Spg3a mutation screening in english families with early onset autosomal dominant hereditary spastic paraplegia. (2003 Nov)
spg3a mutation screening in english families with early onset autosomal dominant hereditary spastic paraplegia . mutations in the spg3a gene encoding the novel gtpase atlastin have recently been implicated in causing autosomal dominant hereditary spastic paraplegia ( adhsp ) in six unrelated families . The phenotype of affected individuals in all cases has been of an early onset uncomplicated form of the disease . One particular missense mutation , r239c , in exon 7 of spg3a has been identified in three of these families . We performed mutation screening by direct sequencing of all 14 exons and flanking sequences of the spg3a gene in affected individuals from 12 unrelated english families , all with an early onset uncomplicated adhsp in whom spastin mutations had previously been excluded . The r239c mutation was found to co segregate with the disease in one english adhsp family confirming a widespread prevalence for this commonly occurring mutation . No additional spg3a mutations were identified in the remaining 11 families suggesting that even within this specific sub set of early onset uncomplicated adhsp patients atlastin mutations are relatively rare .

Early onset ALS with long term survival associated with spastin gene mutation. (2005 Jul)
early onset ALS with long term survival associated with spastin gene mutation . The authors report a 73 year old patient with a natural history of early onset ALS for 49 years presenting with limb and bulbar amyotrophy and a pyramidal syndrome . analysis of the locus SPG4 identified a heterozygous duplication mutation ( c . 304 309dupgcctcg ) within exon 1 of the spastin gene . We propose that sequence alterations of spastin may comprise a genetic risk factor in a greater spectrum of motor neuron disorders including clinical variants of ALS .

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 .

Recognition of C terminal amino acids in tubulin by pore loops in spastin is important for microtubule severing. (2007 Mar)
recognition of C terminal amino acids in tubulin by pore loops in spastin is important for microtubule severing . spastin , an AAA atpase mutated in the neurodegenerative disease hereditary spastic paraplegia , severs microtubules . Many other AAA proteins form ring shaped hexamers and contain pore loops , which project into the ring s central cavity and act as ratchets that pull on target proteins , leading , in some cases , to conformational changes . We show that spastin assembles into a hexamer and that loops within the central pore recognize C terminal amino acids of tubulin . Key pore loop amino acids are required for severing , including one altered by a disease associated mutation . We also show that spastin contains a second microtubule binding domain that makes a distinct interaction with microtubules and is required for severing . given that spastin engages the MT in two places and that both interactions are required for severing , we propose that severing occurs by forces exerted on the C terminal tail of tubulin , which results in a conformational change in tubulin , which releases it from the polymer .

Spastin related hereditary spastic paraplegia with dysplastic corpus callosum. (2005 Aug)
spastin related hereditary spastic paraplegia with dysplastic corpus callosum . Thin corpus callosum has been recently observed in two patients with an autosomal dominant trait of hereditary spastic paraplegia ( HSP ) linked to a novel mutation in the spastin gene ( SPG4 ) . In the same two patients cerebellar atrophy has been found . reportedly , in other members of the same family , there has been a variable presence of mental retardation . We report on the clinical and genetic investigation of an austrian family with a novel mutation in the spastin gene . genetic analysis of the SPG4 locus revealed a mutation ( c1120a ) and a known intronic polymorphism ( 996 47G A ) of the spastin gene . In one affected family member , previously undescribed dysplasia of the corpus callosum ( CC ) was found in conjunction with otherwise uncomplicated HSP . dysplastic CC was not paralleled with cortical atrophy , cognitive impairment or other phenotypic variations . Two further affected family members showed the same mutation and polymorphism , but no evidence of CC abnormalities . We conclude that apparently pure HSP may present with MRI features of dysplastic CC . This finding extended the spastin related phenotype which is distinct from previous reports of thin CC in HSP .

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 .

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 .

Quantitative and functional analyses of spastin in the nervous system : implications for hereditary spastic paraplegia. (2008 Feb)
quantitative and functional analyses of spastin in the nervous system : implications for hereditary spastic paraplegia . spastin and P60 katanin are two distinct microtubule severing proteins . autosomal dominant mutations in the SPG4 locus corresponding to spastin are the most common cause of hereditary spastic paraplegia ( HSP ) , a neurodegenerative disease that afflicts the adult corticospinal tracts . Here we sought to evaluate whether SPG4 based HSP is best understood as a loss of function disease . using various rat tissues , we found that P60 katanin levels are much higher than spastin levels during development . In the adult , P60 katanin levels plunge dramatically but spastin levels decline only slightly . quantitative data of spastin expression in specific regions of the nervous system failed to reveal any obvious explanation for the selective sensitivity of adult corticospinal tracts to loss of spastin activity . An alternative explanation relates to the fact that the mammalian spastin gene has two start codons , resulting in a 616 amino acid protein called M1 and a slightly shorter protein called M85 . We found that M1 is almost absent from developing neurons and most adult neurons but comprises 20 25 of the spastin in the adult spinal cord , the location of the axons that degenerate during HSP . experimental expression in cultured neurons of a short dysfunctional M1 polypeptide ( but not a short dysfunctional M85 peptide ) is deleterious to normal axonal growth . In squid axoplasm , …

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 .

