Paraplegin gene analysis in hereditary spastic paraparesis ( HSP ) pedigrees in northeast england. (2001 Mar)
paraplegin gene analysis in hereditary spastic paraparesis ( HSP ) pedigrees in northeast england . objective : To identify the frequency and characterize the phenotype of paraplegin mutations in the hereditary spastic paraparesis ( HSP ) population in the northeast of england . background : HSP is a disorder that shows both clinical and genetic heterogeneity . To date , 13 loci have been associated with an HSP phenotype , with the causative gene having been identified in four of these . Two autosomal genes have been identified , paraplegin and spastin , and two X linked genes have been identified , l1cam ( cell adhesion molecule ) and proteolipid protein . methods : thirty HSP pedigrees from the northeast of england were analyzed for mutation in each of the 17 exons of the paraplegin gene . results : A single family with a paraplegin mutation was identified in which the paraplegin mutation co segregates with an HSP phenotype in an apparent dominant manner . The authors also describe frequent polymorphism in the paraplegin gene in both the HSP and control populations . conclusion : mutations in the paraplegin gene are not a common cause of HSP in the northeast of england . The phenotype of the paraplegin related HSP family described had several striking features including amyotrophy , raised creatine kinase , sensorimotor peripheral neuropathy , and oxidative phosphorylation defect on muscle biopsy .

Drosophila spastin regulates synaptic microtubule networks and is required for normal motor function. (2004 Dec)
drosophila spastin regulates synaptic microtubule networks and is required for normal motor function . The most common form of human autosomal dominant hereditary spastic paraplegia ( AD HSP ) is caused by mutations in the SPG4 ( spastin ) gene , which encodes an AAA atpase closely related in sequence to the microtubule severing protein katanin . patients with AD HSP exhibit degeneration of the distal regions of the longest axons in the spinal cord . Loss of function mutations in the drosophila spastin gene produce larval neuromuscular junction ( NMJ ) phenotypes . NMJ synaptic boutons in spastin mutants are more numerous and more clustered than in wild type , and transmitter release is impaired . spastin null adult flies have severe movement defects . They do not fly or jump , they climb poorly , and they have short lifespans . spastin hypomorphs have weaker behavioral phenotypes . overexpression of spastin erases the muscle microtubule network . This gain of function phenotype is consistent with the hypothesis that spastin has microtubule severing activity , and implies that spastin loss of function mutants should have an increased number of microtubules . surprisingly , however , we observed the opposite phenotype : in spastin null mutants , there are fewer microtubule bundles within the NMJ , especially in its distal boutons . The drosophila NMJ is a glutamatergic synapse that resembles excitatory synapses in the mammalian spinal cord , so the reduction of organized presynaptic microtubules that we observe in …

Clinical features of hereditary spastic paraplegia due to spastin mutation. (2006 Jul)
clinical features of hereditary spastic paraplegia due to spastin mutation . background : mutations in the spastin gene are the commonest cause of hereditary spastic paraparesis ( HSP ) , accounting for up to 40 of autosomal dominant cases . The phenotype associated with HSP due to mutation in the spastin gene ( SPG4 ) tends to be pure HSP . objective : To characterize in more detail the genetic and phenotypic characteristics of SPG4 by examining a large cohort of patients with HSP . methods : The authors identified patients who tested positive for spastin mutation using a direct sequencing approach of all exons . results : The authors identified spastin mutations in 53 patients . twenty seven of the mutations identified were novel . The phenotype in the majority of patients was of pure HSP . In one individual , a complicated phenotype with progressive bulbar dysfunction and respiratory insufficiency was observed . evidence of lower motor neuron dysfunction in a subgroup of SPG4 patients was identified . The missense changes S44L and P45Q were identified in patients with other spastin mutations and seemed to be exerting a phenotype modifying effect . conclusion : these findings add to the number of spastin mutations identified and demonstrate the importance of screening the whole gene , given the possibility of double mutations and intragenic modifiers . The identification of the complicated phenotypes has important implications for identifying the phenotype of patients in whom spastin screening should be considered . The …

