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

Volume 52 Issue 8

Aug. 2025

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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
Publish Date: 2025-01-14

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

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References

Agerschou, E.D., Flagmeier, P., Saridaki, T., Galvagnion, C., Komnig, D., Heid, L., Prasad, V., Shaykhalishahi, H., Willbold, D., Dobson, C.M., et al., 2019. An engineered monomer binding-protein for alpha-synuclein efficiently inhibits the proliferation of amyloid fibrils. Elife 8, e46112.

Alazami, A.M., Adly, N., Al Dhalaan, H., Alkuraya, F.S., 2011. A nullimorphic ERLIN2 mutation defines a complicated hereditary spastic paraplegia locus (SPG18). Neurogenetics 12, 333-336.

Branchu, J., Boutry, M., Sourd, L., Depp, M., Leone, C., Corriger, A., Vallucci, M., Esteves, T., Matusiak, R., Dumont, M., et al., 2017. Loss of spatacsin function alters lysosomal lipid clearance leading to upper and lower motor neuron degeneration. Neurobiol. Dis. 102, 21-37.

Cheng, H.L., Shao, Y.R., Dong, Y., Dong, H.L., Yang, L., Ma, Y., Shen, Y., Wu, Z.Y., 2021. Genetic spectrum and clinical features in a cohort of Chinese patients with autosomal recessive cerebellar ataxias. Transl. Neurodegener. 10, 40.

Darios, F., Mochel, F., Stevanin, G., 2020. Lipids in the physiopathology of hereditary spastic paraplegias. Front. Neurosci. 14, 74.

De Michele, G., De Fusco, M., Cavalcanti, F., Filla, A., Marconi, R., Volpe, G., Monticelli, A., Ballabio, A., Casari, G., Cocozza, S., 1998. A new locus for autosomal recessive hereditary spastic paraplegia maps to chromosome 16q24.3. Am. J. Hum. Genet. 63, 135-139.

Deng, R., Medico-Salsench, E., Nikoncuk, A., Ramakrishnan, R., Lanko, K., Kuhn, N.A., van der Linde, H.C., Lor-Zade, S., Albuainain, F., Shi, Y., et al., 2023a. AMFR dysfunction causes autosomal recessive spastic paraplegia in human that is amenable to statin treatment in a preclinical model. Acta. Neuropathol. 146, 353-368.

Deng, Z., Chen, H., Xiao, L., Jin, H., Zhang, Q., Jiao, R., Wei, C., 2023b. Gain of function screen of PATs reveals an essential role of Hip14 in Drosophila host defense. J. Genet. Genomics 50, 1014-1017.

Dimova, R., 2014. Recent developments in the field of bending rigidity measurements on membranes. Adv. Colloid. Interface. Sci. 208, 225-234.

Dong, H.L., Ma, Y., Yu, H., Wei, Q., Li, J.Q., Liu, G.L., Li, H.F., Chen, L., Chen, D.F., Bai, G., et al., 2021. Bi-allelic loss of function variants in COX20 gene cause autosomal recessive sensory neuronopathy. Brain 144, 2457-2470.

Estrada-Cuzcano, A., Martin, S., Chamova, T., Synofzik, M., Timmann, D., Holemans, T., Andreeva, A., Reichbauer, J., De Rycke, R., Chang, D.I., et al., 2017. Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78). Brain 140, 287-305.

Ferris, H.A., Perry, R.J., Moreira, G.V., Shulman, G.I., Horton, J.D., Kahn, C.R., 2017. Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism. Proc. Natl. Acad. Sci. U. S. A. 114, 1189-1194.

Fink, J.K., 2013. Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta. Neuropathol. 126, 307-328.

Greenberg, A.S., Coleman, R.A., Kraemer, F.B., McManaman, J.L., Obin, M.S., Puri, V., Yan, Q.W., Miyoshi, H., Mashek, D.G., 2011. The role of lipid droplets in metabolic disease in rodents and humans. J. Clin. Invest. 121, 2102-2110.

Gregory, J.M., Whiten, D.R., Brown, R.A., Barros, T.P., Kumita, J.R., Yerbury, J.J., Satapathy, S., McDade, K., Smith, C., Luheshi, L.M., et al., 2017. Clusterin protects neurons against intracellular proteotoxicity. Acta Neuropathol. Commun. 5, 81.

Harding, A.E., 1983. Classification of the hereditary ataxias and paraplegias. Lancet 1 1151-1155.

Hirst, J., Edgar, J.R., Esteves, T., Darios, F., Madeo, M., Chang, J., Roda, R.H., Durr, A., Anheim, M., Gellera, C., et al., 2015. Loss of AP-5 results in accumulation of aberrant endolysosomes: defining a new type of lysosomal storage disease. Hum. Mol. Genet. 24, 4984-4996.

