Network-based analysis of key regulatory genes implicated in Type 2 Diabetes Mellitus and Recurrent Miscarriages in Turner Syndrome

Abstract

The information on the genotype–phenotype relationship in Turner Syndrome (TS) is inadequate because very few specific candidate genes are linked to its clinical features. We used the microarray data of TS to identify the key regulatory genes implicated with TS through a network approach. The causative factors of two common co-morbidities, Type 2 Diabetes Mellitus (T2DM) and Recurrent Miscarriages (RM), in the Turner population, are expected to be different from that of the general population. Through microarray analysis, we identified nine signature genes of T2DM and three signature genes of RM in TS. The power-law distribution analysis showed that the TS network carries scale-free hierarchical fractal attributes. Through local-community-paradigm (LCP) estimation we find that a strong LCP is also maintained which means that networks are dynamic and heterogeneous. We identified nine key regulators which serve as the backbone of the TS network. Furthermore, we recognized eight interologs functional in seven different organisms from lower to higher levels. Overall, these results offer few key regulators and essential genes that we envisage have potential as therapeutic targets for the TS in the future and the animal models studied here may prove useful in the validation of such targets.

Hyperglycemia in Turner syndrome: Impact, mechanisms, and areas for future research

“…Several studies have demonstrated abnormal gene expression profiles ( 32 , 68 ) and differentially methylated X chr and autosomal genes in individuals with TS ( 68 , 69 ) Functional annotations of TS datasets (RNA sequencing and DNA methylation analysis of fibroblasts) demonstrate enrichment in genes involved in carbohydrate metabolism and glucose import ( 68 , 70 ). Two recent studies have employed bioinformatics approaches to identify differentially expressed genes in TS and used pathway analysis to determine key differentially regulated pathways relevant to diabetes ( 71 , 72 ). Candidate signature genes of DM in TS include 8 upregulated autosomal genes, including SLC29A2, THBS1, GPRC5B, CSHL1, ADAM22, IGHM, WIZ, IGHD , and 1 downregulated autosomal gene, COX11 ( 72 ).…”

“…Two recent studies have employed bioinformatics approaches to identify differentially expressed genes in TS and used pathway analysis to determine key differentially regulated pathways relevant to diabetes ( 71 , 72 ). Candidate signature genes of DM in TS include 8 upregulated autosomal genes, including SLC29A2, THBS1, GPRC5B, CSHL1, ADAM22, IGHM, WIZ, IGHD , and 1 downregulated autosomal gene, COX11 ( 72 ). It is not known if these altered autosomal genetic signatures are involved in the pathogenesis of diabetes in TS individuals.…”