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 …

Spastic paraplegia caused by a novel mutation in the spastin gene ( 1207c G , p361r ) clinical features of … (2008 Feb)
spastic paraplegia caused by a novel mutation in the spastin gene ( 1207c G , p361r ) clinical features of a patient without family history A 52 year old man with no apparent family history of neurodegenerative diseases developed gait disturbance at age 47 . neurological examination at aged 52 revealed spastic paraplegia , generalized hyperreflexia , decreased of vibration sense in the lower limbs , and pollakisuria . ocular symptoms , deafness , cerebellar ataxia , extrapyramidal signs , mental deterioration , dementia , peripheral neuropathy , retinal pigment degeneration , ichthyosis and syndactyly were absent . MRI of the brain was normal . A pure form of hereditary spastic paraplegia was diagnosed . genetic analysis revealed a novel missense mutation in the spastin gene ( 1207c G , p361r ) . The clinical features of this patient were consistent with those of patient with the pure form of SPG4 . Gene analysis should be considered for patients with spastic paraplegia even in the absence of any family history .

Reduced regional cerebral blood flow in SPG4 linked hereditary spastic paraplegia. (2005 Jul)
reduced regional cerebral blood flow in SPG4 linked hereditary spastic paraplegia . hereditary spastic paraplegia ( HSP ) linked to the spastic gait gene 4 ( SPG4 ) is controversial , as the pure form traditionally has been considered confined to the long axons of the spinal cord . however , recent immunolabeling experiments have demonstrated extensive spastin expression in the cortex and striatum . This could indicate a more widespread neuropathology from mutations in the SPG4 gene than previously assumed . The aim of this study was therefore to ascertain the extent of cerebral involvement in SPG4 linked HSP by neuropsychological examination and measurement of the regional cerebral blood flow ( rCBF ) as an indirect marker of regional neuronal activity . eighteen SPG4 patients and 18 matched control subjects were studied . resting state rCBF was measured using positron emission tomography ( PET ) and the ( 15 ) O labelled water bolus technique and relative group differences were explored using statistical parametric mapping ( SPM 99 ) . neuropsychological assessment was performed using established and nationally validated tests ( RH basic battery ) . compared to healthy controls , the patient group had significantly decreased rCBF in the left fronto temporal cortex ( P 0 . 05 ) , and more extensive changes were observed in a separate analysis of the most disabled individuals . The neuropsychological assessment revealed only significantly impaired recognition memory for faces . In summary , the findings support cerebral pathology in SPG4 …

Compound heterozygosity in the SPG4 gene causes hereditary spastic paraplegia. (2008 Feb)
compound heterozygosity in the SPG4 gene causes hereditary spastic paraplegia . The SPG4 gene is frequently mutated in autosomal dominant form of hereditary spastic paraplegia ( HSP ) . We report that the compound heterozygous sequence variants S44L , a known polymorphism , and c . 1687g A , a novel mutation in SPG4 cause a severe form of HSP in a patient . The family members carrying solely c . 1687g A mutation are asymptomatic for HSP . The reverse transcriptase polymerase chain reaction ( RT PCR ) analysis revealed that the c . 1687g A mutation is a splice site mutation and causes skipping of the exon 15 of spastin . furthermore , quantification of RT PCR products by sequencing and quantification of allele specific expression by pyrosequencing assay revealed that c . 1687g A is a leaky or hypomorphic splice site mutation . At the protein level , c . 1687g A mutation in SPG4 leads to e563k substitution . In ex vivo study , about 10 of cells expressing e563k mutant spastin showed filamentous expression pattern , suggesting a hypomorphic effect at the protein level . collectively , our results suggest that S44L in association with c . 1687g A ( e563k ) drops the functional level of spastin below a threshold limit sufficient to manifest HSP .

Eight novel mutations in SPG4 in a large sample of patients with hereditary spastic paraplegia. (2006 May)
eight novel mutations in SPG4 in a large sample of patients with hereditary spastic paraplegia . background : hereditary spastic paraplegia ( HSP ) is a group of genetically heterogeneous disorders characterized by progressive spasticity of the lower limbs . mutations in the SPG4 gene , which encodes spastin protein , are responsible for up to 45 of autosomal dominant cases . objective : To search for disease causing mutations in a large series of italian patients with HSP . design : samples of DNA were analyzed by direct sequencing of all exons in SPG4 . samples from a subset of patients were also analyzed by direct sequencing of all exons in spg3a , SPG6 , spg10 , and spg13 . setting : molecular testing facility in italy . patients : sixty unrelated italian patients with pure ( n 50 ) and complicated ( n 10 ) HSP . MAIN outcome measures : mutations in SPG4 , spg3a , SPG6 , spg10 , and spg13 . results : We identified 12 different mutations , 8 of which were novel , in 13 patients . No mutations of any of the other HSP genes tested were found in 15 patients with sporadic pure HSP who did not have mutations in the SPG4 gene . conclusions : The overall rate of mutation in the SPG4 gene within our sample was 22 , rising to 26 when only patients with pure HSP were considered . The negative result obtained in 15 patients without …

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 .

