Affinage

SPAST

Spastin · UniProt Q9UBP0

Length
616 aa
Mass
67.2 kDa
Annotated
2026-06-10
100 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SPAST encodes spastin, a microtubule-severing AAA-ATPase expressed in neurons whose enzymatic activity maintains the pool of stable, dynamically regulated axonal microtubules (PMID:12490534, PMID:19714378). The gene produces two principal isoforms from distinct translation start sites—the longer M1 (80 kDa) and the shorter M87 (60 kDa), the latter driven additionally by a cryptic promoter within exon 1 that generates a short 5'-UTR transcript (PMID:18613979)—and the native protein partitions between perinuclear cytoplasm and the nucleus via two independent nuclear localization signals encoded in exons 1 and 6 (PMID:15147984). Microtubule severing requires an intact AAA ATPase domain, and disease-associated substitutions in this domain (R560Q, I344K) abolish ATPase and severing activity (PMID:19714378, PMID:30006150). Two genetically distinct disease mechanisms converge on the same axonal pathology: most loss-of-function mutations cause haploinsufficiency by eliminating protein, destabilizing transcripts, or inactivating severing without dominant-negative effect (PMID:12490534, PMID:16476945), whereas certain truncating and missense alleles produce stabilized M1 protein that decorates microtubules, renders them resistant to depolymerization, and impairs their dynamics in a dominant-negative manner (PMID:20430936, PMID:28495799, PMID:34927746). The downstream consequence is a reduced pool of stable, acetylated microtubules that slows microtubule-dependent transport of peroxisomes and mitochondria, increases vulnerability to oxidative stress, and produces neurite swellings and reduced neurite complexity—deficits rescued by restoring spastin dosage or by microtubule-stabilizing drugs such as epothilone D (PMID:24381312, PMID:27229699, PMID:23264559, PMID:32457567). Genetic epistasis in mouse models shows that reduced spastin function and gain-of-function toxicity act in combination to determine disease severity (PMID:34935948). SPAST is transcriptionally activated by NRF1 and SOX11 and post-transcriptionally repressed by miR-96 and miR-182 (PMID:22574173).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2003 Medium

    Established that SPAST nonsense and frameshift mutations produce neither truncated protein nor mutant transcript, defining haploinsufficiency as a primary disease mechanism and localizing spastin expression to neurons.

    Evidence Western blotting, immunolabeling, and RT-PCR on patient tissues, identifying two isoforms (75/80 kDa)

    PMID:12490534

    Open questions at the time
    • Did not resolve the molecular origin of the two isoforms
    • Did not test whether any mutations act by gain-of-function
  2. 2004 Medium

    Answered where spastin acts by showing it carries two functional NLSs and distributes between nucleus and perinuclear cytoplasm, broadening the protein's potential roles beyond cytoplasmic microtubules.

    Evidence Polyclonal antibody staining plus a Tetra-GFP reporter assay testing NLS functionality

    PMID:15147984

    Open questions at the time
    • Nuclear function of spastin not defined
    • Relative contribution of each NLS to physiological localization unknown
  3. 2008 Medium

    Explained the origin of the shorter isoform by identifying a cryptic exon-1 promoter that selectively drives M87 translation, providing a mechanistic basis for isoform-specific regulation.

    Evidence Promoter-less constructs and luciferase assays across HeLa, HEK293, NSC34, SH-SY5Y cells

    PMID:18613979

    Open questions at the time
    • Physiological tissue contexts favoring cryptic-promoter activity not mapped
    • Functional difference between M1 and M87 not addressed here
  4. 2007 Low

    Proposed that some N-terminal missense variants act not through haploinsufficiency but by stabilizing the M87 isoform, introducing isoform-competition as a candidate mechanism.

    Evidence Protein stability and isoform-specific expression assays in cells

    PMID:17916079

    Open questions at the time
    • Isoform-competition mechanism not directly demonstrated
    • Functional consequence of M87 stabilization untested
  5. 2009 High

    Demonstrated directly that an invariant ATPase-domain substitution (R560Q) abolishes spastin's enzymatic activity, causally linking the AAA domain to severing function and disease.

