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

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

doi:10.3892/br.2022.1554

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

Authors:
- Mohammed A. Al-Obaide
- Ibtisam I. Al-Obaidi
- Tetyana L. Vasylyeva
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Affiliations: Department of Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
Published online on: June 24, 2022 https://doi.org/10.3892/br.2022.1554
Article Number: 71
Copyright: © Al-Obaide et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Fabry disease (FD) is a rare inherited disease characterized by a wide range of symptoms attributed to GLA mutations resulting in defective α‑galactosidase A (α‑Gal A) and accumulation of glycosphingolipids. The GLA locus is paired in a divergent manner with the heterogeneous nuclear ribonucleoprotein HNRNPH2 locus mapped in the RPL36A‑HNRNPH2 readthrough locus. As a follow‑up to our recent finding of the co‑regulation of GLA and HNRNPH2 via a bidirectional promoter (BDP) in normal kidney and skin cells, the potential accumulative influence of BDP methylation and GLA mutation on the severity of FD in patients from the same family, two males and two females carrying a GLA deletion mutation, c.1033_1034delTC (p.Ser345Argfs) was addressed in the present study. The molecular analyses of the FD patients compared with the control revealed that the expression of GLA was significantly low (P<0.05), and HNRNPH2 showed a tendency of low expression (P=0.1) when BDP methylation was elevated in FD patients, compared with low BDP methylation and high GLA expression (P<0.05), and a high trend of HNRNPH2 expression in normal individuals. The accumulative effects of the mutation and BDP methylation with the severity of the disease were observed in three patients. One male FD patient, a member of the FD family diagnosed with progressive loss of kidney function, hypertension, and eventually a stroke, and the lowest level of α‑Gal A enzyme activity showed the highest BDP DNA methylation level. It is concluded that the DNA methylation of GLA‑HNRNPH2 BDP may serve a role in diagnosing and treating FD.

