Department Neurobiology and Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, 56128, Italy.
Department of Neurology and Stroke Unit, Ospedale del Mare Hospital, Naples, Italy.
Ann Clin Transl Neurol. 2024 Jul;11(7):1879-1886. doi: 10.1002/acn3.52094. Epub 2024 Jun 5.
Biallelic mutations in PRDX3 have been linked to autosomal recessive spinocerebellar ataxia type 32. In this study, which aims to contribute to the growing body of knowledge on this rare disease, we identified two unrelated patients with mutations in PRDX3. We explored the impact of PRDX3 mutation in patient skin fibroblasts and the role of the gene in neurodevelopment.
We performed trio exome sequencing that identified mutations in PRDX3 in two unrelated patients. We also performed functional studies in patient skin fibroblasts and generated a "crispant" zebrafish (Danio rerio) model to investigate the role of the gene during nervous system development.
Our study reports two additional patients. Patient 1 is a 19-year-old male who showed a novel homozygous c.525_535delGTTAGAAGGTT (p. Leu176TrpfsTer11) mutation as the genetic cause of cerebellar ataxia. Patient 2 is a 20-year-old male who was found to present the known c.425C>G/p. Ala142Gly variant in compound heterozygosity with the p. Leu176TrpfsTer11 one. While the fibroblast model failed to recapitulate the pathological features associated with PRDX3 loss of function, our functional characterization of the prdx3 zebrafish model revealed motor defects, increased susceptibility to reactive oxygen species-triggered apoptosis, and an impaired oxygen consumption rate.
We identified a new variant, thereby expanding the genetic spectrum of PRDX3-related disease. We developed a novel zebrafish model to investigate the consequences of prdx3 depletion on neurodevelopment and thus offered a potential new tool for identifying new treatment opportunities.
PRDX3 的双等位基因突变与常染色体隐性遗传小脑共济失调 32 型有关。在这项旨在为这一罕见疾病不断增长的知识库做出贡献的研究中，我们鉴定了两名携带 PRDX3 突变的无关联患者。我们研究了 PRDX3 突变对患者皮肤成纤维细胞的影响，以及该基因在神经发育中的作用。
我们进行了 trio 外显子组测序，在两名无关联的患者中发现了 PRDX3 的突变。我们还在患者皮肤成纤维细胞中进行了功能研究，并生成了“crispant”斑马鱼（Danio rerio）模型，以研究该基因在神经系统发育过程中的作用。
我们的研究报告了另外两名患者。患者 1 是一名 19 岁男性，携带一种新的纯合 c.525_535delGTTAGAAGGTT（p.Leu176TrpfsTer11）突变，这是小脑共济失调的遗传原因。患者 2 是一名 20 岁男性，被发现携带已知的 c.425C>G/p.Ala142Gly 杂合突变，与 p.Leu176TrpfsTer11 突变复合杂合。虽然成纤维细胞模型未能重现与 PRDX3 功能丧失相关的病理特征，但我们对 prdx3 斑马鱼模型的功能表征显示运动缺陷、对活性氧触发的细胞凋亡的易感性增加以及耗氧量降低。
我们鉴定了一种新的变体，从而扩大了 PRDX3 相关疾病的遗传谱。我们开发了一种新的斑马鱼模型来研究 prdx3 耗竭对神经发育的影响，从而为发现新的治疗机会提供了一种新的潜在工具。
