All neuropathies great and small. (2005 Nov)
All neuropathies great and small . autosomal dominant pure hereditary spastic paraplegia ( AD HSP ) is characterized by the degeneration of long axons in corticospinal tracts and dorsal columns , resulting in spasticity and difficulty walking . mutations in the SPG4 gene product spastin are the predominant genetic lesions associated with this inherited disease . In this issue , Orso et al . examine and reconcile existing drosophila mutants of spastin and generate a new model for HSP by overexpression of a fly spastin transgene that carries a mutation prevalent in human AD HSP ( see the related article beginning on page 3026 ) . expression of this mutant spastin protein produces pathology in flies reminiscent of the human disease , including adult locomotion defects , in addition to causing aberrant synaptic morphology and altered microtubule stability . Both movement and synaptic defects in fly mutants were ameliorated by treatment with the microtubule modifying agent vinblastine . The results are consistent with disease causing mutations in human spastin producing dominant negative proteins and confirm the usefulness of drosophila genetic techniques to understand HSP and other neurodegenerative diseases .

Disease related phenotypes in a drosophila model of hereditary spastic paraplegia are ameliorated by treatment with vinblastine. (2005 Nov)
disease related phenotypes in a drosophila model of hereditary spastic paraplegia are ameliorated by treatment with vinblastine . hereditary spastic paraplegias ( HSPs ) are a group of neurodegenerative diseases characterized by progressive weakness and spasticity of the lower limbs . dominant mutations in the human SPG4 gene , encoding spastin , are responsible for the most frequent form of HSP . spastin is an atpase that binds microtubules and localizes to the spindle pole and distal axon in mammalian cell lines . furthermore , its drosophila homolog , drosophila spastin ( dspastin ) , has been recently shown to regulate microtubule stability and synaptic function at the drosophila larval neuromuscular junction . Here we report the generation of a spastin linked HSP animal model and show that in drosophila , neural knockdown of dspastin and , conversely , neural overexpression of dspastin containing a conserved pathogenic mutation both recapitulate some phenotypic aspects of the human disease , including adult onset , locomotor impairment , and neurodegeneration . At the subcellular level , neuronal expression of both dspastin RNA interference and mutant dspastin cause an excessive stabilization of microtubules in the neuromuscular junction synapse . In addition , we provide evidence that administration of the microtubule targeting drug vinblastine significantly attenuates these phenotypes in vivo . Our findings demonstrate that loss of spastin function elicits HSP like phenotypes in drosophila , provide novel insights into the molecular mechanism of spastin mutations , and raise the possibility that therapy with vinca …

Mutation analysis of the spastin gene ( SPG4 ) in patients in germany with autosomal dominant hereditary spastic paraplegia. (2002 Jul)
mutation analysis of the spastin gene ( SPG4 ) in patients in germany with autosomal dominant hereditary spastic paraplegia . hereditary spastic paraplegias ( HSP ) comprise a genetically and clinically heterogeneous group of neurodegenerative disorders characterized by progressive spasticity and hyperreflexia of the lower limbs . autosomal dominant hereditary spastic paraplegia 4 linked to chromosome 2p ( SPG4 ) is the most common form of autosomal dominant hereditary spastic paraplegia . It is caused by mutations in the SPG4 gene encoding spastin , a member of the AAA protein family of atpases . In this study the spastin gene of HSP patients from 161 apparently unrelated families in germany was analyzed . The authors identified mutations in 27 out of the 161 HSP families ; 23 of these mutations have not been described before and only one mutation was found in two families . among the detected mutations are 14 frameshift , four nonsense , and four missense mutations , one large deletion spanning several exons , as well as four mutations that affect splicing . Most of the novel mutations are located in the conserved AAA cassette encoding region of the spastin gene . The relative frequency of spastin gene mutations in an unselected group of german HSP patients is approximately 17 . frameshift mutations account for the majority of SPG4 mutations in this population . The proportion of splice mutations is considerably lower than reported elsewhere .

Clinical characteristics and spastin gene mutation analysis on an autosomal dominant kindred with hereditary spastic paraplegia objective : To investigate … (2007 Apr)
clinical characteristics and spastin gene mutation analysis on an autosomal dominant kindred with hereditary spastic paraplegia objective : To investigate the clinical characteristics and analyze spastin gene mutation on a kindred with hereditary spastic paraplegia ( HSP ) . methods : All family members were studied through clinical examinations . The proband and another two patients in this kindred were subjected to electromyography ( EMG ) examinations . The proband was subjected to thoracic MRI examination too . mutation analysis of spastin gene was screened by polymerase chain reaction combined with DNA sequencing in the proband and his father . results : All patients in the kindred manifested as classical HSP . thoracic MRI revealed atrophies of the spinal cord in the proband . No abnormal spastin gene mutation was detected in these two patients . conclusion : This kindred has typical clinical manifestations of HSP . The pathogenesis has no association with mutation of the exons of spastin gene .