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1	Mehta A and Hughes DA: Fabry Disease. Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW and Amemiya A (eds). GeneReviews^® Seattle: University of Washington, Seattle, WA, 1993-2018, 2017.
2	Garman SC and Garboczi DN: The molecular defect leading to Fabry disease: Structure of human alpha-galactosidase. J Mol Biol. 337:319–335. 2004.PubMed/NCBI View Article : Google Scholar
3	Zarate YA and Hopkin RJ: Fabry's disease. Lancet. 372:1427–1435. 2008.PubMed/NCBI View Article : Google Scholar
4	Svarstad E and Marti HP: The changing landscape of Fabry disease. Clin J Am Soc Nephrol. 15:569–576. 2020.PubMed/NCBI View Article : Google Scholar
5	Rozenfeld P and Neumann PM: Treatment of fabry disease: Current and emerging strategies. Curr Pharm Biotechnol. 12:916–922. 2011.PubMed/NCBI View Article : Google Scholar
6	Lidove O, West ML, Pintos-Morell G, Reisin R, Nicholls K, Figuera LE, Parini R, Carvalho LR, Kampmann C, Pastores GM and Mehta A: Effects of enzyme replacement therapy in Fabry disease: A comprehensive review of the medical literature. Genet Med. 12:668–679. 2010.PubMed/NCBI View Article : Google Scholar
7	Keating GM: Agalsidase alfa: A review of its use in the management of Fabry disease. BioDrugs. 26:335–354. 2012.PubMed/NCBI View Article : Google Scholar
8	Thurberg BL, Rennke H, Colvin RB, Dikman S, Gordon RE, Collins AB, Desnick RJ and O'Callaghan M: Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy. Kidney Int. 62:1933–1946. 2002.PubMed/NCBI View Article : Google Scholar
9	Khanna R, Soska R, Lun Y, Feng J, Frascella M, Young B, Brignol N, Pellegrino L, Sitaraman SA, Desnick RJ, et al: The pharmacological chaperone 1-deoxygalactonojirimycin reduces tissue globotriaosylceramide levels in a mouse model of Fabry disease. Mol Ther. 18:23–33. 2010.PubMed/NCBI View Article : Google Scholar
10	Germain DP, Hughes DA, Nicholls K, Bichet DG, Giugliani R, Wilcox WR, Feliciani C, Shankar SP, Ezgu F, Amartino H, et al: Treatment of Fabry's disease with the pharmacologic chaperone migalastat. N Engl J Med. 375:545–555. 2016.PubMed/NCBI View Article : Google Scholar
11	Modrego A, Amaranto M, Godino A, Mendoza R, Barra JL and Corchero JL: Human α-galactosidase A mutants: Priceless tools to develop novel therapies for Fabry disease. Int J Mol Sci. 22(6518)2021.PubMed/NCBI View Article : Google Scholar
12	Al-Obaide MA, Al-Obaidi II and Vasylyeva TL: Unexplored regulatory sequences of divergently paired GLA and HNRNPH2 loci pertinent to Fabry disease in human kidney and skin cells: Presence of an active bidirectional promoter. Exp Ther Med. 21(154)2021.PubMed/NCBI View Article : Google Scholar
13	Ng EK, Leung CP, Shin VY, Wong CL, Ma ES, Jin HC, Chu KM and Kwong A: Quantitative analysis and diagnostic significance of methylated SLC19A3 DNA in the plasma of breast and gastric cancer patients. PLoS One. 6(e22233)2011.PubMed/NCBI View Article : Google Scholar
14	Shaker MM, Shalabi TA and Amr KS: Correlation of methylation status in MTHFR promoter region with recurrent pregnancy loss. J Genet Eng Biotechnol. 19(44)2021.PubMed/NCBI View Article : Google Scholar
15	Whybra C, Bähner F and Baron K: Measurement of disease severity and progression in Fabry disease. In: Fabry Disease: Perspectives from 5 Years of FOS. Mehta A, Beck M and Sunder-Plassmann G (eds). Chapter 32. Oxford: Oxford PharmaGenesis, 2006.
16	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
17	Schmittgen TD and Livak KJ: Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 3:1101–1108. 2008.PubMed/NCBI View Article : Google Scholar
18	Ashley GA, Shabbeer J, Yasuda M, Eng CM and Desnick RJ: Fabry disease: Twenty novel alpha-galactosidase A mutations causing the classical phenotype. J Hum Genet. 46:192–196. 2001.PubMed/NCBI View Article : Google Scholar
19	Germain D, Biasotto M, Tosi M, Meo T, Kahn A and Poenaru L: Fluorescence-assisted mismatch analysis (FAMA) for exhaustive screening of the alpha-galactosidase A gene and detection of carriers in Fabry disease. Hum Genet. 98:719–726. 1996.PubMed/NCBI View Article : Google Scholar
20	Lukas J, Giese AK, Markoff A, Grittner U, Kolodny E, Mascher H, Lackner KJ, Meyer W, Wree P, Saviouk V and Rolfs A: Functional characterisation of alpha-galactosidase a mutation as a basis for a new classification system in fabry disease. PLoS Genet. 9(e1003632)2013.PubMed/NCBI View Article : Google Scholar
21	Nakano S, Morizane Y, Makisaka N, Suzuki T, Togawa T, Tsukimura T, Kawashima I, Sakuraba H and Shibasaki F: Development of a highly sensitive immuno-PCR assay for the measurement of α-galactosidase A protein levels in serum and plasma. PLoS One. 8(e78588)2013.PubMed/NCBI View Article : Google Scholar
22	Rodríguez-Marí A, Coll MJ and Chabás A: Molecular analysis in Fabry disease in Spain: Fifteen novel GLA mutations and identification of a homozygous female. Hum Mutat. 22(258)2003.PubMed/NCBI View Article : Google Scholar
