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 missense mutation in the coiled coil domain of the kif5a gene and late onset hereditary spastic paraplegia. (2006 Feb)
A missense mutation in the coiled coil domain of the kif5a gene and late onset hereditary spastic paraplegia . background : To our knowledge , up to now , only 2 mutations in the kif5a gene , a member of the kinesin superfamily , have been identified as the molecular cause of early onset autosomal dominant hereditary spastic paraparesis ( adhsp ) . objective : To assess the genetic defect in a family with late onset adhsp . patients AND methods : Only the proband agreed to undergo complete neurological testing and mutational analysis . The proband was screened for mutations in the spastin , atlastin , nipa1 , and kif5a genes , either by denaturing high performance liquid chromatography or sequence analysis . results : The history of the family was consistent with adhsp characterized by late onset of the disease . mutational analysis results were negative for the spastin , atlastin , and nipa1 genes but identified a missense mutation ( c . 1082c T ) in the coiled coil coding region of the kif5a gene . conclusions : This finding enlarges the phenotypic spectrum of adhsp linked to kif5a and enhances the role of that gene in the epidemiology of this disease . We propose that the kif5a gene should be routinely analyzed in patients with hereditary spastic paraplegia negative for spastin and atlastin mutations .

Identification of the drosophila melanogaster homolog of the human spastin gene. (2003 Aug)
identification of the drosophila melanogaster homolog of the human spastin gene . The human SPG4 locus encodes the spastin gene , which is responsible for the most prevalent form of autosomal dominant hereditary spastic paraplegia ( AD HSP ) , a neurodegenerative disorder . Here we identify the predicted gene product cg5977 as the drosophila homolog of the human spastin gene , with much higher sequence similarities than any other related AAA domain protein in the fly . furthermore we report a new potential transmembrane domain in the N terminus of the two homologous proteins . during embryogenesis , the expression pattern of drosophila spastin becomes restricted primarily to the central nervous system , in contrast to the ubiquitous expression of the vertebrate spastin genes . given this nervous system specific expression , it will be important to determine if drosophila spastin loss of function mutations also lead to neurodegeneration .

Spinal cord magnetic resonance imaging in autosomal dominant hereditary spastic paraplegia. (2005 Oct)
spinal cord magnetic resonance imaging in autosomal dominant hereditary spastic paraplegia . hereditary spastic paraplegia ( HSP ) is a genetically heterogeneous group of neurodegenerative disorders characterized by progressive lower extremity weakness and spasticity . HSP pathology involves axonal degeneration that is most pronounced in the terminal segments of the longest descending ( pyramidal ) and ascending ( dorsal columns ) tracts . In this study , we compared spinal cord magnetic resonance imaging ( MRI ) in 13 HSP patients with four different types of autosomal dominant hereditary spastic paraplegia ( spg3a , SPG4 , SPG6 , and SPG8 ) with age matched control subjects . The cross section area of HSP subjects at cervical level C2 was 59 . 42 / 12 . 57 mm2 and at thoracic level T9 was 28 . 58 / 5 . 25 mm2 . Both of these values were less than in the healthy controls ( p 0 . 001 ) . The degree of cord atrophy was more prominent in patients with SPG6 and SPG8 who had signs of severe cord atrophy ( 47 . 60 / 6 . 58 mm2 at C2 , 21 . 40 / 2 . 4 mm2 at T9 ) than in subjects with SPG3 and SPG4 ( 66 . 0 / 8 . 94 mm2 at C2 , p 0 . 02 ; 31 . 75 / 2 . 76 mm2 at T9 , p 0 . 001 ) . these observations indicate that spinal …

Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations. (2004 Oct)
intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations . hereditary spastic paraplegia ( HSP ) is a genetically heterogeneous neurodegenerative disease characterized by wide variability in phenotypic expression , both within and among families . The most common cause of autosomal dominant HSP is mutation of the gene encoding spastin , a protein of uncertain function . We report the existence of intragenic polymorphisms of spastin that modify the HSP phenotype . One ( S44L ) is a previously described recessively acting allele and the second is a novel allele affecting the adjacent amino acid residue ( P45Q ) . In 4 HSP families in which either L44 or Q45 segregates independently of a missense or splicing mutation in the AAA domain of spastin , L44 and Q45 are each associated with a striking decrease in age at onset in the presence of the AAA domain mutations . using a bioinformatics approach , we found that the highly conserved S44 is predicted to be phosphorylated by a number of family members of the proline directed serine / threonine cyclin dependent kinases ( Cdks ) . Cdk1 and Cdk5 showed no kinase activity toward synthetic spastin peptide in an in vitro kinase assay , suggesting that this serine residue may be phosphorylated by a different Cdk . Our identification of S44L and P45Q as modifiers of the HSP phenotype suggests a role for spastin phosphorylation by Cdks in the neurodegeneration of the most common form of HSP .

Hereditary spastic paraplegia with cerebellar ataxia : a complex phenotype associated with a new SPG4 gene mutation. (2005 Jan)
hereditary spastic paraplegia with cerebellar ataxia : a complex phenotype associated with a new SPG4 gene mutation . complex forms of hereditary spastic paraplegia ( HSP ) are rare and usually transmitted in an autosomal recessive pattern . A family of four generations with autosomal dominant hereditary spastic paraplegia ( AD HSP ) and a complex phenotype with variably expressed co existing ataxia , dysarthria , unipolar depression , epilepsy , migraine , and cognitive impairment was investigated . genetic linkage analysis and sequencing of the SPG4 gene was performed and electrophysiologic investigations were carried out in six individuals and positron emission tomography ( PET ) in one patient . The disease was linked to the SPG4 locus on chromosome 2p as previously reported for pure HSP . sequence analysis of the SPG4 ( spastin ) gene identified a novel 1593 C T ( gln490stop ) mutation leading to premature termination of exon 12 with ensuing truncation of the encoded protein . however , the mutation was only identified in those individuals who were clinically affected by a complex phenotype consisting of HSP and cerebellar ataxia . other features noted in this kindred including epilepsy , cognitive impairment , depression , and migraine did not segregate with the HSP phenotype or mutation , and therefore the significance of these features to SPG4 is unclear . electrophysiologic investigation showed increased central conduction time at somatosensory evoked potentials measured from the lower limbs as the only abnormal finding in two affected individuals …

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 .

Meta analysis of age at onset in spastin associated hereditary spastic paraplegia provides no evidence for a correlation with mutational … (2003 Sep)
Meta analysis of age at onset in spastin associated hereditary spastic paraplegia provides no evidence for a correlation with mutational class .

Subcellular localization of spastin : implications for the pathogenesis of hereditary spastic paraplegia. (2005 Oct)
subcellular localization of spastin : implications for the pathogenesis of hereditary spastic paraplegia . hereditary spastic paraplegia ( HSP ) is a group of clinically and genetically heterogeneous diseases characterized by neuronal degeneration that is maximal at the distal ends of the longest axons of the central nervous system . The most common cause of autosomal dominant HSP is mutation of a novel gene encoding spastin , a protein whose function is still being elucidated . One clue concerning spastin function is its intracellular localization . Here , we describe a novel anti spastin antiserum designed to a unique epitope contained within all splicing isoforms . The antiserum exhibits specific immunostaining of recombinant spastin in intact , fixed cells . using this reagent , we find that endogenous spastin is located at the centrosome in a variety of cell types at all points in the cell cycle . This localization is resistant to microtubule disruption , suggesting that spastin may be an integral centrosomal protein . In addition to the centrosome , spastin also localizes at discrete focal regions along the axons of primary cultured neurons . these data lend additional support to the emerging hypothesis that spastin plays a role in microtubule dynamics , with a crucial role in microtubule organization .

