Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking.
Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking.
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DOI：
10.1093/brain/awaa459
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发表时间：
2021-04-12
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影响因子：
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通讯作者：
Kaya N
中科院分区：
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作者：
Sanderson LE;Lanko K;Alsagob M;Almass R;Al-Ahmadi N;Najafi M;Al-Muhaizea MA;Alzaidan H;AlDhalaan H;Perenthaler E;van der Linde HC;Nikoncuk A;Kühn NA;Antony D;Owaidah TM;Raskin S;Vieira LGDR;Mombach R;Ahangari N;Silveira TRD;Ameziane N;Rolfs A;Alharbi A;Sabbagh RM;AlAhmadi K;Alawam B;Ghebeh H;AlHargan A;Albader AA;Binhumaid FS;Goljan E;Monies D;Mustafa OM;Aldosary M;AlBakheet A;Alyounes B;Almutairi F;Al-Odaib A;Aksoy DB;Basak AN;Palvadeau R;Trabzuni D;Rosenfeld JA;Karimiani EG;Meyer BF;Karakas B;Al-Mohanna F;Arold ST;Colak D;Maroofian R;Houlden H;Bertoli-Avella AM;Schmidts M;Barakat TS;van Ham TJ;Kaya N
膜运输是真核细胞中一个复杂的、必要的过程，负责蛋白质的运输和加工。液泡蛋白分选（VPS）蛋白是运输的关键调节因子，其缺陷会导致细胞内大分子和细胞器的异常分离，并与人类疾病有关。VPS蛋白是由VPS11、VPS16、VPS18、VPS33A、VPS39和VPS41组成的同型融合和液泡蛋白分选（HOPS）系聚复合物的一部分。据报道，hops特异性亚基VPS41可促进帕金森病中多巴胺能神经元的活力，但迄今为止尚未与人类疾病联系起来。在这里，我们描述了5个不相关的家庭，有9个受影响的个体，都携带VPS41的纯合变异体，我们显示了影响蛋白的功能。所有受影响的个体均表现为进行性神经发育障碍，包括认知障碍、小脑萎缩/发育不全、运动障碍伴共济失调和肌张力障碍以及眼球震颤。斑马鱼疾病模型支持VPS41功能障碍参与该疾病，表明整个大脑溶酶体失调，并为VPS41突变时小脑和小胶质细胞异常提供支持。这提供了与HOPS特异性亚基VPS41相关的人类疾病的第一个例子，并表明HOPS复合物活性对小脑功能的重要性。Sanderson等人描述了10个空泡蛋白分选蛋白VPS41编码基因双等位变异的个体，表现为小脑功能障碍和异常的膜结合囊泡。突变斑马鱼再现了小脑功能障碍表型，进一步暗示VPS41是一种人类疾病基因。
Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson’s disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function. Sanderson et al. describe ten individuals with biallelic variants in the gene encoding the vacuolar protein sorting protein VPS41, presenting with cerebellar dysfunction and abnormal membrane-bound vesicles. Mutant zebrafish recapitulate the cerebellar dysfunction phenotype, further implicating VPS41 as a human disease gene.