Genetic Analysis of GCA Repeats in the GLS Gene: Implications for Undiagnosed Ataxia and Spinocerebellar Ataxia 3 in Mainland China

IF 7.6 1区医学 Q1 CLINICAL NEUROLOGY Movement Disorders Pub Date : 2024-12-19 DOI:10.1002/mds.30083

Lijing Lei MD, Linliu Peng MD, Linlin Wan MD, Zhao Chen MD, Chunrong Wang MD, Huirong Peng MD, Rong Qiu PhD, Beisha Tang MD, Hong Jiang MD

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Abstract

Background

Recent studies have reported that expanded GCA repeats in the GLS gene can cause glutaminase deficiency with ataxia phenotype. However, to data, no studies have investigated the distribution and role of GCA repeats in the GLS gene of Chinese individuals.

Objective

The aim was to investigate the distribution of GCA repeats in Chinese individuals, including undiagnosed ataxia patients for identifying causal factors, healthy controls for determining the normal range, and ATX−ATXN3 (spinocerebellar ataxia type 3, SCA3) patients for exploring genetic modifiers.

Methods

We combined whole-genome sequencing (WGS), repeat-primed polymerase chain reaction, capillary electrophoresis (RP−PCR/CE), and ExpansionHunter to screen the GCA repeats in the GLS gene of 349 undiagnosed ataxia individuals, 1505 healthy controls, and 1236 ATX−ATXN3 (SCA3) patients from mainland China.

Results

No expanded GCA repeats in the GLS gene were detected across any of the samples. The average number of GCA repeats was 11 (range: 8–31), 12 (range: 6–33), and 11 (range: 6–33) for undiagnosed ataxia patients, healthy controls, and SCA3 patients, respectively. The intermediate repeat size (9 < repeat size ≤ 13) of the nonexpanded GCA allele in the GLS gene was associated with later disease onset in ATX−ATXN3 (SCA3) patients.

Conclusions

Abnormal expansions of GLS GCA repeats are rare in the Chinese population. However, intermediate-length normal GCA repeat sizes may influence the age at onset (AAO) in ATX-ATXN3 (SCA3) patients. © 2024 International Parkinson and Movement Disorder Society.

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GLS基因GCA重复序列的遗传分析：对中国大陆未确诊的共济失调和脊髓小脑性共济失调3的意义。

背景：最近的研究报道了GLS基因中扩增的GCA重复序列可导致谷氨酰胺酶缺乏症伴共济失调表型。然而，目前还没有研究调查GCA重复序列在中国个体GLS基因中的分布和作用。目的：研究GCA重复序列在中国个体中的分布，包括未确诊的共济失调患者以确定病因，健康对照者以确定正常范围，以及ATX-ATXN3（脊髓小脑性共济失调3型，SCA3）患者以探索遗传修饰因子。方法：采用全基因组测序（WGS）、重复引物聚合酶链反应（pcr）、毛细管电泳（RP-PCR/CE）和ExpansionHunter技术，对349例未确诊的共济失调患者、1505例健康对照和1236例ATX-ATXN3 （SCA3）患者GLS基因中GCA重复序列进行筛选。结果：所有样本均未检测到GLS基因中扩增的GCA重复序列。在未确诊的共济失调患者、健康对照组和SCA3患者中，GCA的平均重复数分别为11（范围8-31）、12（范围6-33）和11（范围6-33）。结论：GLS - GCA重复序列异常扩增在中国人群中罕见。然而，中等长度的正常GCA重复大小可能会影响ATX-ATXN3 （SCA3）患者的发病年龄（AAO）。©2024国际帕金森和运动障碍学会。

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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.