Biallelic Variants in EPG5 Gene Are Associated with Parkinson's Disease
Qi-Ying Sun MD, PhD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
These authors contributed equally to this work.
Search for more papers by this authorFu-Liang Tang MD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, China
These authors contributed equally to this work.
Search for more papers by this authorYao Zhou MD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
Search for more papers by this authorHong-Xu Pan MD, PhD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
Search for more papers by this authorXun Zhou MD, PhD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
Search for more papers by this authorYu-Wen Zhao MD, PhD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
Search for more papers by this authorRun-Cheng He MD, PhD
Department of Neurology, Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, China
Search for more papers by this authorSheng Zeng MD, PhD
Department of Neurology, Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, China
Search for more papers by this authorJun-Pu Wang PhD
Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
Search for more papers by this authorWei Lin PhD
Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
Search for more papers by this authorWei-Qian Zeng PhD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, China
Search for more papers by this authorDan-dan Wang MSc
Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, China
Search for more papers by this authorXue-Jing Wang MD, PhD
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
Search for more papers by this authorZhen-Hua Liu MD, PhD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
Search for more papers by this authorQian Xu MD, PhD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
Search for more papers by this authorJin-Chen Li PhD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
Search for more papers by this authorXin-Xiang Yan MD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
Search for more papers by this authorJi-Feng Guo MD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
Search for more papers by this authorCorresponding Author
Jian Qiu PhD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
MOE Key Lab of Rare Pediatric Diseases and Hunan Key Laboratory of Medical Genetics and Hunan Key Laboratory of Animal Models for Human Diseases, School of Life Sciences, Central South University, Changsha, China
Furong Laboratory, Changsha, China
Address correspondence to Dr Jian Qiu, Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China. E-mail: [email protected]
Dr Bei-Sha Tang, Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, 410008, China. E-mail: [email protected]
Search for more papers by this authorCorresponding Author
Bei-Sha Tang MD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
Department of Neurology, The First Affiliated Hospital, University of South China, Hengyang, China
Address correspondence to Dr Jian Qiu, Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China. E-mail: [email protected]
Dr Bei-Sha Tang, Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, 410008, China. E-mail: [email protected]
Search for more papers by this authorQi-Ying Sun MD, PhD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
These authors contributed equally to this work.
Search for more papers by this authorFu-Liang Tang MD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, China
These authors contributed equally to this work.
Search for more papers by this authorYao Zhou MD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
Search for more papers by this authorHong-Xu Pan MD, PhD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
Search for more papers by this authorXun Zhou MD, PhD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
Search for more papers by this authorYu-Wen Zhao MD, PhD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
Search for more papers by this authorRun-Cheng He MD, PhD
Department of Neurology, Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, China
Search for more papers by this authorSheng Zeng MD, PhD
Department of Neurology, Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, China
Search for more papers by this authorJun-Pu Wang PhD
Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
Search for more papers by this authorWei Lin PhD
Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
Search for more papers by this authorWei-Qian Zeng PhD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, China
Search for more papers by this authorDan-dan Wang MSc
Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, China
Search for more papers by this authorXue-Jing Wang MD, PhD
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
Search for more papers by this authorZhen-Hua Liu MD, PhD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
Search for more papers by this authorQian Xu MD, PhD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
Search for more papers by this authorJin-Chen Li PhD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
Search for more papers by this authorXin-Xiang Yan MD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
Search for more papers by this authorJi-Feng Guo MD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
Search for more papers by this authorCorresponding Author
Jian Qiu PhD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
MOE Key Lab of Rare Pediatric Diseases and Hunan Key Laboratory of Medical Genetics and Hunan Key Laboratory of Animal Models for Human Diseases, School of Life Sciences, Central South University, Changsha, China
Furong Laboratory, Changsha, China
Address correspondence to Dr Jian Qiu, Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China. E-mail: [email protected]
Dr Bei-Sha Tang, Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, 410008, China. E-mail: [email protected]
Search for more papers by this authorCorresponding Author
Bei-Sha Tang MD
Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
Department of Neurology, The First Affiliated Hospital, University of South China, Hengyang, China
Address correspondence to Dr Jian Qiu, Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China. E-mail: [email protected]
Dr Bei-Sha Tang, Department of Neurology, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, 410008, China. E-mail: [email protected]
Search for more papers by this authorAbstract
Objective
Despite substantial advancements in uncovering the genetic basis of Parkinson's disease (PD), a significant portion of cases characterized by familial PD remain genetically elusive. Here, we reported that biallelic variants in EPG5, a key autophagy gene responsible for Vici syndrome, are associated with PD.
Methods
Whole-exome sequencing (WES) was performed in the first cohort including 171 pedigrees with autosomal recessive PD (ARPD), 1,746 cases of sporadic early-onset PD (sEOPD, age at onset ≤ 50 years) and 1,652 healthy controls. Whole-genome sequencing (WGS) was performed in the second cohort consisting of 1,947 sporadic late-onset PD (sLOPD, age at onset >50 years) and 2,478 healthy controls.
Results
We identified 7 participants harboring compound heterozygous variants within the EPG5 gene across 1 family with ARPD (ARPD-F1), 4 sporadic EOPD cases, and 1 sporadic LOPD individual. A total of 10 novel variants in EPG5 were discovered in the 7 individuals, comprising 3 nonsense variants and 7 missense variants. The compound heterozygous variants in the EPG5 gene led to decreased expression of EPG5 protein, and impaired autophagy-lysosome function in cells derived from EPG5-PD individuals. We also revealed several key pathological features, including abnormal accumulation of autophagic vacuoles, aggregation of α-synuclein in skin tissue from EPG5-PD individuals. In mice, EPG5 deficiency led to progressive dopaminergic neurodegeneration in the substantia nigra of the midbrain.