A large family with hereditary spastic paraparesis due to a frame shift mutation of the spastin ( SPG4 ) gene … (2001 Nov)
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 . hereditary spastic paraparesis ( HSP ) is a clinically and genetically heterogeneous neurodegenerative disorder characterised by progressive lower limb spasticity and weakness . Some forms have been associated with white matter lesions and complex phenotypes . This study was prompted by the diagnosis of multiple sclerosis ( MS ) in two sisters from a large pedigree with hereditary spastic paraparesis . twelve affected members of the extended family were examined ( MRI and EEG were carried out and evoked potentials measured in five ) , and historical information was obtained from six affected deceased persons . The inherited disease phenotype was confirmed as autosomal dominant hereditary spastic paraparesis associated with epilepsy in four affected persons . None of the extended family had evidence of MS . genetic analysis of the family has shown linkage to chromosome 2p and sequencing of the spastin gene has identified a 1406delt frameshift mutation in exon 10 . This kindred demonstrates the clinical heterogeneity of HSP associated with spastin mutations . The possible relevance of the concurrence of HSP and MS in the sib pair is discussed .

The drosophila homologue of the hereditary spastic paraplegia protein , spastin , severs and disassembles microtubules. (2005 Apr)
The drosophila homologue of the hereditary spastic paraplegia protein , spastin , severs and disassembles microtubules . hereditary spastic paraplegias ( HSPs ) , a group of neurodegenerative disorders characterized by lower extremity spasticity and weakness , are most commonly caused by mutations in the spastin gene , which encodes a AAA atpase related to the microtubule severing protein katanin . A drosophila homolog of spastin ( D spastin ) was identified recently , and D spastin RNAi treated or genetic null flies show neurological defects , and protein overexpression decreases the density of cellular microtubules . elucidating spastin s function and disease mechanism will require a more detailed understanding of its structure and biochemical mechanism . Here , we have investigated the effects of D spastin , individual D spastin domains , and D spastin proteins bearing disease mutations on microtubules in cellular and in vitro assays . We show that D spastin , like katanin , displays atpase activity and uses energy from ATP hydrolysis to sever and disassemble microtubules ; disease mutations abolish or partially interfere with these activities .

Interaction of two hereditary spastic paraplegia gene products , spastin and atlastin , suggests a common pathway for axonal maintenance. (2006 Jul)
interaction of two hereditary spastic paraplegia gene products , spastin and atlastin , suggests a common pathway for axonal maintenance . hereditary spastic paraplegia ( HSP ) is a neurodegenerative disorder that is characterized by retrograde axonal degeneration that primarily affects long spinal neurons . The disease is clinically heterogeneous , and there are 20 genetic loci identified . Here , we show a physical interaction between spastin and atlastin , two autosomal dominant HSP gene products . spastin encodes a microtubule ( MT ) severing AAA atpase ( atpase associated with various activities ) , and atlastin encodes a golgi localized integral membrane protein gtpase . atlastin does not regulate the enzymatic activity of spastin . We also identified a clinical mutation in atlastin outside of the gtpase domain that prevents interaction with spastin in cells . therefore , we hypothesize that failure of appropriate interaction between these two HSP gene products may be pathogenetically relevant . these data indicate that at least a subset of HSP genes may define a cellular biological pathway that is important in axonal maintenance .

Novel spastin ( SPG4 ) mutations in italian patients with hereditary spastic paraplegia. (2006 Jun)
novel spastin ( SPG4 ) mutations in italian patients with hereditary spastic paraplegia . spastic paraplegia type 4 is caused by mutations in the gene that encodes spastin ( SPG4 ) , a member of the AAA protein family . A cohort of 34 unrelated italian patients with pure spastic paraplegia , of which 18 displayed autosomal dominant inheritance and 16 were apparently sporadic , were screened for mutations in the SPG4 gene by denaturing high performance liquid chromatography . We identified a previously reported mutation in a sporadic patient with pure hereditary spastic paraplegia . We also identified eight unrelated patients with pure autosomal dominant hereditary spastic paraplegia carrying five novel mutations in the SPG4 gene ( one missense mutation , c . 1304 C T ; one nonsense mutation , c . 807C A ; two frameshift mutations , c . 1281dupt , c . 1514 1515insata ; and one splicing mutation , c . 1322 2A C ) . The frequency for SPG4 mutations detected in autosomal dominant hereditary spastic paraplegia was 44 . 4 . This study contributes to expand the spectrum of SPG4 mutations in italian population .

