CEINGE - Biotecnologie Avanzate, Via Gaetano Salvatore, 486, 80145, Naples, Italy.
Department of Public Health, University Federico II of Naples, Via S. Pansini, 5, 80131, Naples, Italy.
Clin Epigenetics. 2021 Feb 2;13(1):24. doi: 10.1186/s13148-021-01019-3.
Fabry disease (FD) is a rare X-linked disease caused by mutations in GLA gene with consequent lysosomal accumulation of globotriaosylceramide (Gb3). Women with FD often show highly heterogeneous symptoms that can manifest from mild to severe phenotype.
The phenotypic variability of the clinical manifestations in heterozygous women with FD mainly depends on the degree and direction of inactivation of the X chromosome. Classical approaches to measure XCI skewness might be not sufficient to explain disease manifestation in women. In addition to unbalanced XCI, allele-specific DNA methylation at promoter of GLA gene may influence the expression levels of the mutated allele, thus impacting the onset and the outcome of FD. In this regard, analyses of DNA methylation at GLA promoter, performed by approaches allowing distinction between mutated and non-mutated allele, may be much more informative. The aim of this review is to critically evaluate recent literature articles addressing the potential role of DNA methylation in the context of FD. Although up to date relatively few works have addressed this point, reviewing all pertinent studies may help to evaluate the importance of DNA methylation analysis in FD and to develop new research and technologies aimed to predict whether the carrier females will develop symptoms.
Relatively few studies have addressed the complexity of DNA methylation landscape in FD that remains poorly investigated. The hope for the future is that ad hoc and ultradeep methylation analyses of GLA gene will provide epigenetic signatures able to predict whether pre-symptomatic female carriers will develop symptoms thus helping timely interventions.
法布里病（FD）是一种罕见的 X 连锁疾病，由 GLA 基因突变引起，导致溶酶体中糖鞘脂（Gb3）积累。FD 的女性患者常表现出高度异质性的症状，可表现为轻度至重度表型。
杂合子女性 FD 临床表现的表型变异性主要取决于 X 染色体失活的程度和方向。经典的 XCI 偏斜测量方法可能不足以解释女性的疾病表现。除了 XCI 不平衡外，GLA 基因启动子上的等位基因特异性 DNA 甲基化可能会影响突变等位基因的表达水平，从而影响 FD 的发病和结局。在这方面，通过允许区分突变和非突变等位基因的方法对 GLA 启动子上的 DNA 甲基化进行分析可能更具信息量。本文的目的是批判性地评估最近的文献，这些文献涉及 DNA 甲基化在 FD 中的潜在作用。尽管迄今为止相对较少的研究涉及到这一点，但回顾所有相关的研究可能有助于评估 DNA 甲基化分析在 FD 中的重要性，并开发旨在预测携带女性是否会出现症状的新研究和技术。
相对较少的研究涉及 FD 中 DNA 甲基化图谱的复杂性，该图谱仍未得到充分研究。未来的希望是，对 GLA 基因进行专门和超深度甲基化分析将提供能够预测有症状的女性携带者是否会出现症状的表观遗传特征，从而有助于及时进行干预。