    Evidence Recombinant protein expression and in vitro ATPase activity assay in a bovine recessive model

    PMID:19714378

    Open questions at the time
    • Did not assay microtubule severing directly
    • Cellular consequences of ATPase loss not examined
  6. 2010 Medium

    Showed that HSP mutations outside the AAA domain can act by conferring dominant-negative activity specifically to M1, establishing that not all disease cases derive from reduced severing activity.

    Evidence In vitro severing assays plus cell-based dominant-negative testing of four mutations

    PMID:20430936

    Open questions at the time
    • Molecular basis of M1-specific dominant-negative effect unresolved
    • E112K pathogenic mechanism left unexplained
  7. 2012 Medium

    Connected reduced spastin to a measurable microtubule defect by showing patient progenitor cells lose acetylated tubulin and gain stathmin, slowing organelle transport, with rescue by sub-nanomolar microtubule-binding drugs.

    Evidence Patient-derived neural progenitor cells, immunostaining, organelle live imaging, pharmacological rescue

    PMID:23264559

    Open questions at the time
    • Causal link between stathmin increase and transport defect not isolated
    • In vivo relevance not tested
  8. 2012 Medium

    Defined the regulatory inputs controlling SPAST levels by identifying NRF1/SOX11 as transcriptional activators and miR-96/miR-182 as post-transcriptional repressors.

    Evidence Conservation analysis, transcription factor binding assays, miRNA reporter/overexpression, RT-PCR and western blot

    PMID:22574173

    Open questions at the time
    • Physiological conditions engaging these regulators unknown
    • Whether dysregulation contributes to disease untested
  9. 2013 High

    Used patient iPSC neurons to show that reduced spastin lowers all isoforms, decreases neurite complexity, imbalances axonal transport, and produces microtubule-disrupted swellings, with isoform-specific overexpression rescuing the phenotype in a dosage-dependent manner.

    Evidence hiPSC-derived neurons, live axonal transport imaging, electron microscopy, overexpression rescue

    PMID:24381312

    Open questions at the time
    • Did not separate haploinsufficiency from gain-of-function in this allele
    • Mechanism linking transport imbalance to swellings not fully resolved
  10. 2016 Medium

    Pinpointed reduced stable microtubule number (not impaired organelle-microtubule binding) as the cause of slowed peroxisome transport and linked this to elevated oxidative stress, rescued by epothilone D.

    Evidence Patient olfactory stem cells, automated time-lapse imaging, epothilone D rescue, oxidative stress assays

    PMID:27229699

    Open questions at the time
    • Mechanism connecting transport deficit to oxidative vulnerability not detailed
    • Generalizability beyond peroxisomes unclear here
  11. 2017 Medium

    Showed that truncating mutations produce M1 truncation products that over-accumulate and are more detrimental to neurite outgrowth than truncated M87, and can trigger reinitiation to a severing-competent M187 isoform.

    Evidence Western blotting, neurite outgrowth assays, severing assays, translation initiation analysis

    PMID:28495799

    Open questions at the time
    • Why truncated M1 accumulates preferentially not mechanistically resolved
    • In vivo significance of M187 reinitiation unknown
  12. 2018 High

    Provided a detailed gain-of-function mechanism: the AAA-domain mutant I344K loses ATPase/severing activity, gains a prolonged half-life via altered degradation, decorates but cannot sever microtubules, and physically interacts with wild-type spastin, with WT overexpression dose-dependently mitigating toxicity.

    Evidence In vitro ATPase and severing assays, co-IP, half-life assays, neurite outgrowth in multiple neuronal cell types

    PMID:30006150

    Open questions at the time
    • Specific post-translational modifications altering degradation not identified
    • Stoichiometry of WT/mutant interaction not quantified
  13. 2020 High

    Confirmed in iPSC forebrain neurons that reduced stable microtubules lower peroxisome transport and number, increase axon swellings, and sensitize axons to oxidative-stress fragmentation, with rescue by epothilone D and noscapine.

    Evidence Three patient hiPSC lines, peroxisome tracking, microtubule stability assays, oxidative challenge, pharmacological rescue

    PMID:32457567

    Open questions at the time
    • Did not establish whether oxidative damage is cause or consequence of axon degeneration
    • Long-term therapeutic durability untested
  14. 2021 Medium

    Distinguished the isoform-specific behavior of a frameshift allele by showing truncated M1 decorates microtubules and confers depolymerization resistance whereas truncated M87 is diffuse and inert, refining the dominant-negative model to M1.

