Biallelic variants in <i>SREBF2</i> cause autosomal recessive spastic paraplegia

Qiao Wei; Wenlu Fan; Hong-Fu Li; Pei-Shan Wang; Man Xu; Hai-Lin Dong; Hao Yu; Jialan Lyu; Wen-Jiao Luo; Dian-Fu Chen; Wanzhong Ge; Zhi-Ying Wu

doi:10.1016/j.jgg.2025.01.004

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Biallelic variants in SREBF2 cause autosomal recessive spastic paraplegia

doi: 10.1016/j.jgg.2025.01.004

a. Department of Medical Genetics and Center for Rare Diseases, Second Affiliated Hospital, Zhejiang University School of Medicine and Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation, Hangzhou, Zhejiang 310009, China;
b. Nanhu Brain-computer Interface Institute, Hangzhou, Zhejiang 311100, China;
c. Division of Human Reproduction and Developmental Genetics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China;
d. MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang 310012, China;
e. CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai 200031, China

Funds:

This study was supported by the grants from the National Natural Science Foundation of China to Zhi-Ying Wu (82230062, Beijing), Qiao Wei (82402156, Beijing), and Wanzhong Ge (31970668, Beijing), and the research foundation for distinguished scholar of Zhejiang University (188020-193810101/089, Hangzhou) to Zhi-Ying Wu. The authors sincerely thank the participants for their help and willingness to participate in this study. Thanks for the technical support by the Core Facilities, Zhejiang University School of Medicine.

Received Date: 2024-08-27
Accepted Date: 2025-01-05
Rev Recd Date: 2025-01-03

Available Online: 2025-07-11

Abstract

Abstract

Hereditary spastic paraplegias (HSPs) refer to a genetically and clinically heterogeneous group of neurodegenerative disorders characterized by the degeneration of motor neurons. To date, a significant number of patients still have not received a definite genetic diagnosis. Therefore, identifying unreported causative genes continues to be of great importance. Here, we perform whole exome sequencing in a cohort of Chinese HSP patients. Three homozygous variants (p.L604W, p.S517F, and p.T984A) within the sterol regulatory element-binding factor 2 (SREBF2) gene are identified in one autosomal recessive family and two sporadic patients, respectively. Co-segregation is confirmed by Sanger sequencing in all available members. The three variants are rare in the public or in-house database and are predicted to be damaging. The biological impacts of variants in SREBF2 are examined by functional experiments in patient-derived fibroblasts and Drosophila. We find that the variants upregulate cellular cholesterol due to the overactivation of SREBP2, eventually impairing the autophagosomal and lysosomal functions. The overexpression of the mature form of SREBP2 leads to locomotion defects in Drosophila. Our findings identify SREBF2 as a causative gene for HSP and highlight the impairment of cholesterol as a critical pathway for HSP.
- Hereditary spastic paraplegia,
- Causative gene,
- SREBF2,
- Cholesterol,
- Locomotion defects