鸟苷酸激酶 1 缺乏症:线粒体 DNA 缺失/缺失症:一种新颖且可治疗的疾病

IF 8.1 1区 医学 Q1 CLINICAL NEUROLOGY Annals of Neurology Pub Date : 2024-09-04 DOI:10.1002/ana.27071
Agustin Hidalgo-Gutierrez PhD, Jonathan Shintaku, Javier Ramon, Eliana Barriocanal-Casado, Alba Pesini, Russell P. Saneto, Gloria Garrabou, Jose Cesar Milisenda, Ana Matas-Garcia, Laura Gort, Olatz Ugarteburu, Yue Gu, Lahari Koganti, Tian Wang, Saba Tadesse, Megi Meneri, Monica Sciacco, Shuang Wang, Kurenai Tanji, Marshall S. Horwitz, Michael O. Dorschner, Mahesh Mansukhani, Giacomo Pietro Comi, Dario Ronchi, Ramon Marti, Antonia Ribes, Frederic Tort, Michio Hirano MD
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引用次数: 0

摘要

目的:线粒体 DNA(mtDNA)缺失/缺失综合征(MDDS)是由原发性常染色体 mtDNA 维护缺陷引起的一组疾病。我们的目的是研究4名缺乏已知遗传病因变异的患者的MDDS病因:方法:我们对患者进行了全外显子组测序,以确定致病变体。我们通过分析 mtDNA、线粒体 dNTP 池、呼吸链活性和 GUK1 活性验证了线粒体缺陷。为了证实 GUK1 缺乏症的致病性,我们在患者细胞中表达了 2 种 GUK1 异构体:结果:我们在所有4名出现上睑下垂、眼肌麻痹、肌病性近端肢体无力以及可变肝病和T淋巴细胞特征改变的患者中发现了双倍拷贝GUK1致病变体。所有受试者的肌肉活检结果都显示存在mtDNA缺失或缺失,以及线粒体呼吸链酶活性降低。GUK1 编码鸟苷酸激酶,最初被认为是一种细胞膜酶。GUK1 存在长短两种异构体。我们观察到,长异构体在线粒体内,短异构体在细胞质内。在原发性成纤维细胞中,我们注意到 GUK1 活性的降低导致线粒体 dNTP 池不平衡,以及复制和静止成纤维细胞中 mtDNA 的耗竭,这表明 GUK1 缺乏会损害新核苷酸和挽救核苷酸的途径。用脱氧鸟苷和/或嘌呤磷酸酶抑制剂福尔可定处理原带成纤维细胞可改善mtDNA耗竭,这表明药物疗法具有潜力:原发性GUK1缺乏症是导致MDDS的一种新的可治疗病因。GUK1的细胞膜异构体可能会导致T淋巴细胞异常,这在其他MDDS疾病中尚未观察到。ann neurol 2024.
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Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease

Objective

Mitochondrial DNA (mtDNA) depletion/deletions syndrome (MDDS) comprises a group of diseases caused by primary autosomal defects of mtDNA maintenance. Our objective was to study the etiology of MDDS in 4 patients who lack pathogenic variants in known genetic causes.

Methods

Whole exome sequencing of the probands was performed to identify pathogenic variants. We validated the mitochondrial defect by analyzing mtDNA, mitochondrial dNTP pools, respiratory chain activities, and GUK1 activity. To confirm pathogenicity of GUK1 deficiency, we expressed 2 GUK1 isoforms in patient cells.

Results

We identified biallelic GUK1 pathogenic variants in all 4 probands who presented with ptosis, ophthalmoparesis, and myopathic proximal limb weakness, as well as variable hepatopathy and altered T-lymphocyte profiles. Muscle biopsies from all probands showed mtDNA depletion, deletions, or both, as well as reduced activities of mitochondrial respiratory chain enzymes. GUK1 encodes guanylate kinase, originally identified as a cytosolic enzyme. Long and short isoforms of GUK1 exist. We observed that the long isoform is intramitochondrial and the short is cytosolic. In probands’ fibroblasts, we noted decreased GUK1 activity causing unbalanced mitochondrial dNTP pools and mtDNA depletion in both replicating and quiescent fibroblasts indicating that GUK1 deficiency impairs de novo and salvage nucleotide pathways. Proband fibroblasts treated with deoxyguanosine and/or forodesine, a purine phosphatase inhibitor, ameliorated mtDNA depletion, indicating potential pharmacological therapies.

Interpretation

Primary GUK1 deficiency is a new and potentially treatable cause of MDDS. The cytosolic isoform of GUK1 may contribute to the T-lymphocyte abnormality, which has not been observed in other MDDS disorders. ANN NEUROL 2024;96:1209–1224

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来源期刊
Annals of Neurology
Annals of Neurology 医学-临床神经学
CiteScore
18.00
自引率
1.80%
发文量
270
审稿时长
3-8 weeks
期刊介绍: Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.
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