    Evidence Western blotting, immunofluorescence, microtubule depolymerization assay in cells

    PMID:34927746

    Open questions at the time
    • Endogenous expression level of the truncated isoforms in patient neurons not measured
    • Contribution to clinical phenotype not assessed
  15. 2022 High

    Demonstrated through genetic epistasis that haploinsufficiency and gain-of-function are distinct but interacting contributions, since a KO background worsened and accelerated mutant-spastin phenotypes alongside altered HDAC6 and tubulin modifications.

    Evidence hSPAST-C448Y transgenic and Spast-KO mouse models, crossbreeding, gait/histology, HDAC6 and tubulin immunostaining

    PMID:34935948

    Open questions at the time
    • Molecular role of HDAC6 changes in pathology not mechanistically resolved
    • Whether human disease combines both mechanisms in the same patient not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • The nuclear function of spastin and the precise molecular link between reduced stable-microtubule-dependent transport and oxidative-stress vulnerability remain undefined.
  • No defined nuclear substrate or role for spastin despite two functional NLSs
  • Mechanism converting transport deficits into oxidative damage not isolated
  • Direct interacting partners and oligomerization stoichiometry incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0008092 cytoskeletal protein binding 2 GO:0016787 hydrolase activity 2 GO:0140657 ATP-dependent activity 2
Localization
GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2 GO:0005634 nucleus 1
Partners
SPAST