Horton, J.D., Goldstein, J.L., Brown, M.S., 2002. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125-1131.

Huber, M.D., Vesely, P.W., Datta, K., Gerace, L., 2013. Erlins restrict SREBP activation in the ER and regulate cellular cholesterol homeostasis. J. Cell. Biol. 203, 427-436.

Jones, L., Harold, D., Williams, J., 2010. Genetic evidence for the involvement of lipid metabolism in Alzheimer's disease. Biochim. Biophys. Acta 1801, 754-761.

Klebe, S., Stevanin, G., Depienne, C., 2015. Clinical and genetic heterogeneity in hereditary spastic paraplegias: from SPG1 to SPG72 and still counting. Rev. Neurol. (Paris) 171, 505-530.

Li, A.Q., Li, S.S., Zhang, R.X., Zhao, X.Y., Liu, Z.Y., Hu, Y., Wang, B., Neely, G.G., Simpson, S.J., Wang, Q.P., 2023. Nutritional geometry framework of sucrose taste in Drosophila. J. Genet. Genomics 50, 233-240.

Li, Q.F., Dong, Y., Yang, L., Xie, J.J., Ma, Y., Du, Y.C., Cheng, H.L., Ni, W., Wu, Z.Y., 2019. Neurofilament light chain is a promising serum biomarker in spinocerebellar ataxia type 3. Mol. Neurodegener 14, 39.

Lu, C., Li, L.X., Dong, H.L., Wei, Q., Liu, Z.J., Ni, W., Gitler, A.D., Wu, Z.Y., 2018. Targeted next-generation sequencing improves diagnosis of hereditary spastic paraplegia in Chinese patients. J. Mol. Med. (Berl) 96, 701-712.

Marelli, C., Lamari, F., Rainteau, D., Lafourcade, A., Banneau, G., Humbert, L., Monin, M.L., Petit, E., Debs, R., Castelnovo, G., et al., 2018. Plasma oxysterols: biomarkers for diagnosis and treatment in spastic paraplegia type 5. Brain 141, 72-84.

Martinello, C., Panza, E., Orlacchio, A., 2023. Hereditary spastic paraplegias proteome: common pathways and pathogenetic mechanisms. Expert. Rev. Proteomics 20, 171-188.

Miserez, A.R., Cao, G., Probst, L.C., Hobbs, H.H., 1997. Structure of the human gene encoding sterol regulatory element binding protein 2 (SREBF2). Genomics 40, 31-40.

Mizushima, N., Yoshimori, T., 2007. How to interpret LC3 immunoblotting. Autophagy 3, 542-545.

Mizushima, N., Yoshimori, T., Levine, B., 2010. Methods in mammalian autophagy research. Cell 140, 313-326.

Montag, J., Brameier, M., Schmadicke, A.C., Gilch, S., Schatzl, H.M., Motzkus, D., 2012. A genome-wide survey for prion-regulated miRNAs associated with cholesterol homeostasis. B.M.C. Genomics 13, 486.

Motamed, M., Zhang, Y., Wang, M.L., Seemann, J., Kwon, H.J., Goldstein, J.L., Brown, M.S., 2011. Identification of luminal Loop 1 of Scap protein as the sterol sensor that maintains cholesterol homeostasis. J. Biol .Chem. 286, 18002-18012.

Murala, S., Nagarajan, E., Bollu, P.C., 2021. Hereditary spastic paraplegia. Neurol. Sci. 42, 883-894.

Novarino, G., Fenstermaker, A.G., Zaki, M.S., Hofree, M., Silhavy, J.L., Heiberg, A.D., Abdellateef, M., Rosti, B., Scott, E., Mansour, L., et al., 2014. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 343, 506-511.

Renvoise, B., Chang, J., Singh, R., Yonekawa, S., FitzGibbon, E.J., Mankodi, A., Vanderver, A., Schindler, A., Toro, C., Gahl, W.A., et al., 2014. Lysosomal abnormalities in hereditary spastic paraplegia types SPG15 and SPG11. Ann. Clin .Transl. Neurol. 1, 379-389.

Rickman, O.J., Baple, E.L., Crosby, A.H., 2020. Lipid metabolic pathways converge in motor neuron degenerative diseases. Brain 143, 1073-1087.

Roussel, B.D., Newton, T.M., Malzer, E., Simecek, N., Haq, I., Thomas, S.E., Burr, M.L., Lehner, P.J., Crowther, D.C., Marciniak, S.J., et al., 2013. Sterol metabolism regulates neuroserpin polymer degradation in the absence of the unfolded protein response in the dementia FENIB. Hum. Mol. Genet. 22, 4616-4626.