Spastin and atlastin , two proteins mutated in autosomal dominant hereditary spastic paraplegia , are binding partners. (2006 Jan)
spastin and atlastin , two proteins mutated in autosomal dominant hereditary spastic paraplegia , are binding partners . The pure hereditary spastic paraplegias ( HSPs ) are a group of conditions in which there is a progressive length dependent degeneration of the distal ends of the corticospinal tract axons , resulting in spastic paralysis of the legs . Pure HSPs are most frequently inherited in an autosomal dominant pattern and are commonly caused by mutations either in the SPG4 gene spastin or in the spg3a gene atlastin . To identify binding partners for spastin , we carried out a yeast two hybrid screen on a brain cDNA library , using spastin as bait . remarkably , nearly all of the positive interacting prey clones coded for atlastin . We have verified the physiological relevance of this interaction using co immunoprecipitation , glutathione S transferase pull down and intracellular co localization experiments . We show that the spastin domain required for binding to atlastin lies within the N terminal 80 residues of the protein , a region that is only present in the predominantly cytoplasmic , full length spastin isoform . these data suggest that spastin and atlastin function in the same biochemical pathway and that it is the cytoplasmic function of spastin which is important for the pathogenesis of HSP . They also provide further evidence for a physiological and pathological role of spastin in membrane dynamics .

Spg3a : An additional family carrying a new atlastin mutation. (2002 Dec)
spg3a : An additional family carrying a new atlastin mutation . The authors report on a novel frameshift mutation ( c . 1688insa ) in the spg3a gene resulting in premature translation termination of the gene product atlastin . these data add a new variant to the second disease gene in autosomal dominant hereditary spastic paraplegia ( adhsp ) and lend definitive support to its causative role . By combining direct testing of spast and spg3a , at least 50 of adhsp families can now receive appropriate genetic diagnosis .

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 .

Unexpected pathogenic mechanism of a novel mutation in the coding sequence of SPG4 ( spastin ). (2006 Feb)
unexpected pathogenic mechanism of a novel mutation in the coding sequence of SPG4 ( spastin ) . The authors report a nucleotide substitution ( c . 1216a G ) in SPG4 ( spastin ) causing hereditary spastic paraplegia . This apparent missense mutation in the atpase domain confers aberrant , in frame splicing and results in destabilization of mutated transcript . mutated protein is deficient in microtubule severing activity but , unlike neighboring mutations , shows regular subcellular localization . The authors data point to haploinsufficiency rather than a dominant negative effect as the disease causing mechanism for this mutation .

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 .

Hereditary spastic paraplegia caused by mutations in the SPG4 gene. (2001 Jan)
hereditary spastic paraplegia caused by mutations in the SPG4 gene . autosomal dominant hereditary spastic paraplegia ( AD HSP ) is a genetically heterogeneous neurodegenerative disorder characterised by progressive spasticity of the lower limbs . The SPG4 locus at 2p21 p22 accounts for 40 50 of all AD HSP families . The SPG4 gene was recently identified . It is ubiquitously expressed in adult and foetal tissues and encodes spastin , an atpase of the AAA family . We have now identified four novel SPG4 mutations in german AD HSP families , including one large family for which anticipation had been proposed . mutations include one frame shift and one missense mutation , both affecting the walker motif B . Two further mutations affect two donor splice sites in introns 12 and 16 , respectively . RT PCR analysis of both donor splice site mutations revealed exon skipping and reduced stability of aberrantly spliced SPG4 mRNA . All mutations are predicted to cause loss of functional protein . In conclusion , we confirm in german families that SPG4 mutations cause AD HSP . Our data suggest that SPG4 mutations exert their dominant effect not by gain of function but by haploinsufficiency . If a threshold level of spastin were critical for axonal preservation , such threshold dosage effects might explain the variable expressivity and incomplete penetrance of SPG4 linked AD HSP .

Mutations in a newly identified gtpase gene cause autosomal dominant hereditary spastic paraplegia. (2001 Nov)
mutations in a newly identified gtpase gene cause autosomal dominant hereditary spastic paraplegia . The hereditary spastic paraplegias ( HSPs ; strümpell lorrain syndrome , MIM number 18260 ) are a diverse class of disorders characterized by insidiously progressive lower extremity spastic weakness ( reviewed in refs . 1 3 ) . eight autosomal dominant HSP ( adhsp ) loci have been identified , the most frequent of which is that linked to the SPG4 locus on chromosome 2p22 ( found in approximately 42 ) , followed by that linked to the spg3a locus on chromosome 14q11 q21 ( in approximately 9 ) . Only SPG4 has been identified as a causative gene in adhsp . Its protein ( spastin ) is predicted to participate in the assembly or function of nuclear protein complexes . Here we report the identification of mutations in a newly identified gtpase gene , spg3a , in adhsp affected individuals .

