TBK1 p.Y153Qfs*9 variant may be associated with young-onset, rapidly progressive amyotrophic lateral sclerosis through a haploinsufficiency mechanism

Sep 29, 2026

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Background: TBK1 variants have been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia spectrum disorder. Methods: Coding regions of TBK1, SOD1, TARDBP, and FUS were evaluated using Sanger sequencing; the C9ORF72 GGGGCC repeat was assessed with repeat-primed PCR. A detailed clinical workup complemented in vitro transfection assays to test functional effects. Results: A novel TBK1 frameshift truncating variant, c.456_457delGT (p.Y153Qfs*9), was found in a man with young-onset rapidly progressive ALS. Conclusions: The heterozygous TBK1 p.Y153Qfs*9 variant may contribute through haploinsufficiency.

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J Chin MedAssoc Original article TBK1 p.Y153Qfs*9 variant may be associated with young-onset, rapidly progressive amyotrophic lateral sclerosis through a haploinsufficiency mechanism Shih-Yu Fanga,b, Pei-Chien Tsaic,d, Kang-Yang Jiha,b,e, Fang-Chi Hsuc, Yi-Chu Liaoa,b,f, Chih-Chao Yangg, Yi-Chung Leea,b,f,h,i,* aDepartment of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC; bDepartment of Neurology, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan, ROC; cDepartment of Life Sciences, National Chung Hsing University, Taichung, Taiwan, ROC; dThe iEGG and Animal Biotechnology Research Center, National Chung Hsing University, Taichung, Taiwan, ROC; eDepartment of Physiology, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC; fBrain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC; gDepartment of Neurology, National Taiwan University Hospital, Taipei, Taiwan, ROC; hDepartment of Biological Science and Technology, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan, ROC; iCenter for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu, Taiwan, ROC Abstract Background: TBK1 variants have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia spectrum disorder. The current study elucidated the clinical and molecular genetic features of a novel TBK1 variant identified in a patient with young-onset, rapidly progressive ALS. Methods: The coding regions of TBK1 , SOD1 , TARDBP , and FUS were genetically analyzed using Sanger sequencing. Repeatprimed polymerase chain reaction (PCR) was used to survey the GGGGCC repeat in C9ORF72 . The study participant underwent a comprehensive clinical evaluation. The functional effects of the TBK1 variant were analyzed through in vitro transfection studies. Results: We identified a novel frameshift truncating TBK1 variant, c.456_ 457delGT (p.Y153Qfs*9), in a man with ALS. The disease initially manifested as right hand weakness at the age of 39 years but progressed rapidly, with the revised ALS Functional Rating Scale score declining at an average monthly rate of 1.92 points in the first year after diagnosis. The patient had no cognitive dysfunction. However, Technetium-99m single photon emission tomography indicated hypoperfusion in his bilateral superior and middle frontal cortices. In vitro studies revealed that the p.Y153Qfs*9 variant resulted in a truncated TBK1 protein product, reduced TBK1 protein expression, loss of kinase function, reduced interaction with optineurin, and impaired dimerization. Conclusion: The heterozygous TBK1 p.Y153Qfs*9 variant may be associated with young-onset, rapidly progressive ALS through a haploinsufficiency mechanism. Keywords: Amyotrophic lateral sclerosis; Frontotemporal dementia; TANK-binding kinase 1 (TBK1) gene 1. INTRODUCTION Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of devastating neurodegenerative diseases characterized by relentless deterioration of voluntary muscle function resulting from degeneration of upper and lower motor neurons. Patients with ALS manifest progressive muscular weakness and atrophy, bulbar palsy, and ultimately respiratory failure, with a *Address correspondence: Dr. Yi-Chung Lee, Department of Neurology, Taipei Veterans General Hospital, 201, Section 2, Shi-Pai Road, Taipei 112, Taiwan, [ROC. E-mail address: ycli@vghtpe.gov.tw](ROC. E-mail address: ycli@vghtpe.gov.tw) (Y.-C. Lee). Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article. Journal of Chinese Medical Association. (2024) 87: 920-926. Received January 19, 2024; accepted May 3, 2024. doi: 10. 1097/JCMA.0000000000001147 Copyright © 2024, the Chinese Medical Association. This is an open access article

FAQs

What was the main objective of the study?

To characterize the clinical and molecular genetic features of a novel TBK1 variant identified in a patient with young-onset, rapidly progressive ALS.

How did the researchers identify genetic variants?

They analyzed TBK1, SOD1, TARDBP, and FUS coding regions by Sanger sequencing, and assessed the C9ORF72 GGGGCC repeat using repeat-primed PCR.

What key variant did the study find, and what were its molecular effects?

A novel frameshift truncating TBK1 variant, c.456_457delGT (p.Y153Qfs*9), which produced a truncated TBK1 protein with reduced expression, loss of kinase function, reduced optineurin interaction, and impaired dimerization.

What mechanism did the authors propose for the variant’s association with ALS?

The heterozygous TBK1 p.Y153Qfs*9 variant may be associated with young-onset, rapidly progressive ALS through a haploinsufficiency mechanism.

Sep 29, 2026

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