Affinage

SPAST

Spastin · UniProt Q9UBP0

Length
616 aa
Mass
67.2 kDa
Annotated
2026-04-28
100 papers in source corpus 17 papers cited in narrative 17 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Spastin is a microtubule-severing AAA ATPase whose loss-of-function mutations cause hereditary spastic paraplegia type 4 (SPG4), the most common form of autosomal dominant HSP. Two major isoforms (M1, 68 kDa; M87, 60 kDa) arise from alternative transcriptional and translational initiation: M87 is ubiquitously expressed, whereas M1 is enriched in adult spinal cord and inserts into the endoplasmic reticulum membrane via a unique N-terminal hydrophobic domain, where it interacts with reticulons, atlastin, and REEP1 to participate in ER morphogenesis (PMID:18613979, PMID:26094131). Disease-causing mutations act through haploinsufficiency—ATPase-domain mutations abolish microtubule-severing activity and reduce spastin dosage (PMID:19714378, PMID:12490534)—and through isoform-specific toxic gain-of-function, whereby truncated or missense M1 proteins accumulate, decorate and hyperstabilize microtubules, and impair axonal organelle transport (PMID:34927746, PMID:28495799, PMID:34935948). Reduced spastin function in patient-derived neurons leads to diminished stabilized microtubules, slowed peroxisome transport, axonal swellings, and increased vulnerability to oxidative stress, phenotypes that are rescued by microtubule-stabilizing drugs or restoration of spastin expression (PMID:24381312, PMID:32457567, PMID:27229699).

Mechanistic history

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

    Establishing the primary disease mechanism: whether SPAST mutations in HSP patients produce toxic truncated protein or simply reduce functional spastin levels was unknown; analysis of patient tissues showed that nonsense/frameshift mutations cause transcript degradation and no truncated protein, establishing haploinsufficiency as the predominant disease mechanism and revealing dual nuclear–cytoplasmic localization of spastin.

    Evidence Polyclonal antibody immunolabeling, western blotting, and RT-PCR in patient tissues

    PMID:12490534

    Open questions at the time
    • Single lab study; haploinsufficiency model does not account for all mutation types
    • Nuclear function of spastin not characterized
  2. 2004 Medium

    Identifying structural determinants of nuclear localization: spastin was shown to harbor two independent NLS motifs (in exons 1 and 6), each sufficient for nuclear import, defining the structural basis for the nuclear pool of spastin.

    Evidence Tetra-GFP reporter nuclear localization assay with NLS-containing spastin fragments

    PMID:15147984

    Open questions at the time
    • Nuclear function of spastin remains unknown
    • Physiological role of dual NLS redundancy not tested
  3. 2006 High

    Demonstrating that apparent missense mutations can act through splicing defects: a c.1216A>G ATPase-domain substitution was shown to cause aberrant splicing and transcript destabilization, with the resulting protein lacking microtubule-severing activity, reinforcing haploinsufficiency as the mechanism for this mutation class.

    Evidence Splicing analysis, microtubule-severing activity assay, and immunofluorescence localization

    PMID:16476945

    Open questions at the time
    • Only one mutation characterized at this level of splicing detail
    • Whether other apparent missense mutations act similarly is unknown
  4. 2007 Medium

    Revealing an alternative disease mechanism for N-terminal variants: S44L and related N-terminal missense mutations were found to selectively enhance M87 isoform stability rather than cause haploinsufficiency or dominant-negative effects, suggesting isoform-specific protein stabilization as a distinct pathogenic pathway.

    Evidence Protein stability assays and expression-level measurements of M1 and M87 isoforms

    PMID:17916079

    Open questions at the time
    • Downstream consequences of increased M87 stability not defined
    • Single lab; no in vivo validation
  5. 2008 High

    Defining the dual-isoform architecture of SPAST: a cryptic promoter within exon 1 was shown to drive tissue-regulated expression of the shorter M87 isoform, establishing that M1 and M87 arise from both alternative transcription initiation and alternative translation, have distinct subcellular localizations, and interact with different protein partners.

    Evidence Promoter-less reporter constructs, luciferase assays, RT-PCR, and promoter mapping in multiple cell lines

    PMID:18613979

    Open questions at the time
    • Tissue-specific transcription factors driving the cryptic promoter not fully identified
    • Functional consequences of isoform-specific interactions only partially characterized
  6. 2009 High

    Directly linking ATPase domain integrity to enzymatic function: the R560Q disease-causing mutation was shown to severely impair recombinant spastin ATPase activity in vitro, providing biochemical proof that AAA domain mutations cause loss of catalytic function.