Exon deletions of SPG4 are a frequent cause of hereditary spastic paraplegia. (2007 Apr)
Exon deletions of SPG4 are a frequent cause of hereditary spastic paraplegia . background : point mutations in SPG4 , the gene encoding spastin , are a frequent cause of autosomal dominant hereditary spastic paraplegia ( AD HSP ) . however , standard methods for genetic analyses fail to detect exonic microdeletions . methods : 121 mutation negative probands were screened for rearrangements in SPG4 by multiplex ligation dependent probe amplification . results : 24 patients with 16 different heterozygotic exon deletions in SPG4 ( 20 ) were identified , ranging from one exon to the whole coding sequence . comparison with 78 patients with point mutations showed a similar clinical picture but an earlier age at onset . conclusions : Exon deletions in SPG4 are as frequent as point mutations , and SPG4 is responsible for 40 of AD HSP .

The role of hereditary spastic paraplegia related genes in multiple sclerosis. (2007 Nov)
The role of hereditary spastic paraplegia related genes in multiple sclerosis . A study of disease susceptibility and clinical outcome . multiple sclerosis ( MS ) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome . It has been observed that axonal loss in MS is significant and that irreversible clinical disability relates to such axonal loss . The clinical similarities between hereditary spastic paraplegia ( HSP ) and progressive MS , along with their analogous profiles of axonal loss in the long tracts , make the genes known to cause HSP biologically relevant candidates for the study of clinical outcome in MS . A cohort of sporadic MS cases and a set of unaffected controls were used to determine the role of HSP genes on MS susceptibility and disease severity . The MS cases were taken from opposite extremes of the putative distribution of long term outcome using the most stringent clinical criteria to date . genotyping the two sets of MS patients and controls could not provide any evidence to suggest that genes involved in the pathogenesis of HSP ( paraplegin , nipa1 , kif5a , hspd1 , atlastin , spartin , spastin , PLP1 , l1cam , maspardin and bscl2 ) play a role in susceptibility to , or modifying the course of , MS , although small effects of these genes cannot be ruled out .

An atypical intronic deletion widens the spectrum of mutations in hereditary spastic paraplegia. (2001 Jun)
An atypical intronic deletion widens the spectrum of mutations in hereditary spastic paraplegia . objective : To identify the genetic mutation responsible for autosomal dominant spastic paraplegia ( HSP ) in a large family with a pure form of the disorder . background : The disease locus in most families with HSP is genetically linked to the SPG4 locus on chromosome 2p21 p22 . Some of these families have mutations in the splice site or coding regions of the spastin gene ( spast ) . methods : linkage and mutational analyses were used to identify the location and the nature of the genetic defect causing the disorder in a large family . after the disease phenotype was linked to the SPG4 locus , all 17 coding regions and flanking intronic sequences of spast were analyzed by single strand conformation polymorphism analysis ( SSCP ) and compared between affected and normal individuals . direct sequencing and subcloning methods were used to investigate incongruous mobility shifts . results : The genomic sequence of spast showed a heterozygous four base pair deletion ( deltaat ) near the 3 splice site of exon three in all 11 affected individuals but not in 21 normal family members or in 50 unrelated controls ( 100 chromosomes ) . conclusions : This study identifies an atypical intronic microdeletion in spast that causes HSP and widens the spectrum of genetic abnormalities that cause the disorder .

A novel insertion mutation in spastin gene is the cause of spastic paraplegia in a chinese family. (2003 May)
A novel insertion mutation in spastin gene is the cause of spastic paraplegia in a chinese family . A total of eight loci for autosomal dominant hereditary spastic paraplegia ( adhsp ) has been mapped to chromosome 14q , 2p , 15q , 8q , 10q , 12q , 19q , 2q , respectively , among which the SPG4 gene on chromosome 2p21 22 encoding spastin , an atpase of the AAA family , accounts for 40 50 of all adhsp families and is expressed in both adult and fetal tissues . In this work , we reveal a novel insertion mutation in exon 11 of the SPG4 gene found in a big chinese family composed of 47 members , including 20 affected ones , using linkage analysis . The mutation was well demonstrated to be the cause of loss of production of the functional protein by pre termination of translation in AAA cassette region . To our knowledge , this is the first report of spastin mutation in china .