Saffari, A., Kellner, M., Jordan, C., Rosengarten, H., Mo, A., Zhang, B., Strelko, O., Neuser, S., Davis, M.Y., Yoshikura, N., et al., 2023. The clinical and molecular spectrum of ZFYVE26-associated hereditary spastic paraplegia: SPG15. Brain 146, 2003-2015.

Schob, C., Hempel, M., Safka Brozkova, D., Jiang, H., Kim, S.Y., Batzir, N.A., Orenstein, N., Bierhals, T., Johannsen, J., Uhrova Meszarosova, A., et al., 2021. Dominant KPNA3 mutations cause infantile-onset hereditary spastic paraplegia. Ann. Neurol. 90, 738-750.

Seo, Y.K., Jeon, T.I., Chong, H.K., Biesinger, J., Xie, X., Osborne, T.F., 2011. Genome-wide localization of SREBP-2 in hepatic chromatin predicts a role in autophagy. Cell Metab. 13, 367-375.

Shibata, M., Yoshimura, K., Tamura, H., Ueno, T., Nishimura, T., Inoue, T., Sasaki, M., Koike, M., Arai, H., Kominami, E., et al., 2010. LC3, a microtubule-associated protein1A/B light chain3, is involved in cytoplasmic lipid droplet formation. Biochem. Biophys. Res. Commun. 393, 274-279.

Singh, R., Kaushik, S., Wang, Y., Xiang, Y., Novak, I., Komatsu, M., Tanaka, K., Cuervo, A.M., Czaja, M.J., 2009. Autophagy regulates lipid metabolism. Nature 458, 1131-1135.

Tabara, L.C., Al-Salmi, F., Maroofian, R., Al-Futaisi, A.M., Al-Murshedi, F., Kennedy, J., Day, J.O., Courtin, T., Al-Khayat, A., Galedari, H., et al., 2022. TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia. Brain 145, 3095-3107.

Tsaousidou, M.K., Ouahchi, K., Warner, T.T., Yang, Y., Simpson, M.A., Laing, N.G., Wilkinson, P.A., Madrid, R.E., Patel, H., Hentati, F., et al., 2008. Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration. Am. J. Hum. Genet. 82, 510-515.

Walther, T.C., Farese, R.V., Jr., 2012. Lipid droplets and cellular lipid metabolism. Annu. Rev. Biochem. 81, 687-714.

Wang, H., Humbatova, A., Liu, Y., Qin, W., Lee, M., Cesarato, N., Kortum, F., Kumar, S., Romano, M.T., Dai, S., et al., 2020. Mutations in SREBF1, encoding sterol regulatory element binding transcription factor 1, cause autosomal-dominant IFAP syndrome. Am. J. Hum. Genet. 107, 34-45.

Wang, Y., Thiele, C., Huttner, W.B., 2000. Cholesterol is required for the formation of regulated and constitutive secretory vesicles from the trans-Golgi network. Traffic. 1, 952-962.

Wei, Q., Dong, H.L., Pan, L.Y., Chen, C.X., Yan, Y.T., Wang, R.M., Li, H.F., Liu, Z.J., Tao, Q.Q., Wu, Z.Y., 2019. Clinical features and genetic spectrum in Chinese patients with recessive hereditary spastic paraplegia. Transl. Neurodegener. 8, 19.

Wei, Q., Luo, W.J., Yu, H., Wang, P.S., Dong, H.L., Li, H.F., Wu, Z.Y., 2021. A novel PCYT2 mutation identified in a Chinese consanguineous family with hereditary spastic paraplegia. J. Genet. Genomics. 48, 751-754.

Yan, Y.T., Wei, Q., Zheng, Y., Luo, W.J., Dong, H.L., Lu, C., Zhang, J., Chen, M.J., Bao, Y.X., Li, H.F., 2019. Clinical and genetic characterization of a cohort of Chinese patients with hereditary spastic paraplegia. Clin. Genet. 95, 637-639.

Yang, T., Espenshade, P.J., Wright, M.E., Yabe, D., Gong, Y., Aebersold, R., Goldstein, J.L., Brown, M.S., 2002. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 110, 489-500.

Zhang, J., Xue, R., Ong, W.Y., Chen, P., 2009. Roles of cholesterol in vesicle fusion and motion. Biophys. J. 97, 1371-1380.

Zhang, Y., Wu, Z.Y., 2024. Gene therapy for monogenic disorders: challenges, strategies, and perspectives. J. Genet. Genomics 5, 133-143.

Zheng, Z., Zhang, X., Huang, B., Liu, J., Wei, X., Shan, Z., Wu, H., Feng, Z., Chen, Y., Fan, S., et al., 2021. Site-1 protease controls osteoclastogenesis by mediating LC3 transcription. Cell. Death. Differ. 28, 2001-2018.

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