The potential consequences of bidirectional promoter methylation on GLA and HNRNPH2 expression in Fabry disease phenotypes in a family of patients carrying a GLA deletion variant

Biomed Rep. 2022 Jun 24;17(2):71. doi: 10.3892/br.2022.1554.

PMID: 35910704

Mohammed A Al-Obaide, Ibtisam I Al-Obaidi, Tetyana L Vasylyeva

Highlights: According to the data obtained in this study, the DNA methylation of GLA-HNRNPH2 BDP may serve a role in diagnosing and treating Fabry disease (FD).

Abstract

Background: A variety of symptoms are present in Fabry disease (FD), a rare inherited condition caused by GLA mutations that impair α-galactosidase A (α-Gal A) and cause glycosphingolipid accumulation. The heterogeneous nuclear ribonucleoprotein HNRNPH2 locus, which is mapped in the RPL36A-HNRNPH2 readthrough locus, is paired divergently with the GLA locus.

Objective: The current study examined the potential cumulative impact of BDP methylation and GLA mutation on the severity of FD in patients from the same family, two males and two females carrying the GLA deletion mutation, c.1033_1034delTC (p.Ser345Argfs). This was done as a follow-up to our recent discovery that GLA and HNRNPH2 are co-regulated via a bidirectional promoter (BDP) in normal kidney and skin cells.

Results: When the BDP methylation level in FD patients was elevated compared to low BDP methylation and high GLA expression (P<0.05) and a high trend of HNRNPH2 expression in normal people, the molecular analyses of the FD patients and control group showed that the expression of GLA was significantly low (P<0.05) and HNRNPH2 showed a tendency of low expression (P=0.1). Three patients showed the accumulative impact of the mutation and BDP methylation with the severity of the condition. The highest degree of BDP DNA methylation was observed in one male FD patient, a member of the FD family, who had the lowest level of α-Gal A enzyme activity and was diagnosed with progressive kidney dysfunction, hypertension, and eventually a stroke.

Conclusion: It is concluded that GLA-HNRNPH2 BDP DNA methylation may aid in the detection and management of FD.

Keywords: DNA methylation, Fabry disease, GLA, HNRNPH2, bidirectional promoter