Abstract
More than 80 known or suspected genes/loci have been reported to be involved in hereditary spastic paraplegia (HSP). Genetic and clinical overlap have been reported between HSP and other neurological condition, yet about 50% of HSP patients remain genetically undiagnosed. To identify novel genes involved in HSP, we performed a genetic analysis of 383 HSP patients from 289 families with HSP. Two patients with biallelic SPTAN1 variants were identified; one carried the c.2572G>T p.(Ala858Ser) and c.4283C>G p.(Ala1428Gly) variants, and the second also carried the c.2572G>T p.(Ala858Ser) variant, and an additional variant, c.6990G>C p.(Met2330Ile). In silico predictive and structural analyses suggested that these variants are likely to be deleterious. SPTAN1 was highly intolerant for functional variants (in the top 0.31% of intolerant genes) with much lower observed vs. expected number of loss-of-function variants (8 vs. 142.7, p < 5 × 10−15). Using public databases of animal models and previously published data, we have found previously described zebrafish, mouse, and rat animal models of SPTAN1 deficiency, all consistently showing axonal degeneration, fitting the pathological features of HSP in humans. This study expands the phenotype of SPTAN1 mutations, which at the heterozygous state, when occurred de novo, may cause early infantile epileptic encephalopathy-5 (EIEE5). Our results further suggest that SPTAN1 may cause autosomal recessive HSP, and that it should be included in genetic screening panels for genetically undiagnosed HSP patients.
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Acknowledgements
We thank the patients and their families for their participation. We thank all the members of CanHSP. JFT holds a Canada Research Chair in Structural Pharmacology. GAR holds a Canada Research Chair in Genetics of the Nervous System and the Wilder Penfield Chair in Neurosciences. ZGO is supported by grants from the Michael J. Fox Foundation, the Canadian Consortium on Neurodegeneration in Aging (CCNA), the Canadian Glycomics Network (GlycoNet), the Canada First Research Excellence Fund (CFREF) through the Healthy Brains for Healthy Lives (HBHL) program and Parkinson’s Canada. ZGO holds a Fonds de recherche du Québec—Santé (FRQS) Chercheurs-boursiers award and a Young Investigator Award from Parkinson’s Canada. We thank Helene Catoire, Daniel Rochefort, and Vessela Zeharieva for their assistance.
Funding
This study was funded by CIHR Emerging Team Grant, in collaboration with the Canadian Organization for Rare Disorders (CORD), grant number RN127580–260005. This work was done as a part of a Canadian collaboration to study HSP (CanHSP).
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Leveille, E., Estiar, M.A., Krohn, L. et al. SPTAN1 variants as a potential cause for autosomal recessive hereditary spastic paraplegia. J Hum Genet 64, 1145–1151 (2019). https://doi.org/10.1038/s10038-019-0669-2
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DOI: https://doi.org/10.1038/s10038-019-0669-2
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