Analysis and mapping of cacnb4 , chrna1 , kcnj3 , scn2a and SPG4 , physiological candidate genes for porcine congenital … (2007 Sep)
analysis and mapping of cacnb4 , chrna1 , kcnj3 , scn2a and SPG4 , physiological candidate genes for porcine congenital progressive ataxia and spastic paresis . The cause of porcine congenital progressive ataxia and spastic paresis ( CPA ) is unknown . This severe neuropathy manifests shortly after birth and is lethal . The disease is inherited as a single autosomal recessive allele , designated cpa . In a previous study , we demonstrated close linkage of cpa to microsatellite sw902 on porcine chromosome 3 ( SSC3 ) , which corresponds syntenically to human chromosome 2 . This latter chromosome contains ion channel genes ( Ca ( 2 ) , K ( ) and Na ( ) ) , a cholinergic receptor gene and the spastin ( SPG4 ) gene , which cause human epilepsy and ataxia when mutated . We mapped porcine cacnb4 , kcnj3 , scn2a and chrna1 to ssc15 and SPG4 to SSC3 with the INRA minnesota porcine radiation hybrid panel ( imprh ) and we sequenced the entire open reading frames of cacnb4 and SPG4 without finding any differences between healthy and affected piglets . An anti epileptic drug treatment with ethosuximide did not change the severity of the disease , and pigs with CPA did not exhibit the corticospinal tract axonal degeneration found in humans suffering from hereditary spastic paraplegia , which is associated with mutations in SPG4 . For all these reasons , the hypothesis that cacnb4 , chrna1 , kcnj3 , scn2a or …

Spastin , the protein mutated in autosomal dominant hereditary spastic paraplegia , is involved in microtubule dynamics. (2002 Jan)
spastin , the protein mutated in autosomal dominant hereditary spastic paraplegia , is involved in microtubule dynamics . hereditary spastic paraplegia ( HSP ) is characterized by progressive weakness and spasticity of the lower limbs , caused by the specific degeneration of the corticospinal tracts , the longest axons in humans . Most cases of the autosomal dominant form of the disease are due to mutations in the SPG4 gene , which encodes spastin , an atpase belonging to the AAA family . The cellular pathways in which spastin operates and its role in causing degeneration of motor axons are currently unknown . By expressing wild type or atpase defective spastin in several cell types , we now show that spastin interacts dynamically with microtubules . spastin association with the microtubule cytoskeleton is mediated by the N terminal region of the protein , and is regulated through the atpase activity of the AAA domain . expression of all the missense mutations into the AAA domain , which were previously identified in patients , leads to constitutive binding to microtubules in transfected cells and induces the disappearance of the aster and the formation of thick perinuclear bundles , suggesting a role of spastin in microtubule dynamics . consistently , wild type spastin promotes microtubule disassembly in transfected cells . these data suggest that spastin may be involved in microtubule dynamics similarly to the highly homologous microtubule severing protein , katanin . impairment of fine regulation of the microtubule cytoskeleton in long …

Autosomal dominant hereditary spastic paraplegia : report of a large italian family with r581x spastin mutation. (2007 Aug)
autosomal dominant hereditary spastic paraplegia : report of a large italian family with r581x spastin mutation . We describe a large kindred with a typical pure form of autosomal dominant hereditary spastic paraplegia ( adhsp ) . On the basis of maximum LOD score of 1 . 94 at theta ( max ) 0 with marker d2s367 , we obtained suggestive evidence for linkage of adhsp to SPG4 locus . denaturing high performance liquid chromatography ( dhplc ) and direct sequence analysis allowed us to identify a nonsense mutation ( 1741 C T ) in exon 17 of the spastin gene . This transition , carried by all the affected family members and two apparently healthy individuals , lead to truncation of the last 36 amino acids in the C terminus of the protein . these results confirm the existence of mutation in the SPG4 gene with a reduced penetrance , indicating that other genetic or environmental factors are required to trigger full blown disease .

Human spastin has multiple microtubule related functions. (2005 Nov)
human spastin has multiple microtubule related functions . hereditary spastic paraplegias ( HSPs ) are neurodegenerative diseases caused by mutations in more than 20 genes , which lead to progressive spasticity and weakness of the lower limbs . The most frequently mutated gene causing autosomal dominant HSP is SPG4 , which encodes spastin , a protein that belongs to the family of atpases associated with various cellular activities ( AAAs ) . A number of studies have suggested that spastin regulates microtubule dynamics . We have studied the atpase activity of recombinant human spastin and examined the effect of taxol stabilized microtubules on this activity . We used spastin translated from the second ATG and provide evidence that this is the physiologically relevant form . We showed that microtubules enhance the atpase activity of the protein , a property also described for katanin , an AAA of the same spastin subgroup . furthermore , we demonstrated that human spastin has a microtubule destabilizing activity and can bundle microtubules in vitro , providing new insights into the molecular pathogenesis of HSP .

