Background Fabry disease (FD) is a rare X-linked inherited disease caused by mutations in the GLA gene. We established a cohort of FD patients and performed whole-exome sequencing (WES) to identify some novel mutations. Aim The aim of this study is to investigate the etiology of the novel mutation (c.72G > A, p.Trp24*）in the GLA gene in affected patients by using induced pluripotent stem cells (iPSCs) as a valuable tool. Methods We explored the clinical implications of this proband and examined the deleteriousness and conservation of the mutation site through bioinformatics analysis. Simultaneously, we collected the peripheral blood mononuclear cells (PBMCs) of the affected patient, then reprogrammed them into iPSCs and assessed their enzymatic activity to confirm the function of lysosomal enzyme α-galactosidase A (α-Gal A). Results Clinical examination of the patient demonstrated a classical FD, such as neuropathic pain, gastrointestinal disorders, deficiency of α-Gal A activity, and accumulation of Lyso-Gb-3. The novel mutation located on the N-terminal region, leading to a truncation of the protein and remaining only 24 amino acids. The α-Gal A activity of the patient-specific iPSC (iPS-FD) was significantly lower (60%) than that of normal iPSCs derived from healthy donors (iPS-B1). Conclusion This work not only elucidated the etiology of novel mutations in affected patients but also highlighted the utility of iPSCs as a valuable tool for clarifying the molecular mechanisms and providing new insights into the therapy of FD.

中文翻译：

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新型 GLA 突变引起的法布里病的临床特征和诱导多能干细胞 (iPSC) 疾病模型

背景法布里病（FD）是一种罕见的 X 连锁遗传病，由 GLA 基因突变引起。我们建立了一组 FD 患者并进行全外显子组测序 (WES) 来识别一些新的突变。目的本研究的目的是利用诱导多能干细胞（iPSC）作为有价值的工具，研究受影响患者 GLA 基因中新突变（c.72G > A，p.Trp24*）的病因。我们探索了该先证者的临床意义，并通过生物信息学分析检查了突变位点的有害性和保守性。同时，我们收集了受影响患者的外周血单核细胞（PBMC），然后将其重新编程为 iPSC，并评估其酶活性以确认溶酶体酶 α-半乳糖苷酶 A (α-Gal A) 的功能。结果 患者的临床检查显示出典型的 FD，如神经性疼痛、胃肠道疾病、α-Gal A 活性缺乏和 Lyso-Gb 积聚-3. 位于N端区域的新突变，导致蛋白质被截短，仅保留24个氨基酸，患者特异性iPSC（iPS-FD）的α-Gal A活性显着降低（60 %) 高于来自健康供体的正常 iPSC (iPS-B1)。结论 这项工作不仅阐明了受影响患者中新突变的病因，而且强调了 iPSC 作为阐明分子机制和为 FD 治疗提供新见解的有价值工具的效用。