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Spastin is expressed as two isoforms of 75 and 80 kDa in human and mouse tissues, with tissue-specific variability in isoform ratio. Immunolabeling showed spastin is expressed in neurons but not glial cells. Protein and transcript analyses of patients with nonsense or frameshift mutations revealed neither truncated protein nor mutated transcripts, indicating these mutations cause loss of spastin function (haploinsufficiency). Western blotting, immunolabeling, RT-PCR, protein analysis from patient tissues Human molecular genetics Medium 12490534
2004 Spastin contains two functional nuclear localization sequences (NLSs) located in exons 1 and 6, both independently capable of mediating nuclear entry. The native protein localizes to both the perinuclear cytoplasm and the nucleus. Polyclonal antibody staining, novel Tetra-GFP reporter system for NLS functionality, subcellular localization experiments Biochemical and biophysical research communications Medium 15147984
2008 The 60-kDa (M87) spastin isoform is produced by a cryptic promoter located within exon 1 of the SPG4 gene (overlapping the 5'-UTR and coding region), which generates a transcript with a shorter 5'-UTR that selectively translates the 60-kDa isoform. The S44L polymorphism, located near this cryptic transcription start site, decreases the activity of the cryptic promoter in luciferase assays. Promoter-less constructs in cell lines (HeLa, HEK293, NSC34, SH-SY5Y), luciferase reporter assays, ruling out cap-independent translation BMC biology Medium 18613979
2010 Four HSP-associated SPAST mutations outside the AAA region (L195V, 46Stop, S44L, E112K) were studied. None affected enzymatic activity or expression levels of M1 or M87. Three mutations (L195V, 46Stop, and surprisingly S44L) conferred dominant-negative activity specifically to the M1 isoform. E112K (symptomatic heterozygously) did not show dominant-negative activity, demonstrating that some HSP-SPG4 cases cannot be explained by reduced microtubule-severing activity. In vitro microtubule-severing assays, expression level analysis, dominant-negative activity assays in cells Human molecular genetics Medium 20430936
2007 N-terminal missense variants (S44L, E43Q, P45Q) of spastin do not affect haploinsufficiency-based disease mechanisms but instead enhance the stability of the shorter (M87/60 kDa) spastin isoform. Their phenotypic effects may be mediated by increasing isoform competition for interacting proteins, substrates, or oligomerization partners. Protein stability assays, isoform-specific expression analysis in cells European journal of neurology Low 17916079
2009 In bovine spinal dysmyelination (a recessive SPAST disease model), the R560Q substitution at an invariant position in the ATPase domain of spastin severely impaired ATPase activity of recombinant spastin in vitro, demonstrating a causal relationship between this SPAST mutation and loss of enzymatic function. Recombinant protein expression, in vitro ATPase activity assay Neurogenetics High 19714378
2013 In hiPSC-derived neurons from SPG4 patients with a c.1684C>T nonsense mutation, all spastin isoforms were reduced, neurite complexity was decreased, axonal transport was imbalanced (less retrograde movement), and neurite swellings with disrupted microtubules were present ultrastructurally. Overexpression of either M1 or M87 spastin isoform restored neurite length, branching, number of primary neurites, and reduced swellings, demonstrating gene dosage-dependent rescue. hiPSC differentiation, live imaging of axonal transport, electron microscopy, overexpression rescue experiments Human molecular genetics High 24381312
2016 In olfactory stem cells from SPAST-mutation patients, average peroxisome movement speed was slower due to reduced numbers of stable microtubules (not impaired peroxisome-microtubule interaction per se). Patient cells showed increased oxidative stress. Epothilone D, which increases stable microtubules, restored peroxisome speed and ameliorated hydrogen peroxide sensitivity, linking reduced stable microtubules to impaired peroxisome transport and oxidative stress. Time-lapse imaging with automated image analysis, epothilone D pharmacological rescue, oxidative stress assays Scientific reports Medium 27229699
2017 Truncating SPAST mutations (N184X, S245X) produce truncated M1 spastin proteins that accumulate to notably higher levels than truncated M87 or wild-type counterparts. Truncated M1 was more detrimental to neurite outgrowth than truncated M87. The N184X mutation also triggers reinitiation of translation at a third start codon, producing a novel M187 isoform capable of severing microtubules. Western blotting for protein accumulation, neurite outgrowth assays, microtubule-severing assays, translation initiation analysis Molecular biology of the cell Medium 28495799
