Biallelic Variants in the DARS2 Gene as a Novel Cause of Axonal Charcot-Marie-Tooth Disease.

IF 7.7 1区医学 Q1 CLINICAL NEUROLOGY

Annals of Neurology Pub Date : 2025-08-15 DOI:10.1002/ana.78005

Berta Estévez-Arias, Siiri Sarv, Nathalie Bonello-Palot, Laura Carrera-García, Carlos Ortez, Jesica Expósito-Escudero, Delia Yubero, Jordi Muchart, Emilien Delmont, Eve Õiglane-Shlik, Teele Meren, Sanna Puusepp, Ülle Murumets, Gajja S Salomons, Bjarne Udd, Liis Väli, Lara Cantarero, Carsten G Bönnemann, Andrés Nascimento, Santiago Ramón-Maiques, Katrin Õunap, Janet Hoenicka, Daniel Natera-de Benito, Francesc Palau

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引用次数: 0

Abstract

Objective: Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic neuropathies, with >90 genes identified. Several aminoacyl-tRNA synthetases have been linked to CMT. DARS2, encoding the mitochondrial aspartyl-tRNA synthetase, has been typically associated with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation. This study aimed to investigate the association between biallelic DARS2 variants and axonal CMT.

Methods: We investigated 5 individuals from 3 unrelated families with axonal CMT and biallelic DARS2 variants. Functional studies in fibroblasts assessed their effects on DARS2 expression, localization, and mitochondrial function. Enzymatic activity was evaluated in HEK293 cells.

Results: The 5 individuals, including 4 adults, presented with childhood-onset progressive axonal CMT. None had leukoencephalopathy, but one showed central nervous system involvement, with intellectual disability and epilepsy. Genetic analysis identified compound heterozygous DARS2 variants: family A, p.Ser238Phe and p.Arg336Cys; family B, p.Ser238Phe and p.Ile25Thrfs*38; family C, c.492+2T>C and p.Pro503Leu. Functional studies revealed reduced DARS2 protein levels, mitochondrial network abnormalities, and impaired mitochondrial function. p.Ser238Phe behaves as a hypomorphic allele, whereas p.Pro503Leu reduced DARS2 enzymatic activity by 75%.

Interpretation: Our findings expand the DARS2-related disease spectrum, establishing a novel association with axonal CMT. Hypomorphic variants, such as p.Ser238Phe, when paired with more deleterious variants, result in isolated axonal CMT, whereas more severe combinations-although not as deleterious as those seen in leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation-result in axonal CMT with central nervous system involvement, albeit without leukoencephalopathy. These observations raise the possibility that DARS2-associated diseases form a continuum rather than representing strictly distinct central or peripheral nervous system disorders. ANN NEUROL 2025.

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DARS2基因双等位变异是轴突性腓骨肌病的新病因。

目的：腓骨肌萎缩症（Charcot-Marie-Tooth， CMT）是一种异质性的遗传性神经病变，已鉴定出bbbb90个基因。一些氨基酰基trna合成酶与CMT有关。DARS2编码线粒体天冬氨酸- trna合成酶，通常与脑干和脊髓受累及乳酸升高的白质脑病相关。本研究旨在探讨双等位基因DARS2变异与轴突CMT之间的关系。方法：我们调查了来自3个不相关家族的5名轴突CMT和双等位基因DARS2变异患者。成纤维细胞的功能研究评估了它们对DARS2表达、定位和线粒体功能的影响。在HEK293细胞中评价酶活性。结果：5例患者，包括4例成人，均表现为儿童期进行性轴突CMT。没有人患有白质脑病，但有一人表现出中枢神经系统受累，伴有智力残疾和癫痫。遗传分析鉴定出复合杂合DARS2变异体：A家族，p.Ser238Phe和p.Arg336Cys；家族B， p.Ser238Phe和p.Ile25Thrfs*38；C族，C .492+2T>C和p.Pro503Leu。功能研究显示DARS2蛋白水平降低，线粒体网络异常，线粒体功能受损。p.Ser238Phe表现为次形等位基因，而p.Pro503Leu使DARS2酶活性降低了75%。解释：我们的研究结果扩大了dars2相关疾病的范围，建立了与轴突CMT的新关联。半形态变异，如p.Ser238Phe，当与更有害的变异配对时，导致孤立的轴突CMT，而更严重的组合-尽管不像脑干和脊髓受累的白质脑病和乳酸升高那样有害-导致轴突CMT伴中枢神经系统受累，尽管没有白质脑病。这些观察结果提高了dars2相关疾病形成连续体的可能性，而不是代表严格不同的中枢或周围神经系统疾病。Ann neurol 2025。

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来源期刊

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.