    Evidence In vitro ATPase activity assay of recombinant R560Q mutant spastin

    PMID:19714378

    Open questions at the time
    • Microtubule-severing activity not directly measured in this study
    • Structural basis of impaired catalysis not resolved
  7. 2010 High

    Expanding the disease mechanism beyond loss of severing: four HSP mutations outside the ATPase domain were shown to retain normal microtubule-severing activity, with three conferring M1-specific dominant-negative effects, proving that spastin pathogenesis extends beyond simple loss of catalytic function.

    Evidence In vitro microtubule-severing assay and cellular dominant-negative activity assay with multiple mutations

    PMID:20430936

    Open questions at the time
    • Molecular targets of M1 dominant-negative effects not identified
    • Whether dominant-negative mechanism involves ER-membrane interactions or cytoskeletal functions not resolved
  8. 2013 High

    Validating the haploinsufficiency model in patient neurons and demonstrating rescue: iPSC-derived neurons from SPG4 patients showed reduced spastin, decreased neurite complexity, disrupted microtubules with swellings, and imbalanced axonal transport; overexpression of either M1 or M87 rescued these phenotypes, confirming gene-dosage dependence.

    Evidence hiPSC differentiation into neurons, live-cell transport imaging, electron microscopy, spastin isoform overexpression rescue

    PMID:24381312

    Open questions at the time
    • Which cargo classes are most affected by transport imbalance not fully defined
    • Long-term axon degeneration not modeled in vitro
  9. 2015 Medium

    Establishing M1 spastin as an ER-shaping protein: the M1-specific N-terminal hydrophobic domain was shown to mediate ER membrane insertion and interaction with reticulons, atlastin, and REEP1, with M1 enriched in adult spinal cord, connecting spastin to the ER-morphogenesis pathway disrupted in multiple HSP subtypes.

    Evidence Western blot tissue expression profiling, ER membrane fractionation, protein interaction studies

    PMID:26094131

    Open questions at the time
    • Evidence synthesized primarily from review; direct biochemical reconstitution of ER-shaping by M1 not demonstrated in a single study
    • Relative contributions of microtubule severing vs. ER shaping to disease not separated
  10. 2016 High

    Linking spastin to peroxisome trafficking and oxidative stress: in SPAST-mutant patient cells, peroxisome transport speed was reduced due to fewer stable microtubules; epothilone D treatment restored transport and reduced oxidative stress vulnerability, establishing a mechanistic chain from microtubule severing to organelle transport to cellular stress resistance.

    Evidence Time-lapse peroxisome tracking, automated image analysis, epothilone D pharmacological rescue, oxidative stress assays in patient olfactory stem cells

    PMID:27229699

    Open questions at the time
    • Whether peroxisome deficiency is the primary driver of neurodegeneration vs. other cargo defects unknown
    • Mechanism by which reduced microtubule dynamics decreases peroxisome speed not fully elucidated
  11. 2017 High

    Demonstrating isoform-specific toxicity of truncated spastin and discovery of a third functional isoform: truncating mutations produced M1 truncated proteins that accumulated to higher levels and were more toxic to neurites than truncated M87; one mutation triggered translation reinitiation producing a novel M187 isoform with microtubule-severing capacity.

    Evidence Western blotting, neurite outgrowth assay, microtubule-severing assay for M187 isoform

    PMID:28495799

    Open questions at the time
    • Physiological relevance of M187 isoform in vivo not tested
    • Mechanism of differential accumulation of truncated M1 vs. M87 not defined
  12. 2018 High

    Demonstrating that ATPase-dead spastin is toxic through protein stabilization: the I344K mutation abolished ATPase and severing activity, prolonged protein half-life by altering proteasomal targeting modifications, caused microtubule accumulation, and inhibited neurite growth; these effects were rescued by wild-type M1, which physically interacts with the mutant.

    Evidence In vitro ATPase and severing assays, protein half-life measurement, co-immunoprecipitation, neurite outgrowth rescue in neuroblastoma and primary neurons

    PMID:30006150

    Open questions at the time
    • Identity of post-translational modifications governing spastin turnover not fully mapped
    • Whether mutant–wild-type hexamer mixing underlies rescue not determined structurally
  13. 2020 High

    Extending the peroxisome–oxidative stress axis to axon degeneration: iPSC-derived forebrain neurons from patients showed fewer peroxisomes, slower peroxisome transport, axon swellings, and heightened susceptibility to oxidative stress–induced axon fragmentation; microtubule-stabilizing drugs rescued transport and protected axons.

