Imprinting aberrations of SNRPN, ZAC1 and INPP5F genes involved in the pathogenesis of congenital heart disease with extracardiac malformations

Abstract

Congenital heart disease (CHD) with extracardiac malformations (EM) is the most common multiple malformation, resulting from the interaction between genetic abnormalities and environmental factors. Most studies have attributed the causes of CHD with EM to chromosomal abnormalities. However, multi‐system dysplasia is usually caused by both genetic mutations and epigenetic dysregulation. The epigenetic mechanisms underlying the pathogenesis of CHD with EM remain unclear. In this study, we investigated the mechanisms of imprinting alterations, including those of the Small nuclear ribonucleoprotein polypeptide N (SNRPN), PLAG1 like zinc finger 1 (ZAC1) and inositol polyphosphate‐5‐phosphatase F (INPP5F) genes, in the pathogenesis of CHD with EM. The methylation levels of SNRPN, ZAC1, and INPP5F genes were analysed by the MassARRAY platform in 24 children with CHD with EM and 20 healthy controls. The expression levels of these genes were detected by real‐time polymerase chain reaction (PCR). The correlation between methylation regulation and gene expression was confirmed using 5‐azacytidine (5‐Aza) treated cells. The methylation levels of SNRPN and ZAC1 genes were significantly increased in CHD with EM, while that of INPP5F was decreased. The methylation alterations of these genes were negatively correlated with expression. Risk analysis showed that abnormal hypermethylation of SNRPN and ZAC1 resulted in 5.545 and 7.438 times higher risks of CHD with EM, respectively, and the abnormal hypomethylation of INPP5F was 8.38 times higher than that of the control group. We concluded that abnormally high methylation levels of SNRPN and ZAC1 and decreased levels of INPP5F imply an increased risk of CHD with EM by altering their gene functions. This study provides evidence of imprinted regulation in the pathogenesis of multiple malformations.

Maternal effect genes: Update and review of evidence for a link with birth defects

“…A role for methylation and imprinting abnormalities in the etiology of structural birth defects is consistent with the occurrence of such conditions in imprinting syndromes (e.g., omphalocele in Beckwith-Wiedemann syndrome) 83 , 93 and has been suggested based on studies of non-syndromic structural birth defects. 94 , 95 , 96 , 97 Further, epigenetic and imprinting differences resulting from ARTs have been suggested as a potential cause for the increased risk of structural birth defects in offspring conceived by in vitro fertilization or intracytoplasmic sperm injection. 98 , 99 Consequently, it may be that any association between structural birth defects and MEGs is limited to the subset of MEGs that are involved in methylation and imprinting.…”

Global RNA editing identification and characterization during human pluripotent-to-cardiomyocyte differentiation

“…Moreover, previous studies reported that SNHG14 and SNRPN are involved in the pathogenesis of cardiac hypertrophy and CHD, respectively. 27 , 28 These results indicated that A-to-I editing events during cardiomyocyte differentiation may also be related to cardiovascular diseases.…”

The role of DNA methylation in syndromic and non-syndromic congenital heart disease

“…Another study on aberrations imprinting genes involved in the pathogenesis of CHD with extracardiac malformations also found the hypermethylation of INPP5F. In addition, risk analysis showed that abnormal hypermethylation of SNRPN and ZAC1 resulted in 5.545 and 7.438 times higher risks of CHD with extracardiac malformations [ 144 ].…”