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. 2009 Apr;54(4):193-8.
doi: 10.1038/jhg.2009.5. Epub 2009 Mar 13.

William's Syndrome: Gene Expression Is Related to Parental Origin and Regional Coordinate Control

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Free PMC article

William's Syndrome: Gene Expression Is Related to Parental Origin and Regional Coordinate Control

Jeremy C Collette et al. J Hum Genet. .
Free PMC article

Abstract

William's syndrome (WS) features a spectrum of neurocognitive and behavioral abnormalities due to a rare 1.5 MB deletion that includes about 24-28 genes on chromosome band 7q11.23. Study of the expression of these genes from the single normal copy provides an opportunity to elucidate the genetic and epigenetic controls on these genes as well as their roles in both WS and normal brain development and function. We used quantitative RT-PCR to determine the transcriptional level of 14 WS gene markers in a cohort of 77 persons with WS and 48 normal controls. Results reported here: (1) show that the expression of the genes deleted in WS is decreased in some but not all cases, (2) demonstrate that the parental origin of the deletion contributes to the level of expression of GTF2I independently of age and gender and (3) indicate that the correlation of expression between GTF2I and some other genes in the WS region differs in WS subjects and normal controls, which in turn points toward a regulatory role for this gene. Interspecies comparisons suggest GTF2I may play a key role in normal brain development.

Figures

Figure 1
Figure 1
William's syndrome chromosome region genes and gene expression. (a) Map of genes commonly deleted in 7q11.23 (black) and analyzed in current report (blue); (b) Expression patterns over all 14 genes are similar for the two groups regardless of whether values are normalized relative to ACTB, PPIA or HPRT1. Data for these calculations are in Supplementary Table 2.
Figure 2
Figure 2
Quantitative expression of 14 genes in William's syndrome. Expression is decreased for many but not all deleted genes. (a) Plots of bivariate analysis for each gene; values for each normal control subject (left) and William's syndrome subjects (right) are normalized to ACTB and shown as ΔCt. Number of subjects in each group is also shown. (b) Bar graph showing each gene's median expression and s.d. (expression in normal controls=1;*=P<0.0001). Data for these calculations are in Supplementary Table 1. Error range is determined by evaluating the expression: 2−ΔΔCt with Δ ΔCt+s and ΔΔCt−s, where s= the standard deviation of the Δ ΔCt value according to User Bulletin No. 2: ABI Prism 7700 Sequence Detection System, December 1997 (Applied Biosystems).
Figure 3
Figure 3
Effect of parental origin on gene expression in two independent groups of William's syndrome subjects. (a) In two independent groups, the expression of GTF2I, but not other selected genes, is lower in subjects with deletions on the maternal chromosome. Left panels show bivariate analysis for each gene in Group 1 (top) and Group 2 (bottom); number of subjects where the deleted chromosome of maternal (M) or paternal (P) is also displayed. Right panel shows leveraged residuals for GTF2I in the combined groups.
Figure 4
Figure 4
Pairwise correlation of expression of WS-deleted-region genes in WS subjects and normal controls. Correlation of GTF2I expression with that of other genes (■) reveals a set that are significantly positive in WS and significantly negative in normal controls. (a) Pearson correlation coefficients of gene pairs in normal controls (x axis) and William's syndrome group 1 (y axis); coefficients less than ±0.35 are not significant (P>0.05). (b) Quantitative pairwise gene to gene correlations used for 4a, displayed as bar graphs. These show that gene-to-gene correlations are similar in magnitude and direction in WS and NC except for GTF2I. The order of gene-to-gene correlations begins with the gene denoted at the left of the plot versus FZD9 then adds genes in genomic order from left to right. (for example, first comparison is WSTF versus FZD9, then TBL2 versus FZD9, TBL2 versus WSTF, followed by WBSCR14 versus FZD9, WBSCR14 versus WSTF, WBSCR14 versus TBL2, etc.). Note that among the largest differences in correlation coefficients between NC and WS are with GTF2I and FZD9, STX1A, CLDN3, CLDN4 and WBSCR23. These correlations change sign and are significant for both NC and WS. (c) Pairwise correlations of deleted WS genes in normal controls (NC), WS group 1 (WSG1) and WS Group 2 (WSG2). The degree of coexpression of CLDN3 and CLDN4 in NC, WSG1 and WSG2 is notable compared to other neighboring genes on chromosome 7 that are oriented head to head and located 50–70kb apart as shown in Supplementary Figure 1.

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