Interpretation
Our results unveil a novel association between biallelic variants in EPG5 gene and PD, providing compelling initial evidence for the involvement of EPG5 and autophagy dysregulation in the development of PD. ANN NEUROL 2025;98:369–385
Potential Conflicts of Interest
The authors declare no competing interests.
Open Research
Data Availability
Datasets supporting the results and conclusions of this manuscript are available from the corresponding author Dr. Beisha Tang (email:[email protected]) upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| ana27242-sup-0001-FigureS1.tifTIFF image, 4.2 MB | Figure S1. Sanger sequencing of 10 EPG5 variants found in the 7 PD individuals harboring compound heterozygous variants within the EPG5 gene in this study. |
| ana27242-sup-0002-FigureS2.tifTIFF image, 1.5 MB | Figure S2. The haplotype analysis of 2 missense variants (p.C2313Y and p.D1770N). (A) Haplotypic analysis revealed that both ARPD-F1 and sEOPD-1 share the same p.C2313Y haplotype, whereas sEOPD-2 and sEOPD-3 exhibit distinct p.D1770N haplotypes (B). |
| ana27242-sup-0003-FigureS3.tifTIFF image, 19.6 MB | Figure S3. Representative test results of ARPD-F1 II2, including abdominal ultrasonography, cardiac assessments (electrocardiogram and echocardiogram), electroencephalogram, ophthalmological evaluations (fundus photography and optical coherence tomography), and hearing tests (audiometry and acoustic impedance). |
| ana27242-sup-0004-FigureS4.tifTIFF image, 12.2 MB | Figure S4. The ultrastructural analysis of skin biopsies from 3 probands (ARPD-F1 II-2 (A), sEOPD-2 II-1 (B) and sEOPD-3 II-3 (C)) using electron microscopy. The results show an increase in lysosomal structures (red arrow), mitochondrial shrinkage and vacuolar degeneration (red triangle), and evidence of endoplasmic reticulum stress (yellow arrow). |
| ana27242-sup-0005-FigureS5.tifTIFF image, 4.1 MB | Figure S5. Autophagy is partially impaired in EPG5-PD individual fibroblast cell. (A) The fibroblast cell derived from EPG5-PD individual showed increased levels of NBR1, P62 and LC3, particularly of processed, lapidated LC3-II. (B) Accumulation of autophagy adaptors NBR1, P62 and the phagophore membrane component LC3 is induced in control and EPG5-PD fibroblasts by 12 hour treatment with rapamycin and bafilomycin. (C) Representative immunocytochemistry images of fibroblasts double-labelled with LC3 and LAMP1. The fusion of LC3-positive autophagosomes with lysosomes is reduced in individual fibroblast. Scale bar = 5 μm. |
| ana27242-sup-0006-FigureS6.tifTIFF image, 2.4 MB | Figure S6. Compare the accumulation of autophagy marker of several neuronal line with U2OS cell line after knocking down EPG5 protein. (A) SH-SY5Y neuroblastoma cell line showed lower basal expression levels of EPG5, p62, and LC3, and no substantial changes in autophagy markers were detected following EPG5 knockdown. (B) HMC3 and U87 showed comparable responses to EPG5 knockdown which observed in U2OS cells. |
| ana27242-sup-0007-FigureS7.tifTIFF image, 4 MB | Figure S7. Overexpression of several hEPG5 plasmids in HEK293T. The hEPG5 (p.C2313Y), hEPG5 (p.R417X), hEPG5 (p.R2445X), hEPG5 (p.Y855X) and hEPG5 (p.Y1190X) were not readily detected and most were expressed at levels lower to that of wild-type hEPG5. hEPG5 (p.Q336R) and hEPG5 (p.D1770N) can be detected easily. |
| ana27242-sup-0008-FigureS8.zipZip archive, 50.8 MB | Figure S8. The unedited version of all the original western blots for Figures 5A and 5C and Supplementary Figures S5A and S5B, and Supplementary Figures S6A and S6B. |
| ana27242-sup-0009-Table S1.docxWord 2007 document , 16 KB | Table S1. Primers for plasmid construction. |
| ana27242-sup-0010-Table S2.docxWord 2007 document , 16.5 KB | Table S2. Basic demographic characteristics of WES cohort and WGS cohort in this study. |
| ana27242-sup-0011-Table S3.docxWord 2007 document , 19.9 KB | Table S3. Summary lists of pathogenic variants in known PD genes excluded from the WES cohort and the WGS cohort. |
| ana27242-sup-0012-Table S4.docxWord 2007 document , 17.4 KB | Table S4. Whole-exome sequencing data in ARPD-Family 1. |
| ana27242-sup-0013-Table S5.docxWord 2007 document , 17.9 KB | Table S5. Three candidate gene variants that conform to the autosomal recessive inheritance pattern in Family 1. |
| ana27242-sup-0014-Table S6.docxWord 2007 document , 36.9 KB | Table S6. LOF and deleterious variants with MAF < 0.01 in EPG5 gene identified in our cohorts. |
| ana27242-sup-0015-Table S7.docxWord 2007 document , 17.1 KB | Table S7. Burden analysis of EPG5 variants in Parkinson's disease of the Chinese population. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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