ArticleMovement disorders : official journal of the Movement Disorder Society2022
A Novel SPAST Mutation Results in Spastin Accumulation and Defects in Microtubule Dynamics.
Article in Movement disorders : official journal of the Movement Disorder Society, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 19 citations in OpenAlex.
- Significant differences in phenotype and age of onset in an SPG4 family caused by whole SPAST deletion combined with a hemizygous S44L modifier.Neurogenetics · 2026Article
- Article
- Comparative Transcriptomics and Intestinal Microbiome Analysis Provide Insights into the Semi-Terrestrial Adaptation ofAnimals : an open access journal from MDPI · 2025Article
- [Successful application of preimplantation genetic testing combined with thirdgeneration sequencing for blocking hereditary spastic paraplegia].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2024Article
- Spastin accumulation and motor neuron defects caused by a novel SPAST splice site mutation.Journal of translational medicine · 2024Article
- NovelFrontiers in genetics · 2024Article
- A novel truncated variant in SPAST results in spastin accumulation and defects in microtubule dynamics.BMC medical genomics · 2023Article
- Long-read sequencing revealing intragenic deletions in exome-negative spastic paraplegias.Journal of human genetics · 2023Article
- A novel missense mutation inMolecular medicine reports · 2023Article
- The Puzzle of Hereditary Spastic Paraplegia: From Epidemiology to Treatment.International journal of molecular sciences · 2022Review
- A novel truncating variant ofFrontiers in neurology · 2022Article
- A novel variant ofAnnals of translational medicine · 2022Article
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15 authors at 4 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
backgroundHaploinsufficiency is widely accepted as the pathogenic mechanism of spastic paraplegia type 4 (SPG4). However, there are some cases that cannot be explained by reduced function of the spastin protein encoded by SPAST.
objectivesTo identify the causative gene of autosomal dominant hereditary spastic paraplegia in three large Chinese families and explore the pathological mechanism of a spastin variant.
methodsThree large Chinese hereditary spastic paraplegia families with a total of 247 individuals (67 patients) were investigated, of whom 59 members were recruited to the study. Genetic testing was performed to identify the causative gene. Western blotting and immunofluorescence were used to analyze the effects of the mutant proteins in vitro.
resultsIn the three hereditary spastic paraplegia families, of whom three index cases were misdiagnosed as other types of neurological diseases, a novel c.985dupA (p.Met329Asnfs*3) variant in SPAST was identified and was shown to cosegregate with the phenotype in the three families. The c.985dupA mutation produced two truncated mutants (mutant M1 and M87 isoforms) that accumulated to a higher level than their wild-type counterparts. Furthermore, the mutant M1 isoform heavily decorated the microtubules and rendered them resistant to depolymerization. In contrast, the mutant M87 isoform was diffusely localized in both the nucleus and the cytoplasm, could not decorate microtubules, and was not able to promote microtubule disassembly.
conclusionsSPAST mutations leading to premature stop codons do not always act through haploinsufficiency. The truncated spastin may damage the corticospinal tracts through an isoform-specific toxic effect.
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