Neurophysiological findings in SPG4 patients differ from other types of spastic paraplegia. (2003 May)
neurophysiological findings in SPG4 patients differ from other types of spastic paraplegia . The authors examined 12 families with autosomal dominant hereditary spastic paraplegia for phenotypic characteristics predicting the underlying genotype . They found no clinical differences between patients with or without mutations in the spastin gene ( SPG4 ) . motor evoked potentials and nerve conduction studies were almost normal in those with SPG4 . In contrast , non SPG4 families had prolonged central motor conduction times or marked peripheral neuropathy , or both .

Large scale disruption of microtubule pathways in morphologically normal human spastin muscle. (2004 Apr)
large scale disruption of microtubule pathways in morphologically normal human spastin muscle . objective : To investigate the molecular pathways disrupted by dominant spastin mutations in apparently unaffected skeletal muscle from patients with motor neuron disease ( SPG4 ) . methods : The authors studied muscle of three individuals from two unrelated families affected by spastic paraplegia caused by spastin mutations . The authors compared RNA expression profiles to 7 normal and 13 pathologic muscle U95A profiles ( duchenne dystrophy , acute quadriplegic myopathy , and spinal muscular atrophy ) . Data were validated with u133a arrays with seven different control specimens . mRNA and protein confirmations were done for a subset of genes . results : Both nonsense and missense mutations in the spastin gene disrupted microtubule pathways in nonpathologic tissue , including microtubule dynamics , stability , exocytosis , and endocytosis . conclusions : normal muscle can be used to uncover biochemical perturbation in motor neuron disease . altered microtubule metabolism in SPG4 linked hereditary spastic paraplegia patients leads to pathology of the long descending tracks of motor neurons that likely have a stringent need for efficient microtubular transport . As many inherited neurologic conditions show a systemic biochemical defect with disease limited to neurons , our data have broader implications for biochemical pathway studies of many neurologic disorders .

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 .

Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases. (2006 Mar)
spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases . background : SPG4 encodes spastin , a member of the AAA protein family , and is the major gene responsible for autosomal dominant spastic paraplegia . It accounts for 10 40 of families with pure ( or eventually complicated ) hereditary spastic paraparesis ( HSP ) . objective : To assess the frequency of SPG4 mutation in patients with spastic paraplegia but without family histories . methods : 146 mostly european probands with progressive spastic paraplegia were studied ( 103 with pure spastic paraplegia and 43 with additional features ) . major neurological causes of paraplegia were excluded . None had a family history of paraplegia . DNA was screened by dhplc for mutations in the 17 coding exons of the SPG4 gene . sequence variants were characterised by direct sequencing . A panel of 600 control chromosomes was used to rule out polymorphisms . results : The overall rate of mutations was 12 ; 19 different mutations were identified in 18 patients , 13 of which were novel . In one family , where both parents were examined and found to be normal , the mutation was transmitted by the asymptomatic mother , indicating reduced penetrance . The parents of other patients were not available for analysis but were reported to be normal . there was no evidence for de novo mutations . The mutations found in these apparently …

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 …

Linking axonal degeneration to microtubule remodeling by spastin mediated microtubule severing. (2005 Feb)
linking axonal degeneration to microtubule remodeling by spastin mediated microtubule severing . mutations in the AAA adenosine triphosphatase ( atpase ) spastin ( SPG4 ) cause an autosomal dominant form of hereditary spastic paraplegia , which is a retrograde axonopathy primarily characterized pathologically by the degeneration of long spinal neurons in the corticospinal tracts and the dorsal columns . using recombinant spastin , we find that six mutant forms of spastin , including three disease associated forms , are severely impaired in atpase activity . In contrast to a mutation designed to prevent adenosine triphosphate ( ATP ) binding , an ATP hydrolysis deficient spastin mutant predicted to remain kinetically trapped on target proteins decorates microtubules in transfected cells . analysis of disease associated missense mutations shows that some more closely resemble the canonical hydrolysis mutant , whereas others resemble the ATP binding mutant . using real time imaging , we show that spastin severs microtubules when added to permeabilized , cytosol depleted cells stably expressing GFP tubulin . using purified components , we also show that spastin interacts directly with microtubules and is sufficient for severing . these studies suggest that defects in microtubule severing are a cause of axonal degeneration in human disease .