    Evidence iPSC-derived cortical neuron differentiation, live-cell axonal transport imaging, axon fragmentation assay, epothilone D and noscapine pharmacological rescue

    PMID:32457567

    Open questions at the time
    • Optimal drug dosing window and long-term safety for translation not addressed
    • Contribution of other organelle transport deficits (e.g., mitochondria, lysosomes) not quantified
  14. 2021 High

    Providing direct evidence for isoform-specific toxic gain-of-function: a frameshift mutation produced truncated M1 that decorated and hyperstabilized microtubules (rendering them resistant to depolymerization), while truncated M87 was diffusely localized and could not sever or decorate microtubules—demonstrating that M1-specific toxic effects are independent of haploinsufficiency.

    Evidence Western blotting, immunofluorescence microtubule decoration and depolymerization assays in transfected cells

    PMID:34927746

    Open questions at the time
    • Whether M1-mediated microtubule stabilization involves ER-anchored vs. cytosolic pools not resolved
    • In vivo demonstration of this mechanism in spinal cord neurons lacking
  15. 2022 High

    Establishing genetic epistasis between haploinsufficiency and gain-of-function in vivo: in transgenic mice, mutant spastin expression caused corticospinal dieback while Spast knockout caused axonal swellings; combining both produced earlier, more severe degeneration, proving that reduced spastin function synergizes with toxic mutant protein effects to drive disease.

    Evidence Transgenic mouse crossbreeding, histological analysis, behavioral gait analysis

    PMID:34935948

    Open questions at the time
    • Whether pharmacological rescue (e.g., microtubule-stabilizing drugs) works in this compound model not tested
    • Cell-type specificity of the synergistic mechanism (upper motor neurons vs. other populations) not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the precise structural basis of spastin hexamer assembly and how mutant subunits poison the oligomer; the nuclear function of spastin; the relative contributions of microtubule severing versus ER morphogenesis to corticospinal axon maintenance; and whether tubulin-binding drug rescue translates to clinical benefit in SPG4 patients.
  • No high-resolution structure of full-length M1 spastin in ER membrane context
  • Nuclear substrates/functions unknown
  • No clinical trial data for microtubule-stabilizing drugs in SPG4

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0140657 ATP-dependent activity 2
Localization
GO:0005634 nucleus 2 GO:0005856 cytoskeleton 2 GO:0005783 endoplasmic reticulum 1 GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
ATL1REEP1RTN1

