PBMC 中的 Sacsin 水平：外周血细胞中 SACS 变体的诊断测定--PROSPAX 研究。

IF 7.4 1区医学 Q1 CLINICAL NEUROLOGY

Movement Disorders Pub Date : 2024-09-24 DOI:10.1002/mds.30012

Ceren Tunca, Eylül Ece İşlek Camadan, Natalia Smolina, Robin J Palvadeau, Özgür Öztop Çakmak, Atay Vural, Andreas Traschütz, Filippo M Santorelli, Bernard Brais, Rebecca Schüle, Matthis Synofzik, A Nazlı Başak

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引用次数: 0

摘要

背景：沙勒沃瓦-萨盖内常染色体隐性痉挛性共济失调症（ARSACS）是一种常见的隐性共济失调症，在全球范围内仍未得到充分诊断。一种易于获得的诊断生物标志物可能有助于诊断确认出现意义不明变异（VUS）或非典型性表型的 SACS 患者：目的：检测外周血单核细胞（PBMCs）中的sacsin，并验证其诊断生物标志物的质量，以区分双倍拷贝SACS患者（包括VUS和/或非典型表型患者）与健康对照组、非ARSACS痉挛性共济失调患者和杂合子SACS携带者：方法：评估患者与对照组 PBMC 中的 Sacsin 蛋白水平，并在皮肤成纤维细胞中进行验证：结果：双偶SACS变异体患者（包括VUS和/或非典型性表型患者）的PBMCs中的Sacsin水平下降，与健康、杂合子和非SACS对照组相比具有鉴别力。这包括所有研究过的 SACS 错义变体。此外，C端变异体逃脱了无义介导的衰变，虽然在表达水平上与对照组没有差异，但在该检测中显示出较低的分子量：结论：使用 PBMCs 评估糖蛋白水平为 ARSACS 提供了一种简便、外周可及的诊断生物标志物，与成纤维细胞相比，PBMCs 侵袭性更小，更易于处理。此外，这也可能成为增加糖蛋白疗法的潜在靶向参与血液生物标志物。© 2024 国际帕金森和运动障碍协会。

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Sacsin levels in PBMCs: A diagnostic assay for SACS variants in peripheral blood cells - A PROSPAX study.

Background: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a common recessive ataxia that is still underdiagnosed worldwide. An easily accessible diagnostic biomarker might help to diagnostically confirm patients presenting SACS variants of unknown significance (VUS) or atypical phenotypes.

Objectives: To detect sacsin in peripheral blood mononuclear cells (PBMCs) and to validate its diagnostic biomarker quality to discriminate biallelic SACS patients (including patients with VUS and/or atypical phenotypes) against healthy controls, non-ARSACS spastic ataxia patients, and heterozygous SACS carriers.

Methods: Sacsin protein levels in PBMCs were assessed in patients versus controls and validated in skin-derived fibroblasts.

Results: Patients with biallelic SACS variants - including patients with VUS and/or atypical phenotypes - showed loss of sacsin in PBMCs, with discriminative performance against healthy, heterozygous, and non-ARSACS controls. This included all investigated SACS missense variants. Also, C-terminal variants escaping nonsense-mediated decay, while not differing from controls in expression level, showed lower molecular weight in this assay.

Conclusions: Assessing sacsin levels using PBMCs offers an easy, peripherally accessible diagnostic biomarker for ARSACS, with PBMCs being much less invasive and easier to handle than fibroblasts. Additionally, this might be a potential target-engagement blood biomarker for sacsin-increasing therapies. © 2024 International Parkinson and Movement Disorder Society.

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来源期刊

Movement Disorders 医学-临床神经学

CiteScore

13.30

自引率

8.10%

发文量

371

审稿时长

12 months

期刊介绍： Movement Disorders publishes a variety of content types including Reviews, Viewpoints, Full Length Articles, Historical Reports, Brief Reports, and Letters. The journal considers original manuscripts on topics related to the diagnosis, therapeutics, pharmacology, biochemistry, physiology, etiology, genetics, and epidemiology of movement disorders. Appropriate topics include Parkinsonism, Chorea, Tremors, Dystonia, Myoclonus, Tics, Tardive Dyskinesia, Spasticity, and Ataxia.