Identification of common differentially expressed genes in Turner (45,X) and Klinefelter (47,XXY) syndromes using bioinformatics analysis

Abstract

Background: Analysis of patients with chromosomal abnormalities, including Turner syndrome and Klinefelter syndrome, has highlighted the importance of X-linked gene dosage as a contributing factor for disease susceptibility. Escape from X-inactivation and X-linked imprinting can result in transcriptional differences between normal men and women as well as in patients with sex chromosome abnormalities.

Objective: To identify differentially expressed genes among patients with Turner (45,X) and Klinefelter (46,XXY) syndrome using bioinformatics analysis.

Methodology: Two gene expression data sets of Turner (45,X) and Klinefelter syndrome (47,XXY) were obtained from the Gene Omnibus Expression (GEO) database of the National Center for Biotechnology Information (NCBI). Statistical analysis was performed using R Bioconductor libraries. Differentially expressed genes (DEGs) were determined using significance analysis of microarray (SAM). The functional annotation of the DEGs was performed with DAVID v6.8 (The Database for Annotation, Visualization, and Integrated Discovery).

Results: There are no genes over-expressed simultaneously in both diseases. However, when crossing the list of under-expressed genes for 45,X cells and the list of over-expressed genes for 47,XXY cells, there are 16 common genes: SLC25A6, AKAP17A, ASMTL, KDM5C, KDM6A, ATRX, CSF2RA, DHRSX, CD99, ZBED1, EIF1AX, MVB12B, SMC1A, P2RY8, DOCK7, DDX3X, eight of which are involved in the regulation of gene expression by epigenetic mechanisms, regulation of splicing processes and protein synthesis.

Conclusion: Of the 16 identified as under-expressed in 45,X cells and over-expressed in 47,XXY cells, 14 are located in X chromosome and 2 in autosomal chromosome; 8 of these genes are involved in the regulation of gene expression: 5 genes are related to epigenetic mechanisms, 2 in regulation of splicing processes, and 1 in the protein synthesis process. Our results are limited by it being the product of a bioinformatic analysis from mRNA isolated from whole blood, this makes necessary further exploration of the relationships between these genes and Turner syndrome and Klinefelter syndrome in the future.

FIGURE 1

The SAM plot of overexpressed and downregulated genes. (a) The Turner's syndrome SAM plot given a d_i = 3.0649, differentially expressed genes deviate from the diagonal area: upregulated genes are colored in red dots in the upright corner and green dots in the bottom‐left corner represent downregulated. (b) The Klinefelter's syndrome SAM plot given a d_i = 0.9579, differentially expressed genes deviate from the diagonal area: upregulated genes are colored in red dot in the upright corner, not observed downregulated genes

FIGURE 2

X‐linked genes upregulated in Klinefelter Syndrome and downregulated in Turner Syndrome. Differential patterns of gene expression obtained from microarray data from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database (a). Presence of 14 common genes on the X chromosome, which are oppositely regulated in Turner syndrome and in Klinefelter syndrome. Pseudoautosomal genes are represented in green and genes coding for gene expression regulators are represented in red. (b) 8 genes involved in the regulation of gene expression: five genes are related to epigenetic mechanisms, two to regulation of splicing processes and one to the protein synthesis process. Include highest earned academic degree for authors on title page. Created with BioRe​nder.com

FIGURE 3

Differentially expressed genes in Turner syndrome and Klinefelter syndrome involved in gene expression mechanisms. Proposed model showing eight genes expressed differentially in TS and KS. KDM5C, KDM6A, ZBED1, ASMTL, and ATRX genes are involved in epigenetic processes. DDX3X and AKAP17A genes encode for regulatory proteins of splicing processes, and EIFIAX is related to the protein synthesis process. Created with BioRe​nder.com