2018 A missense mutation I344K in the AAA domain of spastin (I344K-SPAST) abolished ATPase activity and microtubule-severing activity in vitro and in cells. The mutant protein showed prolonged half-life compared to wild-type SPAST due to altered post-translational modifications for proteasomal degradation. Mutant M1 isoform localized to microtubules but failed to sever them, causing microtubule accumulation and inhibited neurite outgrowth. Overexpression of wild-type M1 SPAST reduced pathogenic effects in a dose-dependent manner, with WT-SPAST shown to interact with I344K-SPAST. In vitro ATPase activity assay, microtubule-severing assay, co-immunoprecipitation, protein stability/half-life assay, neurite outgrowth in neuroblastoma/neural progenitor/primary cortical neuron cells Biochimica et biophysica acta. Molecular basis of disease High 30006150
2012 In patient-derived olfactory mucosa neural progenitor cells with SPAST mutations, acetylated α-tubulin was reduced by 50% and stathmin (a microtubule-destabilizing enzyme) was increased by 150%, with altered intracellular distribution and slower movement of peroxisomes and mitochondria. Sub-nanomolar concentrations of microtubule-binding drugs (paclitaxel, vinblastine) restored acetylated α-tubulin to control levels. Patient-derived neural progenitor cell culture, immunostaining, live imaging of organelle transport, pharmacological intervention Disease models & mechanisms Medium 23264559
2020 In iPS-derived forebrain neurons from SPAST-mutation patients, there were reduced levels of stable microtubules, reduced peroxisome transport speed, reduced peroxisome numbers, higher density of axon swellings, and increased fragmentation after hydrogen peroxide. Treatment with epothilone D and noscapine rescued peroxisome transport and protected against oxidative stress-induced axon fragmentation, establishing that SPAST patient axons are vulnerable to oxidative stress as a consequence of reduced axonal microtubule-dependent transport. hiPSC differentiation into neurons, live peroxisome tracking, microtubule stability assays, oxidative stress challenge, pharmacological rescue with epothilone D and noscapine Frontiers in neuroscience High 32457567
2021 A novel c.985dupA (p.Met329Asnfs*3) SPAST mutation produced truncated M1 and M87 isoforms that accumulated to higher levels than wild-type. Truncated M1 localized on microtubules and rendered them resistant to depolymerization (dominant-negative effect on microtubule dynamics). Truncated M87 was diffusely distributed in nucleus and cytoplasm, could not decorate microtubules, and did not promote microtubule disassembly. Western blotting, immunofluorescence, microtubule depolymerization assay in cells Movement disorders Medium 34927746
2012 SPAST transcription is positively regulated by transcription factors NRF1 and SOX11. miR-96 and miR-182 negatively regulate SPAST by effects on mRNA stability and protein level, providing post-transcriptional regulation. Molecular phylogenetic conservation analysis, transcription factor binding assays, miRNA reporter/overexpression experiments, RT-PCR and western blotting for mRNA and protein levels PloS one Medium 22574173
2006 A nucleotide substitution c.1216A>G in the ATPase domain of SPG4 (apparent missense) causes aberrant in-frame splicing and destabilization of the mutated transcript. The resulting mutant protein is deficient in microtubule-severing activity but shows regular subcellular localization, and the disease mechanism is haploinsufficiency rather than dominant-negative effect. Mutation analysis, RT-PCR for aberrant splicing, microtubule-severing activity assay, subcellular localization analysis Neurology Medium 16476945
2022 hSPAST-C448Y transgenic mice (expressing human mutant spastin) display corticospinal dieback and gait deficiencies but not axonal swellings, while Spast-KO mice display axonal swellings but not dieback or gait deficiencies. Crossbreeding showed KO background worsened gait deficiencies and produced earlier onset plus axonal swellings in hSPAST-C448Y mice, with changes in HDAC6 and tubulin modifications in axons—indicating reduced spastin function exacerbates toxic gain-of-function properties of mutant spastin. Transgenic mouse models (hSPAST-C448Y, Spast-KO), crossbreeding, histological analysis, behavioral gait analysis, immunostaining for HDAC6 and tubulin modifications Human molecular genetics High 34935948

