Widespread DNA hypomethylation and differential gene expression in Turner syndrome

Abstract

Adults with 45,X monosomy (Turner syndrome) reflect a surviving minority since more than 99% of fetuses with 45,X monosomy die in utero. In adulthood 45,X monosomy is associated with increased morbidity and mortality, although strikingly heterogeneous with some individuals left untouched while others suffer from cardiovascular disease, autoimmune disease and infertility. The present study investigates the leukocyte DNAmethylation profile by using the 450K-Illumina Infinium assay and the leukocyte RNA-expression profile in 45,X monosomy compared with karyotypically normal female and male controls. We present results illustrating that genome wide X-chromosome RNA-expression profile, autosomal DNA-methylation profile, and the X-chromosome methylation profile clearly distinguish Turner syndrome from controls. Our results reveal genome wide hypomethylation with most differentially methylated positions showing a medium level of methylation. Contrary to previous studies, applying a single loci specific analysis at well-defined DNA loci, our results indicate that the hypomethylation extend to repetitive elements. We describe novel candidate genes that could be involved in comorbidity in TS and explain congenital urinary malformations (PRKX), premature ovarian failure (KDM6A), and aortic aneurysm formation (ZFYVE9 and TIMP1).

Recognition and management of adults with Turner syndrome: From the transition of adolescence through the senior years

“…Therefore, the frequency of heart and lymphatic problems in Turner syndrome may be best explained by a combination of copy number variation of X chromosome genes and altered expression of autosomal genes that also contribute to congenital defects in the general population. Recent studies identified autosomal gene mutations or epigenetic changes in women with Turner syndrome who have cardiac abnormalities, providing the first evidence to support this hypothesis (Corbitt et al, ; Prakash et al, ; Rajpathak, Vellarikkal, Patowary, Sivasubbu, & Deobagkar, ; Trolle et al, ).…”

Many women with Turner syndrome lack protective antibodies to common respiratory pathogens, Haemophilus influenzae type B and Streptococcus Pneumoniae

“…While the pathogenesis of Tfh cell dysfunction remains to be fully understood, it has been proposed that reduced expression of KDM6A ( UTX) —a gene residing on the X chromosome which has recently proved to have differential methylation and expression in patients with TS —leads to reduced Tfh subset differentiation in TS . This hypothesis is supported by observations of marked increased susceptibility to upper airway and ear infections in patients harbouring KDM6A mutation with Kabuki syndrome—a rare multisystem developmental disorder …”

The pattern of X-inactivation in Human X-linked Disorders and their Model Organisms: A literature review

“…However, a conflicting result has shown by comparing with genomewide RNA expression, that KDM6A has the same expression levels in TS patients and normal females [30]. Although, interestingly, this researcher has also demonstrated different methylation status of KDM6A compared with TS (45, XO) and 46, XX [30]. Based on these research, abnormal methylation status of KM6DA could be the reason of hyperinsulinism in TS patients.…”

“…These facts could be evidence for that KM6DA is probably responsible for hyperinsulinism in TS infants [13]. However, a conflicting result has shown by comparing with genomewide RNA expression, that KDM6A has the same expression levels in TS patients and normal females [30]. Although, interestingly, this researcher has also demonstrated different methylation status of KDM6A compared with TS (45, XO) and 46, XX [30].…”