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Spastin (encoded by SPAST/SPG4) is localized in both the perinuclear cytoplasm and the nucleus of neurons; protein and transcript analyses of patients with nonsense or frameshift mutations show neither truncated protein nor mutated transcripts, indicating these mutations cause loss of spastin function (haploinsufficiency) rather than dominant-negative mechanisms. Polyclonal antibody immunolabeling, western blotting, RT-PCR analysis of patient tissues Human molecular genetics Medium 12490534
2004 Spastin contains two functional nuclear localisation sequences (NLS), located in exons 1 and 6, each independently capable of mediating nuclear entry, as demonstrated using a novel Tetra-GFP reporter system. Tetra-GFP reporter nuclear localisation assay with NLS-containing spastin fragments Biochemical and biophysical research communications Medium 15147984
2008 A cryptic promoter within exon 1 of the SPAST gene selectively drives expression of the shorter 60-kDa (M87) spastin isoform in a tissue-regulated manner; the two isoforms (68 kDa/M1 and 60 kDa/M87) arise via alternative transcriptional initiation as well as alternative translation initiation from two AUG codons, and have different subcellular localizations and interact with distinct molecules. Promoter-less reporter constructs, luciferase assays, RT-PCR, promoter mapping in multiple cell lines BMC biology High 18613979
2009 A missense mutation R560Q in the ATPase domain of bovine SPAST severely impairs ATPase activity of recombinant Spastin in vitro, demonstrating the causal relationship between ATPase domain integrity and spastin function. In vitro ATPase activity assay of recombinant R560Q mutant Spastin protein Neurogenetics High 19714378
2010 Four HSP-associated SPAST mutations located outside the AAA ATPase region do not affect the microtubule-severing enzymatic activity or expression of M1 or M87 spastin isoforms; three of these mutations (L195V, 46Stop, S44L) confer dominant-negative activity specifically to the M1 isoform, indicating disease mechanisms beyond loss of microtubule-severing activity. In vitro microtubule-severing assay, expression level measurement, dominant-negative activity assay in cells Human molecular genetics High 20430936
2012 SPAST transcription is positively regulated by transcription factors NRF1 and SOX11, and the SPAST mRNA is negatively regulated post-transcriptionally by miR-96 and miR-182, which reduce mRNA stability and protein levels. Molecular phylogenetic conservation analysis, luciferase reporter assays, mRNA stability assays, western blotting PloS one Medium 22574173
2013 In hiPSC-derived neurons from SPG4 patients with a nonsense mutation, all spastin isoforms are reduced; patient neurons show decreased neurite complexity, imbalanced axonal transport with less retrograde movement, neurite swellings with disrupted microtubules. Overexpression of either M1 or M87 spastin isoform restores neurite length, branching, and reduces swellings, demonstrating gene dosage-dependent neurite maintenance. hiPSC differentiation into neurons, live-cell imaging of axonal transport, electron microscopy, spastin isoform overexpression rescue experiments Human molecular genetics High 24381312
2016 In olfactory stem cell lines from SPAST-mutant patients, peroxisome transport speed is reduced due to fewer stable microtubules (not impaired peroxisome-microtubule interactions); treatment with epothilone D, which increases stable microtubules, restores peroxisome speed and reduces oxidative stress sensitivity, linking spastin-dependent microtubule stability to organelle trafficking and oxidative stress resistance. Time-lapse imaging of peroxisome movement, automated image analysis, epothilone D pharmacological rescue, oxidative stress assays Scientific reports High 27229699
2017 Truncating mutations N184X and S245X in the SPAST M1 isoform produce truncated proteins that accumulate to higher levels than truncated M87 or wild-type counterparts; truncated M1 is more detrimental to neurite outgrowth than truncated M87. The N184X mutation also triggers translation reinitiation at a third start codon producing a novel M187 isoform capable of microtubule severing. Western blotting for protein accumulation, neurite outgrowth assay, microtubule-severing assay for M187 isoform Molecular biology of the cell High 28495799
2007 N-terminal missense variants in SPAST (S44L, E43Q, P45Q) enhance the stability of the M87 spastin isoform selectively, rather than acting through haploinsufficiency or dominant-negative mechanisms; their phenotypic effects may be mediated by altering isoform competition for interacting proteins or substrates. Protein stability assays, expression level measurement of M1 and M87 isoforms, functional assessment of known disease mechanisms European journal of neurology Medium 17916079
2006 A c.1216A>G substitution in the SPAST ATPase domain that appears as a missense mutation actually causes aberrant in-frame splicing and destabilization of the mutant transcript; the resulting mutant protein lacks microtubule-severing activity but shows normal subcellular localization, indicating haploinsufficiency as the disease mechanism for this mutation. Splicing analysis, microtubule-severing activity assay, subcellular localization immunofluorescence Neurology High 16476945
2018 The I344K missense mutation in the SPAST ATPase domain abolishes ATPase and microtubule-severing activity in vitro, prolongs protein half-life by altering post-translational modifications for proteasomal degradation, causes microtubule accumulation and inhibits neurite growth in neurons; these effects are rescued by overexpression of wild-type M1 spastin, which physically interacts with the mutant protein. In vitro ATPase assay, microtubule-severing assay, protein half-life measurement, co-immunoprecipitation, neurite outgrowth assay, overexpression rescue in neuroblastoma and primary neurons Biochimica et biophysica acta. Molecular basis of disease High 30006150
2020 iPSC-derived forebrain neurons from SPAST-mutant patients show reduced stabilized microtubules, reduced peroxisome transport speed, fewer peroxisomes, and more axon swellings; patient axons are more susceptible to oxidative stress-induced fragmentation than controls, and treatment with epothilone D or noscapine rescues peroxisome transport and protects against axon fragmentation. iPSC differentiation, live-cell axonal transport imaging, axon fragmentation assay, pharmacological rescue with tubulin-binding drugs Frontiers in neuroscience High 32457567
2021 A novel frameshift SPAST mutation (c.985dupA) produces truncated M1 and M87 isoforms that accumulate to higher levels than wild-type; truncated M1 decorates and stabilizes microtubules (rendering them resistant to depolymerization), while truncated M87 is diffusely localized and cannot decorate or sever microtubules, demonstrating isoform-specific toxic gain-of-function independent of haploinsufficiency. Western blotting, immunofluorescence microtubule decoration and depolymerization assays in transfected cells Movement disorders : official journal of the Movement Disorder Society High 34927746
2022 In transgenic mouse models, expression of human mutant spastin (C448Y) causes corticospinal dieback and gait deficiencies, while Spast knockout causes axonal swellings; crossbreeding the two lines produces both axonal swellings and earlier, more severe corticospinal dieback, indicating that reduced spastin function exacerbates toxic effects of mutant spastin, and that each component (haploinsufficiency and gain-of-function) contributes separately to disease pathology. Transgenic mouse generation, histological analysis, behavioral gait analysis, histone deacetylase 6 and tubulin modification analysis Human molecular genetics High 34935948
2019 miR-33a directly targets the SPAST 3'-UTR (binding site conserved in humans but not mice) and negatively regulates spastin levels; inhibition of miR-33a using locked nucleic acid anti-miR ameliorated pathological phenotypes in SPG4 patient iPSC-derived cortical neurons. miRNA target site analysis, anti-miR LNA treatment, iPSC-derived cortical neuron phenotype rescue assay Clinical science Medium 30777884
2015 M1 spastin, due to its hydrophobic N-terminal domain not shared by M87, can insert into the endoplasmic reticulum membrane and interact with reticulons, atlastin, and REEP1 to play a role in ER morphogenesis; M87 is more abundant in neuronal and non-neuronal tissues, while M1 is predominantly detected in adult spinal cord. Isoform expression analysis by western blot across tissues, ER membrane association experiments (fractionation), protein interaction studies Brain : a journal of neurology Medium 26094131

