Choline transporter-like I deficiency causes a new type of childhood-onset neurodegeneration
Choline transporter-like I deficiency causes a new type of childhood-onset neurodegeneration
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DOI：
10.1093/brain/awz376
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发表时间：
2020-01-01
期刊：
影响因子：
14.5
通讯作者：
Bakovic, Marica
中科院分区：
文献类型：
--
作者：
Fagerberg, Christina R.;Taylor, Adrian;Bakovic, Marica
脑胆碱代谢对于正常脑功能至关重要，其稳态取决于载体介导的运输。在此，我们报告了来自三个家族的四名个体患有神经退行性疾病，其 SLC44A1 基因编码胆碱转运蛋白样蛋白存在纯合移码突变（Asp517Metfs*19、Ser126Metfs*8 和 Lys90Metfs*18），其特征包括进行性共济失调、震颤、认知能力下降、吞咽困难、视神经萎缩、 构音障碍，以及尿失禁和尿失禁。脑部 MRI 显示小脑萎缩和白质脑病。此外，在两个个体中观察到苍白球的低信号强度和高信号条纹以及印质的低信号强度。 Asp517Metfs*19、Ser126Metfs*8 成纤维细胞在结构和功能上无法区分。突变成纤维细胞最显着的超结构变化是游离核糖体的减少、内质网伸长以及线粒体和小囊泡数量显着增加。当长期用胆碱处理时，这些特征消失，突变体超微结构与健康对照细胞相似。功能分析显示胆碱转运减少，但膜磷脂酰胆碱含量保持不变。作为保护胆碱和磷脂酰胆碱机制的一部分，胆碱转运蛋白缺乏与其他磷脂的膜稳态受损有关。胆碱治疗可以恢复膜脂、修复细胞器并保护突变细胞免受急性铁过载的影响。总之，我们描述了一种由胆碱转运蛋白缺乏引起的常染色体隐性遗传的新型儿童期发病的神经代谢疾病。
Cerebral choline metabolism is crucial for normal brain function, and its homoeostasis depends on carrier-mediated transport. Here, we report on four individuals from three families with neurodegenerative disease and homozygous frameshift mutation (Asp517Metfs*19, Ser126Metfs*8, and Lys90Metfs*18) in the SLC44A1 gene encoding choline transporter-like protei n features included progressive ataxia, tremor, cognitive decline, dysphagia, optic atrophy, dysarthria, as well as urinary and hove incontinence. Brain MRI demonstrated cerebellar atrophy and leukoencephalopathy. Moreover, low signal intensity in globus pallidus with hyperintensive streaking and low signal intensity in substantia ingra were seen in two individuals. The Asp517Metfs*19, Ser126Metfs*8 fibroblasts were structurally and functionally indistinguishable. The most prominent ultra structural changes of the mutant fibroblasts were reduced presence of free ribosomes, the appearance of elongated endoplasmic reticulum and strikingly increased number of mitochondria and small vesicles. When chronically treated with choline, those characteristics disappeared and mutant ultrastructure resembled healthy control cells. Functional analysis revealed diminished choline transport yet the membrane phosphatidylcholine content remained unchanged. As part of the mechanism to preserve choline and phosphatidylcholine, choline transporter deficiency was implicated in impaired membrane homeostasis of ot he phospholipids. Choline treatments could restore the membrane lipids, repair cellular organelles and protect mutant cells from acute iron overload. In conclusion, we describe a novel childhood-onset neurometabolic disease caused by choline transporter deficiency with autosomal recessive inheritance.