23	Shabbeer J, Yasuda M, Benson SD and Desnick RJ: Fabry disease: Identification of 50 novel alpha-galactosidase A mutations causing the classic phenotype and three-dimensional structural analysis of 29 missense mutations. Hum Genomics. 2:297–309. 2006.PubMed/NCBI View Article : Google Scholar
24	Di Risi T, Vinciguerra R, Cuomo M, Della Monica R, Riccio E, Cocozza S, Imbriaco M, Duro G, Pisani A and Chiariotti L: DNA methylation impact on Fabry disease. Clin Epigenetics. 13(24)2021.PubMed/NCBI View Article : Google Scholar
25	Spiegel S, Milstien S and Grant S: Endogenous modulators and pharmacological inhibitors of histone deacetylases in cancer therapy. Oncogene. 31:537–551. 2012.PubMed/NCBI View Article : Google Scholar
26	Silva GD, Coeli-Lacchini FB and Leopoldino AM: How do sphingolipids play a role in epigenetic mechanisms and gene expression? Epigenomics. 14:219–222. 2021.PubMed/NCBI View Article : Google Scholar
27	Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE and Jaffrey SR: Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons. Cell. 149:1635–1646. 2012.PubMed/NCBI View Article : Google Scholar
28	Magg B, Riegler C, Wiedmann S, Heuschmann P, Sommer C and Üçeyler N: Self-administered version of the Fabry-associated pain questionnaire for adult patients. Orphanet J Rare Dis. 10(113)2015.PubMed/NCBI View Article : Google Scholar
29	Gibas AL, Klatt R, Johnson J, Clarke JT and Katz J: A survey of the pain experienced by males and females with Fabry disease. Pain Res Manag. 11:185–192. 2006.PubMed/NCBI View Article : Google Scholar
30	Crosbie TW, Packman W and Packman S: Psychological aspects of patients with Fabry disease. J Inherit Metab Dis. 32:745–753. 2009.PubMed/NCBI View Article : Google Scholar
31	Tabira T, Goto I, Kuroiwa Y and Kikuchi M: Neuropathological and biochemical studies in Fabry's disease. Acta Neuropathol. 30:345–354. 1974.PubMed/NCBI View Article : Google Scholar
32	Gadoth N and Sandbank U: Involvement of dorsal root ganglia in Fabry's disease. J Med Genet. 20:309–312. 1983.PubMed/NCBI View Article : Google Scholar
33	Miller JJ, Aoki K, Moehring F, Murphy CA, O'Hara CL, Tiemeyer M, Stucky CL and Dahms NM: Neuropathic pain in a Fabry disease rat model. JCI Insight. 3(e99171)2018.PubMed/NCBI View Article : Google Scholar
34	Rajan JN, Ireland K, Johnson R and Stepien KM: Review of mechanisms, pharmacological management, psychosocial implications, and holistic treatment of pain in Fabry disease. J Clin Med. 10(4168)2021.PubMed/NCBI View Article : Google Scholar
35	Donaldson LF and Beazley-Long N: Alternative RNA splicing: Contribution to pain and potential therapeutic strategy. Drug Discov Today. 21:1787–1798. 2016.PubMed/NCBI View Article : Google Scholar
36	de la Peña JB and Campbell ZT: RNA-binding proteins as targets for pain therapeutics. Neurobiol Pain. 4:2–7. 2018.PubMed/NCBI View Article : Google Scholar
37	Song KY, Choi HS, Law PY, Wei LN and Loh HH: Post-transcriptional regulation of mu-opioid receptor: Role of the RNA-binding proteins heterogeneous nuclear ribonucleoprotein H1 and F. Cell Mol Life Sci. 69:599–610. 2012.PubMed/NCBI View Article : Google Scholar
38	Alkan SA, Martincic K and Milcarek C: The hnRNPs F and H2 bind to similar sequences to influence gene expression. Biochem J. 393:361–371. 2006.PubMed/NCBI View Article : Google Scholar
39	Lev Maor G, Yearim A and Ast G: The alternative role of DNA methylation in splicing regulation. Trends Genet. 31:274–280. 2015.PubMed/NCBI View Article : Google Scholar
40	Al-Obaide MA and Vasylyeva TL: The Knockdown of RPL36A downregulates GLA expression associated with Fabry disease in vitro model. ASN ePosters. (Abstract PO1600)2020.
41	Kim JH, You KR, Kim IH, Cho BH, Kim CY and Kim DG: Over-expression of the ribosomal protein L36a gene is associated with cellular proliferation in hepatocellular carcinoma. Hepatology. 39:129–138. 2004.PubMed/NCBI View Article : Google Scholar
42	Xu M, Wang Y, He HT and Yang Q: MiR-589-5p is a potential prognostic marker of hepatocellular carcinoma and regulates tumor cell growth by targeting MIG-6. Neoplasma. 65:753–761. 2018.PubMed/NCBI View Article : Google Scholar
43	Happle R: X-chromosome inactivation: Role in skin disease expression. Acta Paediatr Suppl. 95:16–23. 2006.PubMed/NCBI View Article : Google Scholar
44	Dobyns WB: The pattern of inheritance of X-linked traits is not dominant or recessive, just X-linked. Acta Paediatr Suppl. 95:11–15. 2006.PubMed/NCBI View Article : Google Scholar
45	Rozenfeld PA: Fabry disease: Treatment and diagnosis. IUBMB Life. 61:1043–1050. 2009.PubMed/NCBI View Article : Google Scholar
46	Weingarten-Gabbay S, Nir R, Lubliner S, Sharon E, Kalma Y, Weinberger A and Segal E: Systematic interrogation of human promoters. Genome Res. 29:171–183. 2019.PubMed/NCBI View Article : Google Scholar
47	Fan S, Wang L, Liang L, Cao X, Tang J and Tian Q: The progress on the estimation of DNA methylation level and the detection of abnormal methylation. Quant Biol. 10:55–66. 2022.