CAG Repeat Expansion in THAP11 Is Associated with a Novel Spinocerebellar Ataxia

Dandan Tan; Cuijie Wei; Zhao Chen; Yu Huang; Jianwen Deng; Jingjing Li; Yidan Liu; Xinhua Bao; Jin Xu; Zhengmao Hu; Suxia Wang; Yanbin Fan; Yizheng Jiang; Ye Wu; Yuan Wu; Shuang Wang; Panyan Liu; Yuehua Zhang; Zhixian Yang; Yuwu Jiang; Hong Zhang; Daojun Hong; Nanbert Zhong; Hong Jiang; Hui Xiong

doi:10.1002/mds.29412

CAG Repeat Expansion in THAP11 Is Associated with a Novel Spinocerebellar Ataxia

Mov Disord. 2023 Jul;38(7):1282-1293. doi: 10.1002/mds.29412. Epub 2023 May 6.

Authors

Dandan Tan¹, Cuijie Wei¹, Zhao Chen², Yu Huang³, Jianwen Deng⁴, Jingjing Li⁵, Yidan Liu¹, Xinhua Bao^{1

6}, Jin Xu⁷, Zhengmao Hu⁸, Suxia Wang⁷, Yanbin Fan¹, Yizheng Jiang⁸, Ye Wu^{1

6}, Yuan Wu¹, Shuang Wang¹, Panyan Liu², Yuehua Zhang^{1

6}, Zhixian Yang^{1

6}, Yuwu Jiang^{1

6}, Hong Zhang⁹, Daojun Hong¹⁰, Nanbert Zhong¹¹, Hong Jiang^{2

8

12

13

14}, Hui Xiong^{1

6}

Affiliations

¹ Department of Pediatrics, Peking University First Hospital, Beijing, P.R. China.
² Department of Neurology, Xiangya Hospital, Central South University, Changsha, P.R. China.
³ Department of Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing, P.R. China.
⁴ Department of Neurology, Peking University First Hospital, Beijing, P.R. China.
⁵ GrandOmics Biosciences, Beijing, P.R. China.
⁶ Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases, Beijing, P.R. China.
⁷ Center of Ultrastructural Pathology, Lab of Electron Microscopy, Peking University First Hospital, Beijing, P.R. China.
⁸ Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, P.R. China.
⁹ Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Peking University Health Science Center, Beijing, P.R. China.
¹⁰ Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China.
¹¹ New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA.
¹² National Clinical Research Center for Geriatric Diseases, Central South University, Changsha, P.R. China.
¹³ National International Collaborative Research Center for Medical Metabolomics, Central South University, Changsha, P.R. China.
¹⁴ Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, P.R. China.

PMID: 37148549
DOI: 10.1002/mds.29412

Abstract

Background: More than 50 loci are associated with spinocerebellar ataxia (SCA), and the most frequent subtypes share nucleotide repeats expansion, especially CAG expansion.

Objective: The objective of this study was to confirm a novel SCA subtype caused by CAG expansion.

Methods: We performed long-read whole-genome sequencing combined with linkage analysis in a five-generation Chinese family, and the finding was validated in another pedigree. The three-dimensional structure and function of THAP11 mutant protein were predicted. Polyglutamine (polyQ) toxicity of THAP11 gene with CAG expansion was assessed in skin fibroblasts of patients, human embryonic kidney 293 and Neuro-2a cells.

Results: We identified THAP11 as the novel causative SCA gene with CAG repeats ranging from 45 to 100 in patients with ataxia and from 20 to 38 in healthy control subjects. Among the patients, the number of CAA interruptions within CAG repeats was decreased to 3 (up to 5-6 in controls), whereas the number of 3' pure CAG repeats was up to 32 to 87 (4-16 in controls), suggesting that the toxicity of polyQ protein was length dependent on the pure CAG repeats. Intracellular aggregates were observed in cultured skin fibroblasts from patients. THAP11 polyQ protein was more intensely distributed in the cytoplasm of cultured skin fibroblasts from patients, which was replicated with in vitro cultured neuro-2a transfected with 54 or 100 CAG repeats.

Conclusions: This study identified a novel SCA subtype caused by intragenic CAG repeat expansion in THAP11 with intracellular aggregation of THAP11 polyQ protein. Our findings extended the spectrum of polyQ diseases and offered a new perspective in understanding polyQ-mediated toxic aggregation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: THAP11 gene; polyglutamine; repeat expansion; spinocerebellar ataxia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Pedigree
Proteins / genetics
Repressor Proteins / genetics
Spinocerebellar Ataxias* / genetics
Trinucleotide Repeat Expansion* / genetics

Substances

Proteins
THAP11 protein, human
Repressor Proteins