used in the discussions provided below. Here, it is worth noting that all the experiments are centered on chromosome 7q11.23, and thus, there is evidence to suggest that most complications associated with WBS relate to major alterations or deletions in the critical region of the chromosome.
##Discussions
Experimental studies show that some of the copy number variants (CNVs) within some duplicated segments of the 7q11.23 region predispose the carriers to the development of WBS (Cusco et al. 683). To determine this factor, the authors studied samples from 180 WBS patients who had been diagnosed of 7q11.23 deletions. Moreover, the study involved 420 blood donors and 180 non-WBS-transmitting progenitors, as the controls.
The study entails extraction of genomic DNA from the peripheral blood samples of the participants. Subsequently, the genomic DNA was analyzed relative to various parameters such as quantification of copy number variants (CNVs), quantification of multicopy microsatellite markers, and sequence analyses (Cusco et al. 684).
In this study, the experimental results show that there is a significant enrichment of the CNVs within the duplicated segments of 7q11.23 and also within regions containing low-copy repeats (LCRs). Moreover, the study shows that some heterozygous deletions within the critical region of 7q11.23 entail a process mediated by homologous recombination (NAHR) of large flanking regions containing low-copy repeats and other structural variants occurring within major inversions mainly in 20-25% of the transmitting progenitors.
Additionally, the study shows that 4.44% of the transmitting progenitors were carriers of some CNVs, which contain huge deletions of the low-copy repeats (LCRs). On the other hand, there were less than 1% of the blood donors and non-transmitting progenitors showing large deletions of LCRs within the CNVs. As a result, the authors concluded that large deletions within the CNVs predispose the carriers to the development of WBS (Cusco et al. 693).
On the other hand, Makeyev et al. (11052) note that the 7q11.23 critical region contains the GTF2IRD2 gene, which encodes products containing two helix-loop-helix repeats which resemble TFII-I family of proteins. Moreover, Makeyev et al. (11053) posit that the large deletions within the critical region of 7q11.23 include the GTF2IRD1 and GTF2I genes.
These two genes encode the TFII-I proteins containing several regions referred to as I-repeats. Conversely, the study utilizes the NCBI database to characterize the GTF2IRD2 gene, which resembles the GTF2IRD1 and GTF2I genes. Here, the authors utilized the exon-by-exon analysis approach in which case they discovered that besides the GTF2IRD2 gene resembling the two paralogs; it is certainly a derivative of the GTF2I gene sequence (Makeyev et al. 11056).
Moreover, the authors compared the gene sequences surrounding the GTF2IRD2 gene derived from humans and mice to show that there is a centromeric breakpoint within the 7q11.23 critical region of WBS patients. Consequently, gene deletions within sequences surrounding the GTF2IRD2 gene are also involved in the development of WBS (Makeyev et al. 11057).
Accordingly, additional experiments show that there is a novel DNA-binding mechanism that triggers negative auto-regulation of the GTF2IRD1 gene in patients with WBS (Palmer et al. 4715). The experiment utilizes knock-out mice and human cells from WBS patients and their relatives to carry out protein expression analyses, cell line analyses and immunofluorescence, RNA expression analyses, electrophoretic mobility shift assays (EMSA), and bioinformatics.
The experimental results show that mice with Gtf2ird1 allele mutations demonstrate behavioral changes and craniofacial abnormalities similar to those found in human WBS patients. Conversely, the study shows that there is a negative Autoregulation mechanism, which plays a pivotal role in compensating for the dosage-sensitive genes in WBS patients. This Autoregulation mechanism entails binding of the gene protein to certain promoter regions containing three binding sites.
Here, the GTF2IRD1 gene protein binds to its promoter region in DNA to control the level of the gene in the body through gene transcription. However, if the Autoregulation mechanism fails, there is no compensation for the lost GTF2IRD1 genes lost in WBS patients (Palmer et al. 4720).
##Conclusion
This research paper presents an elaborate discussion on Williams’ syndrome, which is a neuro-developmental genetic disorder that affects the central nervous system and the connective tissues. The discussions above show that this genetic disorder occurs as a result of gene deletions involving the 7q11.23 critical region, which contains additional genes such as GTF2IRD1, GTF2IRD2, and GTF2I. The three genes are critical to the body because they take part in the production of a family of proteins known as TFII-I, which are regulatory factors.