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia. Human molecular genetics 240 10699187
2015 Hereditary spastic paraplegia SPG4: what is known and not known about the disease. Brain : a journal of neurology 140 26094131
2006 High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia. Neurology 117 17035675
2000 Mutation analysis of the spastin gene (SPG4) in patients with hereditary spastic paraparesis. Journal of medical genetics 113 11015453
2013 Gene dosage-dependent rescue of HSP neurite defects in SPG4 patients' neurons. Human molecular genetics 105 24381312
2006 Exon deletions of SPG4 are a frequent cause of hereditary spastic paraplegia. Journal of medical genetics 99 17098887
2018 Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex. Brain : a journal of neurology 96 30476002
2002 Mutation analysis of the spastin gene (SPG4) in patients in Germany with autosomal dominant hereditary spastic paraplegia. Human mutation 86 12124993
2014 The Alu-rich genomic architecture of SPAST predisposes to diverse and functionally distinct disease-associated CNV alleles. American journal of human genetics 83 25065914
2008 Expansion of mutation spectrum, determination of mutation cluster regions and predictive structural classification of SPAST mutations in hereditary spastic paraplegia. European journal of human genetics : EJHG 77 18701882
2000 Hereditary spastic paraplegia caused by mutations in the SPG4 gene. European journal of human genetics : EJHG 72 11039577
2003 Mutations of SPG4 are responsible for a loss of function of spastin, an abundant neuronal protein localized in the nucleus. Human molecular genetics 70 12490534
2004 Hereditary spastic paraplegia with cerebellar ataxia: a complex phenotype associated with a new SPG4 gene mutation. European journal of neurology 66 15667412
2002 Spectrum of SPG4 mutations in a large collection of North American families with hereditary spastic paraplegia. Archives of neurology 66 11843700
2010 Evaluation of loss of function as an explanation for SPG4-based hereditary spastic paraplegia. Human molecular genetics 60 20430936
1998 Mapping of a complicated familial spastic paraplegia to locus SPG4 on chromosome 2p. Journal of medical genetics 59 9507385
2011 Alu-specific microhomology-mediated deletion of the final exon of SPAST in three unrelated subjects with hereditary spastic paraplegia. Genetics in medicine : official journal of the American College of Medical Genetics 51 21659953
2010 Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia. BMC neurology 51 20932283
2012 A patient-derived stem cell model of hereditary spastic paraplegia with SPAST mutations. Disease models & mechanisms 48 23264559
2010 Hereditary spastic paraplegia due to SPAST mutations in 151 Dutch patients: new clinical aspects and 27 novel mutations. Journal of neurology, neurosurgery, and psychiatry 47 20562464
2009 Dementia in SPG4 hereditary spastic paraplegia: clinical, genetic, and neuropathologic evidence. Neurology 47 19652142
2015 Multimodal MRI-based study in patients with SPG4 mutations. PloS one 44 25658484
2008 A cryptic promoter in the first exon of the SPG4 gene directs the synthesis of the 60-kDa spastin isoform. BMC biology 43 18613979
2004 Identification of nuclear localisation sequences in spastin (SPG4) using a novel Tetra-GFP reporter system. Biochemical and biophysical research communications 43 15147984
2000 Intrafamilial variability in hereditary spastic paraplegia associated with an SPG4 gene mutation. Neurology 42 10980739
2016 Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia. Scientific reports 41 27229699
2013 Targeted next generation sequencing in SPAST-negative hereditary spastic paraplegia. Journal of neurology 41 23812641
2005 Autosomal dominant hereditary spastic paraplegia: DHPLC-based mutation analysis of SPG4 reveals eleven novel mutations. Human mutation 41 15841487
2001 A large family with hereditary spastic paraparesis due to a frame shift mutation of the spastin (SPG4) gene: association with multiple sclerosis in two affected siblings and epilepsy in other affected family members. Journal of neurology, neurosurgery, and psychiatry 39 11723204
2006 Eight novel mutations in SPG4 in a large sample of patients with hereditary spastic paraplegia. Archives of neurology 37 16682546
2004 A new SPG4 mutation in a variant form of spastic paraplegia with congenital arachnoid cysts. Neurology 37 15159500
2008 Silver syndrome variant of hereditary spastic paraplegia: A locus to 4p and allelism with SPG4. Neurology 36 18401025
2000 Phenotype of AD-HSP due to mutations in the SPAST gene: comparison with AD-HSP without mutations. Neurology 35 11134375
2004 Reciprocal inhibition and corticospinal transmission in the arm and leg in patients with autosomal dominant pure spastic paraparesis (ADPSP). Brain : a journal of neurology 34 15509621
2005 Clinical and genetic study of a large SPG4 Italian family. Movement disorders : official journal of the Movement Disorder Society 33 15858810
2017 Truncating mutations of SPAST associated with hereditary spastic paraplegia indicate greater accumulation and toxicity of the M1 isoform of spastin. Molecular biology of the cell 32 28495799
