AUTHOR=Al-Obaide Mohammed A. , Islam Saimul , Al-Obaidi Ibtisam , Vasylyeva Tetyana L. 

TITLE=Novel enhancer mediates the RPL36A-HNRNPH2 readthrough loci and GLA gene expressions associated with fabry disease

JOURNAL=Frontiers in Genetics

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1229088

DOI=10.3389/fgene.2023.1229088

ISSN=1664-8021

ABSTRACT=<p>Fabry disease (FD) is a rare genetic condition caused by mutations in the <italic>GLA</italic> gene, located on the X chromosome in the <italic>RPL36-HNRNPH2</italic> readthrough genomic region. This gene produces an enzyme called alpha-galactosidase A (α-Gal A). When the enzyme does not function properly due to the mutations, it causes harmful substances called globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) to build up in the body’s lysosomes. This accumulation can damage the kidneys, heart, eyes, and nervous system. Recent studies have shown that the <italic>RPL36A-HNRNPH2</italic> readthrough loci, which include <italic>RPL36A</italic> and <italic>HNRNPH2</italic> genes, as well as the regulatory sequence known as the <italic>GLA-HNRNPH2</italic> bidirectional promoter, may also play a role in FD. However, the involvement of enhancer RNAs (eRNAs) in FD is still poorly understood despite their known role in various diseases. To investigate this further, we studied an <italic>RPL36A</italic> enhancer called GH0XJ101390 and showed its genomic setting in the <italic>RPL36-HNRNPH2</italic> readthrough region; the eRNA is rich in Homotypic Clusters of TFBSs (HCTs) type and hosts a CpG Island (CGI). To test the functional correlation further with <italic>GLA</italic>, <italic>RPL36A</italic>, and <italic>HNRNPH2</italic>, we used siRNAs to knock down GH0XJ101390 in human kidney embryonic cells 293T. The results showed a significant decrease in <italic>RPL36A</italic> and <italic>GLA</italic> expression and a non-significant decrease in <italic>HNRNPH2</italic> expression. These findings could have important implications for understanding the regulatory mechanisms of GH0XJ101390 and its potential role in FD. A better understanding of these mechanisms may improve diagnostic and therapeutic methods for FD, which could ultimately benefit patients with this rare condition.</p>