Prenatal diagnosis of autosomal dominant hereditary spastic paraplegia ( SPG4 ) using direct mutation detection. (2004 May)
prenatal diagnosis of autosomal dominant hereditary spastic paraplegia ( SPG4 ) using direct mutation detection . objective : To present a report on prenatal diagnosis using direct SPG4 gene analysis in a family with autosomal dominant hereditary spastic paraplegia ( AD HSP ) . methods : genetic linkage and haplotype analysis were previously carried out with chromosome 2p markers . DNA was obtained from affected individuals , the affected father , the mother , and fetal DNA from an ongoing pregnancy by chorionic villus sampling ( CVS ) in the first trimester . The spastin gene ( SPG4 ) was completely sequenced . results : A novel 832insgdelaa frameshift mutation , predicted to cause loss of functional protein , was identified in the affected father and in the fetal DNA . conclusions : This is the first report on direct prenatal diagnosis of chromosome 2p linked AD HSP ( SPG4 ) . In addition , we report a novel SPG4 combined small insertion / deletion mutation in exon 5 , which may be the first SPG4 mutational hot spot .

Mutation analysis of SPG4 and spg3a genes and its implication in molecular diagnosis of korean patients with hereditary spastic paraplegia. (2005 Jul)
mutation analysis of SPG4 and spg3a genes and its implication in molecular diagnosis of korean patients with hereditary spastic paraplegia . background : hereditary spastic paraplegia ( HSP ) , a genetically and clinically heterogeneous group of neurodegenerative disorders , is characterized by progressive lower limb weakness and spasticity . among the 8 loci associated with the autosomal dominant uncomplicated HSP ( AD HSP ) , the spastin ( SPG4 ) and atlastin ( spg3a ) genes have been known to account for approximately 40 and 10 of all cases , respectively . objective : To investigate the contribution of these 2 genes in the occurrence of HSP in korean patients . design : clinical and genetic study . setting : tertiary care center . patients : eighteen patients with uncomplicated HSP ( 11 AD and 7 sporadic ) underwent screening for gene mutation . MAIN outcome measures : mutations in the SPG4 and spg3a genes as detected by direct sequencing of all coding exons and flanking intronic sequences . results : We identified 8 different SPG4 mutations , 7 of which have not been reported elsewhere . among the detected mutations were 3 missense mutations , 2 in frame deletions , 2 frameshift mutations , and 1 splice site mutation . No mutation was found in the spg3a gene . conclusion : compared with previous studies , a higher frequency of SPG4 gene mutations in AD HSP ( 7 / 11 ; 64 ) was observed , suggesting that …

A novel mutation in the spastin gene in a family with spastic paraplegia. (2002 May)
A novel mutation in the spastin gene in a family with spastic paraplegia . hereditary spastic paraplegia ( HSP ) is a degenerative neuromuscular disease characterized by progressive lower extremity weakness , spasticity and hyperreflexia . inheritance of HSP is commonly autosomal dominant , spastin was identified as the defective gene in chromosome 2p linked autosomal dominant hereditary spastic paraplegia ( AD HSP ) . In a large american family with AD HSP , we have identified a novel spastin mutation at a splice acceptor site in intron 6 ( 1130 1 g a ) and detected a corresponding aberrant transcript generated from a cryptic splice site . This is predicted to cause a frameshift and premature truncation of the abnormal spastin protein . Our data are the first to confirm that a mutation in an acceptor site in the spastin gene results in activation of a cryptic acceptor site and a translational frameshift . The clinical phenotype of this pedigree is also discussed .

Spg3a hereditary spastin paraplegia with genetic anticipation and incomplete penetrance objective : To analyze the spg3a coding sequence and clinical … (2007 Feb)
spg3a hereditary spastin paraplegia with genetic anticipation and incomplete penetrance objective : To analyze the spg3a coding sequence and clinical features in a family with dominantly inherited hereditary spastin paraplegia ( HSP ) characterized by incomplete genetic penetrance and genetic anticipation . methods : analysis of the spg3a coding sequence , being sequence variations in SPG4 / spastin ( S44L and P45Q ) and SPG6 / nipa1 ( GCG 5 11 ) genes were performed for the proband , his affected son , his unaffected parents and unaffected brother . One hundred normal individuals were selected as controls . results : spg3a mutation v253i in the proband , his affected son , and unexpectedly , in his asymptomatic , 72 year old father was identified . No mutation at the same site was found in the other members of this family as well as the control . conclusion : incomplete genetic penetrance due to spg3a mutation v253i was observed in this family . This is the second report . marked phenotype variation ( genetic non penetrance , adult versus childhood onset symptoms ) between subjects with the same spg3a mutation indicates the influence of modifying genetic or environmental factors . progressively earlier symptom onset and increasing symptom severity in this family is consistent with genetic anticipation which has not been previously reported in spg3a HSP .

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 .