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 …

Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia. (2000 Apr)
spectrum of SPG4 mutations in autosomal dominant spastic paraplegia . autosomal dominant hereditary spastic paraplegia ( AD HSP ) is a group of genetically heterogeneous neurodegenerative disorders characterized by pro gressive spasticity of the lower limbs . Five AD HSP loci have been mapped to chromosomes 14q , 2p , 15q , 8q and 12q . The SPG4 locus at 2p21 p22 has been shown to account for approximately 40 of all AD HSP families . SPG4 encoding spastin , a putative nuclear AAA protein , has recently been identified . Here , sequence analysis of the 17 exons of SPG4 in 87 unrelated AD HSP patients has resulted in the detection of 34 novel mutations . these SPG4 mutations are scattered along the coding region of the gene and include all types of DNA modification including missense ( 28 ) , nonsense ( 15 ) and splice site point ( 26 . 5 ) mutations as well as deletions ( 23 ) and insertions ( 7 . 5 ) . The clinical analysis of the 238 mutation carriers revealed a high proportion of both asymptomatic carriers ( 14 / 238 ) and patients unaware of symptoms ( 45 / 238 ) , and permitted the redefinition of this frequent form of AD HSP .

Spectrum of SPG4 mutations in a large collection of north american families with hereditary spastic paraplegia. (2002 Feb)
spectrum of SPG4 mutations in a large collection of north american families with hereditary spastic paraplegia . background : hereditary spastic paraplegia ( HSP ) is a neurodegenerative disease characterized by progressive spasticity and weakness of the lower limbs . The most common form of HSP is caused by mutations in the SPG4 gene , which codes for spastin , an adenosine triphosphatase with various cellular activities ( AAA ) protein family member . objective : To investigate a large collection of predominantly north american patients with HSP for mutations in the spastin encoding gene , SPG4 . methods : DNA from 76 unrelated affected individuals was studied for mutations by single stranded conformational polymorphism analysis and direct sequencing . Each new variant identified was then analyzed in 80 control subjects to determine whether the variant is a common polymorphism or a rare mutation . All DNA samples were amplified by polymerase chain reaction , followed by electrophoresis and autoradiography . results : We identified 8 novel mutations and 5 previously reported mutations in 15 affected individuals . The novel mutations are 4 missense , 1 nonsense , 1 frameshift , and 2 splice mutations . Two polymorphisms ( one in an affected individual ) were also identified . conclusions : Our collection of families with HSP is different on a genetic level from those previously described . The percentage of our families with a SPG4 mutation is 10 lower than the 40 estimate of families with autosomal dominant HSP …

Identification and expression analysis of spastin gene mutations in hereditary spastic paraplegia. (2001 Apr)
identification and expression analysis of spastin gene mutations in hereditary spastic paraplegia . Pure hereditary spastic paraplegia ( SPG ) type 4 is the most common form of autosomal dominant hereditary SPG , a neurodegenerative disease characterized primarily by hyperreflexia and progressive spasticity of the lower limbs . It is caused by mutations in the gene encoding spastin , a member of the AAA family of atpases . We have screened the spastin gene for mutations in 15 families consistent with linkage to the spastin gene locus , SPG4 , and have identified 11 mutations , 10 of which are novel . Five of the mutations identified are in noninvariant splice junction sequences . reverse transcription PCR analysis of mRNA from patients shows that each of these five mutations results in aberrant splicing . One mutation was found to be leaky , or partially penetrant ; that is , the mutant allele produced both mutant ( skipped exon ) and wild type ( full length ) transcripts . This phenomenon was reproduced in in vitro splicing experiments , with a minigene splicing vector construct only in the context of the endogenous splice junctions flanking the splice junctions of the skipped exon . In the absence of endogenous splice junctions , only mutant transcript was detected . The existence of at least one leaky mutation suggests that relatively small differences in the level of wild type spastin expression can have significant functional consequences . This may account , at least in …