Loss-of-function variations in solute carrier family 38 member 6 are associated with essential tremor Article Swipe
Zhangqi Yuan
,
Qiying Sun
,
Junyu Luo
,
Lu Zhang
,
Yichi Zhang
,
Jifeng Guo
,
Cheng Wang
,
Kangjuan Yang
,
Shumin Yang
,
Yu Cao
,
Yinhua Shen
,
Jiaming Cui
,
Hengxiang Cui
,
Hao Sun
,
Tingbin Ma
,
Xuan Xu
,
Chun–Jen Liu
,
Tao Wang
,
An‐Yuan Guo
,
Aifang Cheng
,
Luoying Zhang
,
Jun Liu
,
Man Jiang
,
Beisha Tang
,
Jing Yu Liu
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1038/s41392-025-02380-y
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1038/s41392-025-02380-y
Essential tremor (ET) is a common neurological disease that is characterized by 4–12 Hz kinetic tremors of the upper limbs and high genetic heterogeneity. Although numerous candidate genes and loci have been reported, the etiology of ET remains unclear. A novel ET-related gene was initially identified in a five-generation family via whole-exome sequencing, and other variants were identified in 772 familial ET probands and 640 sporadic individuals via whole-genome sequencing. Among 71 (9.18%) Chinese families and 47 (7.34%) sporadic individuals with ET, we identified 15 types of protein-altering variants in solute carrier family 38 member 6 ( SLC38A6) , which encodes sodium-coupled neutral amino acid transporter 6 (SNAT6) and is inherited in an autosomal dominant pattern. Over-expression of mutant SNAT6 for the three most common human mutations (p.Y108F, p.M281T and p.G318S) significantly impaired L-arginine (L-Arg) uptake in HeLa cells. The homozygous Slc38a6 deletion mice (Slc38a6 -/- ) exhibited reduced L-Arg uptake in their cerebellar neurons, tremor, and cerebellar pathology. Slice electrophysiology revealed reduced neuronal Purkinje cell (PC) excitability and elevated inhibitory synaptic transmission in Slc38a6 -/- mice, in line with elevated “hairy” basket coverage around the PC soma. Furthermore, heterozygous Slc38a6 deletion (Slc38a6 +/- ) and PC-specific Slc38a6 deletion ( Slc38a6 PC-/- ) mice also displayed tremor and PC abnormalities similar to those found in Slc38a6 -/- mice. These PCs displayed mitochondrial abnormalities and elevated ferroptosis markers (ACSL4, TFRC and Fe ions). In conclusion, we identified variants in SLC38A6 that contribute ~8.35% to ET, generated mouse models displaying tremor, and delineated cerebellar cellular abnormalities and potential mechanisms underlying ET etiology.
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- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1038/s41392-025-02380-y
- https://www.nature.com/articles/s41392-025-02380-y.pdf
- OA Status
- gold
- References
- 55
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4414106105
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- OpenAlex ID
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https://openalex.org/W4414106105Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1038/s41392-025-02380-yDigital Object Identifier
- Title
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Loss-of-function variations in solute carrier family 38 member 6 are associated with essential tremorWork title
- Type
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articleOpenAlex work type
- Language
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enPrimary language
- Publication year
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2025Year of publication
- Publication date
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2025-09-10Full publication date if available
- Authors
-
Zhangqi Yuan, Qiying Sun, Junyu Luo, Lu Zhang, Yichi Zhang, Jifeng Guo, Cheng Wang, Kangjuan Yang, Shumin Yang, Yu Cao, Yinhua Shen, Jiaming Cui, Hengxiang Cui, Hao Sun, Tingbin Ma, Xuan Xu, Chun–Jen Liu, Tao Wang, An‐Yuan Guo, Aifang Cheng, Luoying Zhang, Jun Liu, Man Jiang, Beisha Tang, Jing Yu LiuList of authors in order
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https://doi.org/10.1038/s41392-025-02380-yPublisher landing page
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https://www.nature.com/articles/s41392-025-02380-y.pdfDirect link to full text PDF
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YesWhether a free full text is available
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goldOpen access status per OpenAlex
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https://www.nature.com/articles/s41392-025-02380-y.pdfDirect OA link when available
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0Total citation count in OpenAlex
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55Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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