2011 Detection of novel mutations and review of published data suggests that hereditary spastic paraplegia caused by spastin (SPAST) mutations is found more often in males. Journal of the neurological sciences 31 21546041
2003 Neurophysiological findings in SPG4 patients differ from other types of spastic paraplegia. Neurology 31 12743246
2007 Seven novel mutations and four exon deletions in a collection of Norwegian patients with SPG4 hereditary spastic paraplegia. European journal of neurology 29 17594340
2007 Mental deficiency in three families with SPG4 spastic paraplegia. European journal of human genetics : EJHG 29 17957230
2007 Motor and somatosensory evoked potentials in Autosomal Dominant Hereditary Spastic Paraparesis (ADHSP) linked to chromosome 2p, SPG4. Brain research bulletin 28 17720546
2007 A multi-exonic SPG4 duplication underlies sex-dependent penetrance of hereditary spastic paraplegia in a large Brazilian pedigree. European journal of human genetics : EJHG 28 17895902
2005 Mutation analysis of SPG4 and SPG3A genes and its implication in molecular diagnosis of Korean patients with hereditary spastic paraplegia. Archives of neurology 27 16009769
2017 Truncating mutations in SPAST patients are associated with a high rate of psychiatric comorbidities in hereditary spastic paraplegia. Journal of neurology, neurosurgery, and psychiatry 26 28572275
2015 Molecular spectrum of the SPAST, ATL1 and REEP1 gene mutations associated with the most common hereditary spastic paraplegias in a group of Polish patients. Journal of the neurological sciences 25 26671083
2008 The prevalence of hereditary spastic paraplegia and the occurrence of SPG4 mutations in Estonia. Neuroepidemiology 25 19039240
2007 A de novo SPAST mutation leading to somatic mosaicism is associated with a later age at onset in HSP. Neurogenetics 25 17597328
2003 Screening of patients with hereditary spastic paraplegia reveals seven novel mutations in the SPG4 (Spastin) gene. Human mutation 25 12552568
2020 Oxidative Stress-Induced Axon Fragmentation Is a Consequence of Reduced Axonal Transport in Hereditary Spastic Paraplegia SPAST Patient Neurons. Frontiers in neuroscience 24 32457567
2011 Screening for the hereditary spastic paraplaegias SPG4 and SPG3A with the multiplex ligation-dependent probe amplification technique in a large population of affected individuals. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 24 22203332
2009 Mutation analysis of the SPG4 gene in Italian patients with pure and complicated forms of spastic paraplegia. Journal of the neurological sciences 24 19875132
2019 Non-motor symptoms are relevant and possibly treatable in hereditary spastic paraplegia type 4 (SPG4). Journal of neurology 23 31646384
2005 Reduced regional cerebral blood flow in SPG4-linked hereditary spastic paraplegia. Journal of the neurological sciences 23 15939438
2003 Motor system abnormalities in hereditary spastic paraparesis type 4 (SPG4) depend on the type of mutation in the spastin gene. Journal of neurology, neurosurgery, and psychiatry 22 12876245
2012 Transcriptional and post-transcriptional regulation of SPAST, the gene most frequently mutated in hereditary spastic paraplegia. PloS one 21 22574173
2020 Mitochondrial Function in Hereditary Spastic Paraplegia: Deficits in SPG7 but Not SPAST Patient-Derived Stem Cells. Frontiers in neuroscience 20 32973427
2019 Mutational Spectrum of Spast (Spg4) and Atl1 (Spg3a) Genes In Russian Patients With Hereditary Spastic Paraplegia. Scientific reports 20 31594988
2014 Mutation analysis of SPAST, ATL1, and REEP1 in Korean Patients with Hereditary Spastic Paraplegia. Journal of clinical neurology (Seoul, Korea) 20 25045380
2007 Isoform-specific increase of spastin stability by N-terminal missense variants including intragenic modifiers of SPG4 hereditary spastic paraplegia. European journal of neurology 20 17916079
2009 Congenital bovine spinal dysmyelination is caused by a missense mutation in the SPAST gene. Neurogenetics 19 19714378
2002 Missense and splice site mutations in SPG4 suggest loss-of-function in dominant spastic paraplegia. Journal of neurology 19 11985387
2019 Mutations in the SPAST gene causing hereditary spastic paraplegia are related to global topological alterations in brain functional networks. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 18 30737580
2008 Novel SPG3A and SPG4 mutations in dominant spastic paraplegia families. Acta neurologica Scandinavica 18 18664244
1997 Familial spastic paraparesis: evaluation of locus heterogeneity, anticipation, and haplotype mapping of the SPG4 locus on the short arm of chromosome 2. American journal of medical genetics 18 9034002
2019 New hypothesis for the etiology of SPAST-based hereditary spastic paraplegia. Cytoskeleton (Hoboken, N.J.) 17 31108029
2015 Mutational spectrum of the SPAST and ATL1 genes in Korean patients with hereditary spastic paraplegia. Journal of the neurological sciences 17 26208798
2009 Sequence variants in SPAST, SPG3A and HSPD1 in hereditary spastic paraplegia. Journal of the neurological sciences 17 19423133
