Paucar Martin, Li Tianyi, Bergendal Åsa, Savitcheva Irina, Pourhamidi Kaveh, Laffita-Mesa José M, Nordgren Ann, Engvall Martin, Uhlén Per, Lagerstedt-Robinson Kristina, Svenningsson Per
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
Mov Disord. 2025 Apr;40(4):672-682. doi: 10.1002/mds.30116. Epub 2025 Jan 20.
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 (Ca) concentration. Here, we characterize an X-linked syndrome, its underlying genotype, and a functional evaluation of the identified candidate genetic variant.
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 Ca levels in the cytoplasm.
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 Ca.
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.
B细胞受体相关蛋白（BCAP31）的致病变异与X连锁耳聋、肌张力障碍和脑白质发育不全（DDCH）综合征相关。DDCH是先天性且非进行性的，其特征为严重智力障碍（ID）、可变的畸形，有时还与生存期缩短有关。BCAP31编码最丰富的分子伴侣之一，具有多种功能，包括作为内质网（ER）钙离子（Ca）浓度的负调节因子。在此，我们对一种X连锁综合征、其潜在基因型以及鉴定出的候选基因变异进行功能评估。
对运动特征、神经影像学研究、神经生理学和认知测试进行评估。应用全外显子组测序（WES），将编码有或无候选变异的BCAP31的质粒转染到SH-SY5Y细胞中，以评估亚细胞定位并测量细胞质中的Ca水平。
成人期共济失调、认知障碍和导致耳聋的听力损失是主要特征。外显率降低、进展缓慢且在高龄时仍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。这种情况与位于Xq28的BCAP31中的新变异c.22G>A（V8I）相关。V8I BCAP31蛋白的亚细胞定位未改变，但导致细胞质Ca显著升高。
我们的发现将BCAP31中的变异谱从神经发育综合征扩展到包括一种具有可变表达性的进行性神经退行性疾病。这是首次描述与BCAP31变异相关的共济失调，并提供了致病性的功能证据。需要更多具有共济失调特征的BCAP31病例来建立关联。© 2025作者。由Wiley Periodicals LLC代表国际帕金森和运动障碍协会出版的《运动障碍》杂志刊载。