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 139 26094131
2006 High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia. Neurology 116 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 98 17098887
2018 Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex. Brain : a journal of neurology 94 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 82 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 76 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 65 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 58 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 50 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 46 20562464
2009 Dementia in SPG4 hereditary spastic paraplegia: clinical, genetic, and neuropathologic evidence. Neurology 44 19652142
2015 Multimodal MRI-based study in patients with SPG4 mutations. PloS one 43 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 42 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 40 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 36 16682546
2008 Silver syndrome variant of hereditary spastic paraplegia: A locus to 4p and allelism with SPG4. Neurology 35 18401025
2004 A new SPG4 mutation in a variant form of spastic paraplegia with congenital arachnoid cysts. Neurology 35 15159500
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 33 15509621
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
2005 Clinical and genetic study of a large SPG4 Italian family. Movement disorders : official journal of the Movement Disorder Society 32 15858810
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
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
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 24 26671083
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 22 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
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
2019 Mutational Spectrum of Spast (Spg4) and Atl1 (Spg3a) Genes In Russian Patients With Hereditary Spastic Paraplegia. Scientific reports 19 31594988
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
2009 Congenital bovine spinal dysmyelination is caused by a missense mutation in the SPAST gene. Neurogenetics 18 19714378
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
2009 Sequence variants in SPAST, SPG3A and HSPD1 in hereditary spastic paraplegia. Journal of the neurological sciences 17 19423133
2015 Mutational spectrum of the SPAST and ATL1 genes in Korean patients with hereditary spastic paraplegia. Journal of the neurological sciences 16 26208798
2004 Two novel mutations in the spastin gene (SPG4) found by DHPLC mutation analysis. Neuromuscular disorders : NMD 16 15482961
2017 Spastic paraplegia type 4: A novel SPAST splice site donor mutation and expansion of the phenotype variability. Journal of the neurological sciences 15 28870597
2016 Cognitive Impairment Involving Social Cognition in SPG4 Hereditary Spastic Paraplegia. Behavioural neurology 15 27688599
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
2018 Association of Early-Onset Spasticity and Risk for Cognitive Impairment With Mutations at Amino Acid 499 in SPAST. Journal of child neurology 14 29421991
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
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
2020 Cortical Damage Associated With Cognitive and Motor Impairment in Hereditary Spastic Paraplegia: Evidence of a Novel SPAST Mutation. Frontiers in neurology 12 32536902
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
2021 Corticospinal tract and motor cortex degeneration in pure hereditary spastic paraparesis type 4 (SPG4). Amyotrophic lateral sclerosis & frontotemporal degeneration 11 34396852
2019 Novel mutations in the SPAST gene cause hereditary spastic paraplegia. Parkinsonism & related disorders 11 31751864
2018 Patient-Derived Stem Cell Models in SPAST HSP: Disease Modelling and Drug Discovery. Brain sciences 11 30065201
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
2016 SPAST mutation spectrum and familial occurrence among Czech patients with pure hereditary spastic paraplegia. Journal of human genetics 10 27334366
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
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
2004 Prenatal diagnosis of autosomal dominant hereditary spastic paraplegia (SPG4) using direct mutation detection. Prenatal diagnosis 8 15164410
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 8 12460147
2019 MiR-33a is a therapeutic target in SPG4-related hereditary spastic paraplegia human neurons. Clinical science (London, England : 1979) 7 30777884
2019 A p.Arg499His Mutation in SPAST Is Associated with Infantile Onset Ascending Spastic Paralysis Complicated with Dysarthria and Anarthria. Neuropediatrics 7 31486053