Identification of nuclear localisation sequences in spastin ( SPG4 ) using a novel tetra GFP reporter system. (2004 May)
identification of nuclear localisation sequences in spastin ( SPG4 ) using a novel tetra GFP reporter system . mutations in the human spastin gene ( SPG4 ) cause the most prevalent form of autosomal dominant hereditary spastic paraplegia ( HSP ) , a neurodegenerative disorder characterised by progressive weakness and spasticity of the lower limbs . We address the question of intracellular localisation of spastin . using polyclonal antibodies against N terminal spastin sequences , we find that the native protein is localised in both the perinuclear cytoplasm and the nucleus . To identify structural motifs within the protein that can explain entry into the nucleus , we developed a reporter system to test nuclear localisation sequence ( NLS ) functionality based on four in frame fused copies of green fluorescent protein . using this novel tool we demonstrate that spastin carries two NLSs located in exons 1 and 6 . Both are independently functional in mediating nuclear entry .

Transcranial magnetic stimulation study in hereditary spastic paraparesis. (2003 May)
transcranial magnetic stimulation study in hereditary spastic paraparesis . The motor evoked potentials and the cortical excitability by transcranial magnetic stimulation ( TMS ) were studied in a family with chromosome 2p linked ( due to mutations in spastin ) and in a family with chromosome 16q linked ( due to mutations in paraplegin ) hereditary spastic paraparesis ( HSP ) , in order to evaluate the utility of these techniques in identifying the subgroups of the disease . central motor conduction time and motor treshold to TMS were abnormal in some members of both families ; the intracortical inhibition was reduced only in the affected members of the family with chromosome 2p linked HSP , even though the neurological symptoms were sometimes similar and also when clinical features reflecting cortical dysfunction were absent . The motor cortex is differentially involved in the often clinically indistinguishable forms of HSP , and TMS may help in the differential diagnosis .

Screening of patients with hereditary spastic paraplegia reveals seven novel mutations in the SPG4 ( spastin ) gene. (2003 Jan)
screening of patients with hereditary spastic paraplegia reveals seven novel mutations in the SPG4 ( spastin ) gene . hereditary spastic paraplegia ( HSP ) is a heterogeneous condition characterised in its pure form by progressive lower limb spasticity . mutations in SPG4 ( encoding spastin ) may be responsible for up to 40 of autosomal dominant ( AD ) cases . A cohort of 41 mostly pure HSP patients from britain and austria , 30 of whom displayed AD inheritance , was screened for mutations in SPG4 by single strand conformation polymorphism ( SSCP ) analysis followed by sequencing of samples with mobility shifts . We identified eight SPG4 mutations in pure AD HSP patients , seven of which were novel : one missense mutation within the AAA cassette ( 1633g T ) , two splice site mutations ( 1130 1G T , 1853 2T A ) and four frameshift mutations ( 190 208dup19 , 1259 1260delgt , 1702 1705delgaag , 1845delg ) . A novel duplication in intron 11 ( 1538 42 45duptata ) was also detected . We report the HUGO approved nomenclature of these mutations as well . furthermore , we detected a silent change ( 1004g A ; p293p ) , previously reported as a mutation , which was also present in controls . The frequency of SPG4 mutations detected in pure AD HSP was 33 . 3 , suggesting that screening of such patients for SPG4 mutations is worthwhile . Most patients will have …

SPG4 founder effect in french canadians with hereditary spastic paraplegia. (2007 Jun)
SPG4 founder effect in french canadians with hereditary spastic paraplegia . background : The most common cause of autosomal dominant hereditary spastic paraplegia ( HSP ) is mutations in the SPG4 gene . We have previously identified novel SPG4 mutations in a collection of north american families including the c . g1801a mutation present in two families from quebec . The aim of this study is to estimate the frequency of the c . g1801a mutation in the french canadian ( FC ) population and to determine whether this mutation originates from a common ancestor . methods : We collected and sequenced exon 15 in probands of 37 families . genotypes of markers flanking the SPG4 gene were used to construct haplotypes in five families . clinical information was reviewed by a neurologist with expertise in HSP . results : We have identified three additional unrelated families with the c . g1801a mutation and haplotype analysis revealed that all five families share a common ancestor . The mutation is present in 7 of all our FC families and explains half of our spastin linked FC families . The phenotype associated with the c . g1801a genotype is pure HSP with bladder involvement . conclusion : In this study we have determined that the relative frequency of the c . g1801a mutation in our FC collection is 7 , and approximately 50 in the spastin positive FC group . This mutation is the most common HSP mutation identified in this population …