听力损失家族与BCAP31基因新变异相关的X连锁共济失调综合征

IF 7.4 1区医学 Q1 CLINICAL NEUROLOGY

Movement Disorders Pub Date : 2025-01-20 DOI:10.1002/mds.30116

Martin Paucar MD, PhD, Tianyi Li PhD, Åsa Bergendal PhD, Irina Savitcheva MD, PhD, Kaveh Pourhamidi MD, PhD, José M. Laffita-Mesa PhD, Ann Nordgren MD, PhD, Martin Engvall MD, PhD, Per Uhlén PhD, Kristina Lagerstedt-Robinson PhD, Per Svenningsson MD, PhD

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引用次数: 0

摘要

目的：B细胞受体相关蛋白（BCAP31）的致病变异与X连锁、耳聋、肌张力障碍和脑髓鞘退化（DDCH）综合征有关。DDCH是先天性和非进行性的，以严重的智力残疾（ID）、可变畸形为特征，有时与生存期缩短有关。BCAP31编码最丰富的伴侣之一，具有多种功能，包括作为内质网钙离子（Ca2+）浓度的负调节因子。在这里，我们描述了一种X连锁综合征，其潜在的基因型，并对确定的候选遗传变异进行了功能评估。方法运动特征评估、神经影像学检查、神经生理学和认知测试。应用全外显子组测序（WES），将编码BCAP31的质粒转染到SH‐SY5Y细胞中，以评估亚细胞位置并测量细胞质中的Ca2+水平。结果成人发病的共济失调、认知障碍和听力损失导致耳聋是主要特征。外显率降低，进展缓慢，老年时保留行走能力，以及普遍的小脑萎缩是该综合征的其他特征。这种情况与BCAP31在Xq28的新变体c.22G>A （V8I）有关。V8I BCAP31蛋白的亚细胞位置没有改变，但引起细胞质Ca2+的显著升高。结论我们的发现扩大了BCAP31基因变异的范围，包括神经发育综合征的进行性神经退行性疾病。这是首次将共济失调与BCAP31变异联系起来，并提供了致病性的功能证据。需要更多以共济失调为特征的BCAP31病例来建立关联。©2025作者。Wiley期刊有限责任公司代表国际帕金森和运动障碍学会出版的《运动障碍》。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

An X-Linked Ataxia Syndrome in a Family with Hearing Loss Associated with a Novel Variant in the BCAP31 Gene

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An X-Linked Ataxia Syndrome in a Family with Hearing Loss Associated with a Novel Variant in the BCAP31 Gene

Objective

Pathogenic variants in B-cell receptor-associated protein (BCAP31) are associated with X-linked, deafness, dystonia and cerebral hypomyelination (DDCH) syndrome. DDCH is congenital and non-progressive, featuring severe intellectual disability (ID), variable dysmorphism, and sometimes associated with shortened survival. BCAP31 encodes one of the most abundant chaperones, with several functions including acting as a negative regulator of endoplasmic reticulum (ER) calcium ion (Ca²⁺) concentration. Here, we characterize an X-linked syndrome, its underlying genotype, and a functional evaluation of the identified candidate genetic variant.

Methods

Evaluation of motor features, neuroimaging studies, neurophysiological, and cognitive tests. Whole exome sequencing (WES) was applied, a plasmid encoding BCAP31 with and without a candidate variant was transfected into SH-SY5Y cells to assess subcellular location and to measure Ca²⁺ levels in the cytoplasm.

Results

Adult-onset ataxia, cognitive impairment, and hearing loss leading to deafness are the predominant features. Reduced penetrance, slow progression with preserved ability to walk in advance age, and universal cerebellar atrophy are other features for this syndrome. This condition is associated with the new variant c.22G>A (V8I) in BCAP31 at Xq28. The subcellular location of the V8I BCAP31 protein was not altered but caused significant elevation of cytosolic Ca²⁺.

Conclusions

Our findings expand the spectrum of variants in BCAP31 from neurodevelopmental syndromes to include a progressive neurodegenerative disease with variable expressivity. This is the first time ataxia is described in association with a BCAP31 variant and functional evidence of pathogenicity is provided. Additional BCAP31 cases featuring ataxia are needed to establish an association. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of 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.