2017 Spastic paraplegia type 4: A novel SPAST splice site donor mutation and expansion of the phenotype variability. Journal of the neurological sciences 16 28870597
2016 Cognitive Impairment Involving Social Cognition in SPG4 Hereditary Spastic Paraplegia. Behavioural neurology 16 27688599
2004 Two novel mutations in the spastin gene (SPG4) found by DHPLC mutation analysis. Neuromuscular disorders : NMD 16 15482961
2018 Association of Early-Onset Spasticity and Risk for Cognitive Impairment With Mutations at Amino Acid 499 in SPAST. Journal of child neurology 15 29421991
2012 SPAST mutations in Australian patients with hereditary spastic paraplegia. Internal medicine journal 15 23252998
2001 A large Japanese SPG4 family with a novel insertion mutation of the SPG4 gene: a clinical and genetic study. Journal of the neurological sciences 15 11266693
2021 Therapeutic Strategies for Mutant SPAST-Based Hereditary Spastic Paraplegia. Brain sciences 14 34439700
2014 Genetic analysis of SPG4 and SPG3A genes in a cohort of Chinese patients with hereditary spastic paraplegia. Journal of the neurological sciences 14 25454648
2006 Novel spastin (SPG4) mutations in Italian patients with hereditary spastic paraplegia. Neuromuscular disorders : NMD 14 16684598
2021 A Novel SPAST Mutation Results in Spastin Accumulation and Defects in Microtubule Dynamics. Movement disorders : official journal of the Movement Disorder Society 13 34927746
2020 Cortical Damage Associated With Cognitive and Motor Impairment in Hereditary Spastic Paraplegia: Evidence of a Novel SPAST Mutation. Frontiers in neurology 13 32536902
2018 Missense mutation of SPAST protein (I344K) results in loss of ATPase activity and prolonged the half-life, implicated in autosomal dominant hereditary spastic paraplegia. Biochimica et biophysica acta. Molecular basis of disease 13 30006150
2017 A de novo mosaic mutation in SPAST with two novel alternative alleles and chromosomal copy number variant in a boy with spastic paraplegia and autism spectrum disorder. European journal of medical genetics 13 28778789
2002 Three novel spastin (SPG4) mutations in families with autosomal dominant hereditary spastic paraplegia. Journal of the neurological sciences 13 12163196
1999 A fine integrated map of the SPG4 locus excludes an expanded CAG repeat in chromosome 2p-linked autosomal dominant spastic paraplegia. Genomics 13 10493830
2021 Corticospinal tract and motor cortex degeneration in pure hereditary spastic paraparesis type 4 (SPG4). Amyotrophic lateral sclerosis & frontotemporal degeneration 12 34396852
2019 Novel mutations in the SPAST gene cause hereditary spastic paraplegia. Parkinsonism & related disorders 12 31751864
2014 A complex form of hereditary spastic paraplegia in three siblings due to somatic mosaicism for a novel SPAST mutation in the mother. Journal of the neurological sciences 12 25315759
2010 Partial SPAST and DPY30 deletions in a Japanese spastic paraplegia type 4 family. Neurogenetics 12 20857310
2022 Modeling gain-of-function and loss-of-function components of SPAST-based hereditary spastic paraplegia using transgenic mice. Human molecular genetics 11 34935948
2018 Patient-Derived Stem Cell Models in SPAST HSP: Disease Modelling and Drug Discovery. Brain sciences 11 30065201
2016 SPAST mutation spectrum and familial occurrence among Czech patients with pure hereditary spastic paraplegia. Journal of human genetics 11 27334366
2007 Possible anticipation in hereditary spastic paraplegia type 4 (SPG4). The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 11 17598599
2007 Compound heterozygosity in the SPG4 gene causes hereditary spastic paraplegia. Clinical genetics 11 18190593
2014 High frequency of SPG4 in Taiwanese families with autosomal dominant hereditary spastic paraplegia. BMC neurology 10 25421405
2011 Peripheral neuropathy in hereditary spastic paraplegia due to spastin (SPG4) mutation--a neurophysiological study using excitability techniques. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology 10 22192498
2006 Unexpected pathogenic mechanism of a novel mutation in the coding sequence of SPG4 (spastin). Neurology 10 16476945
2006 Identification of a novel mutation in the spastin gene (SPG4) in an Italian family with hereditary spastic paresis. Panminerva medica 9 17122756
2002 A Japanese SPG4 family with a novel missense mutation of the SPG4 gene: intrafamilial variability in age at onset and clinical severity. Acta neurologica Scandinavica 9 12460147
2021 Anticipation Can Be More Common in Hereditary Spastic Paraplegia with SPAST Mutations Than It Appears. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 8 34353391
2019 A p.Arg499His Mutation in SPAST Is Associated with Infantile Onset Ascending Spastic Paralysis Complicated with Dysarthria and Anarthria. Neuropediatrics 8 31486053
2004 Prenatal diagnosis of autosomal dominant hereditary spastic paraplegia (SPG4) using direct mutation detection. Prenatal diagnosis 8 15164410
2021 A p.Arg499His mutation in SPAST is associated with infantile-onset complicated spastic paraplegia: a case report and review of the literature. BMC neurology 7 34753439

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