POLR3B基因的一种新的从头变异与最大神经纤维的原发性轴突受累有关。

IF 3.9 3区 医学 Q1 CLINICAL NEUROLOGY Journal of the Peripheral Nervous System Pub Date : 2023-10-28 DOI:10.1111/jns.12602
Alessandro Geroldi, Stefano Tozza, Chiara Fiorillo, Maria Nolano, Paola Fossa, Floriana Vitale, Regi Domi, Andrea Gaudio, Alessia Mammi, Serena Patrone, Andrea La Barbera, Paola Origone, Clarissa Ponti, Francesca Sanguineri, Federico Zara, Matteo Cataldi, Vincenzo Salpietro, Consuelo Barbara Venturi, Sara Massucco, Angelo Schenone, Fiore Manganelli, Paola Mandich, Emilia Bellone, Fabio Gotta
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引用次数: 0

摘要

背景和目的:POLR3B基因编码RNA聚合酶III(Pol III)的一个亚基。POLR3B中的双等位基因突变与白细胞营养不良有关,但最近在伴有或不伴有中枢受累的早发性外周脱髓鞘神经病中描述了新发杂合突变。在这里,我们报道了意大利首例携带POLR3B从头变异的病例,该病例具有纯神经病变表型和最大神经纤维的原发性轴突受累。方法:按照标准程序进行神经传导研究、交感神经皮肤反应、动态汗液测试、触觉和热定量感觉测试以及脑MRI。对皮肤和腓肠神经活检进行组织病理学检查。先证者及其亲属的分子分析采用下一代测序法进行。通过轮调异构体方法评估鉴定的变体对整体蛋白质结构的影响。结果:自青少年早期以来,患者就表现出多发性神经病的症状,伴有严重的远端无力、萎缩和感觉减退。神经生理学研究显示一种感觉运动轴突多发性神经病,证实有小纤维受累。此外,皮肤活检和腓肠神经活检显示主要的大纤维受累。三人组的全外显子组测序(WES)揭示了POLR3B中一种新的从头变异p。(Arg1046Cys),被归类为可能致病。分子建模数据证实了该变体对蛋白质结构的有害影响。解释:神经生理学和形态学结果表明,POLR3B相关神经病中最大神经纤维的原发性轴突受累。神经病变和白细胞营养不良表型的部分功能丧失机制被提出。这篇文章受版权保护。保留所有权利。
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A novel de novo variant in POLR3B gene associated with a primary axonal involvement of the largest nerve fibers

Background and Aims

POLR3B gene encodes a subunit of RNA polymerase III (Pol III). Biallelic mutations in POLR3B are associated with leukodystrophies, but recently de novo heterozygous mutations have been described in early onset peripheral demyelinating neuropathies with or without central involvement. Here, we report the first Italian case carrying a de novo variant in POLR3B with a pure neuropathy phenotype and primary axonal involvement of the largest nerve fibers.

Methods

Nerve conduction studies, sympathetic skin response, dynamic sweat test, tactile and thermal quantitative sensory testing and brain magnetic resonance imaging were performed according to standard procedures. Histopathological examination was performed on skin and sural nerve biopsies. Molecular analysis of the proband and his relatives was performed with Next Generation Sequencing. The impact of the identified variant on the overall protein structure was evaluated through rotamers method.

Results

Since his early adolescence, the patient presented with signs of polyneuropathy with severe distal weakness, atrophy, and reduced sensation. Neurophysiological studies showed a sensory-motor axonal polyneuropathy, with confirmed small fiber involvement. In addition, skin biopsy and sural nerve biopsy showed predominant large fibers involvement. A trio's whole exome sequencing revealed a novel de novo variant p.(Arg1046Cys) in POLR3B, which was classified as Probably Pathogenic. Molecular modeling data confirmed a deleterious effect of the variant on protein structure.

Interpretation

Neurophysiological and morphological findings suggest a primary axonal involvement of the largest nerve fibers in POLR3B-related neuropathies. A partial loss of function mechanism is proposed for both neuropathy and leukodystrophy phenotypes.

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来源期刊
CiteScore
6.10
自引率
7.90%
发文量
45
审稿时长
>12 weeks
期刊介绍: The Journal of the Peripheral Nervous System is the official journal of the Peripheral Nerve Society. Founded in 1996, it is the scientific journal of choice for clinicians, clinical scientists and basic neuroscientists interested in all aspects of biology and clinical research of peripheral nervous system disorders. The Journal of the Peripheral Nervous System is a peer-reviewed journal that publishes high quality articles on cell and molecular biology, genomics, neuropathic pain, clinical research, trials, and unique case reports on inherited and acquired peripheral neuropathies. Original articles are organized according to the topic in one of four specific areas: Mechanisms of Disease, Genetics, Clinical Research, and Clinical Trials. The journal also publishes regular review papers on hot topics and Special Issues on basic, clinical, or assembled research in the field of peripheral nervous system disorders. Authors interested in contributing a review-type article or a Special Issue should contact the Editorial Office to discuss the scope of the proposed article with the Editor-in-Chief.
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