Characterization of a novel spg3a deletion in a french canadian family. (2007 Jul)
characterization of a novel spg3a deletion in a french canadian family . hereditary spastic paraplegias ( HSPs ) are characterized by progressive lower limb spasticity and weakness . mutations in the spg3a gene , which encodes the large guanosine triphosphatase atlastin , are the second most common cause of autosomal dominant hereditary spastic paraplegia . In a large spg3a screen of 70 hereditary spastic paraplegia subjects , a novel in frame deletion , p . del436n , was identified . characterization of this deletion showed that it affects neither the guanosine triphosphatase activity of atlastin nor interactions between atlastin and spastin . interestingly , immunoblot analysis of lymphoblasts from affected patients demonstrated a significant reduction in atlastin protein levels , supporting a loss of function disease mechanism .

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 …

The cellular and molecular pathology of the motor system in hereditary spastic paraparesis due to mutation of the spastin gene. (2003 Dec)
The cellular and molecular pathology of the motor system in hereditary spastic paraparesis due to mutation of the spastin gene . hereditary spastic paraparesis ( HSP ) is a genetically heterogeneous disorder , the most common cause of which is mutation of the spastin gene . recent evidence suggests a role for spastin in microtubule dynamics , but the distribution of the protein within the CNS is unknown . The core neuropathology of HSP is distal degeneration of the lateral corticospinal tract and of fasciculus gracilis , but there are few neuropathological studies of cases with a defined mutation . We aimed to determine the distribution of spastin expression in the human CNS and to investigate the cellular pathology of the motor system in HSP due to mutation of the spastin gene . using an antibody to spastin , we have carried out immunohistochemistry on postmortem brain . We have demonstrated that spastin is a neuronal protein . It is widely expressed in the CNS so that the selectivity of the degeneration in HSP is not due to the normal cellular distribution of the protein . We have identified mutation of the spastin gene in 3 autopsy cases of HSP . distal degeneration of long tracts in the spinal cord , consistent with a dying back axonopathy , was accompanied by a microglial reaction . The presence of novel hyaline inclusions in anterior horn cells and an alteration in immunostaining for cytoskeletal proteins and mitochondria indicates that long tract degeneration …

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 …

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 .

Large deletion involving the 5 UTR in the spastin gene caused mild phenotype of autosomal dominant hereditary spastic paraplegia. (2005 Feb)
large deletion involving the 5 UTR in the spastin gene caused mild phenotype of autosomal dominant hereditary spastic paraplegia . hereditary spastic paraplegia ( HSP ) due to mutations in the spastin gene ( SPG4 ) located to 2p22 p21 is the most common form of autosomal dominant ( AD ) HSP . We performed PCR based direct sequencing of SPG4 , followed by a linkage analysis and subsequent southern blot analysis in large japanese kindred where 20 of 33 members were evaluated neurologically , and consequently 6 were affected with HSP . clinical evaluation showed that the mean age at disease onset of the patients was older and the disability was less severe than those of previously reported typical patients with SPG4 mutations . direct sequencing of genomic DNA and RT PCR product did not show a SPG4 mutation despite of a strong linkage to the SPG4 locus at 2p . southern blot analysis suggested a deletion involving the 5 UTR of SPG4 . further sequence analysis confirmed a heterozygous 2307 bp deletion spanning from the 5 UTR to intron 1 of SPG4 . The results suggested that transcription of the mutated allele starts from an authentic initiation site , but lacks an authentic translational start site of exon 1 because of a deficient splice donor site and coding region . The abnormal transcripts may result in rapid RNA decay . The novel refractory mutation we identified widens the spectrum of SPG4 mutations . these findings suggest that structural …

Thin corpus callosum and amyotrophy in spastic paraplegia case report and review of literature. (2006 Sep)
Thin corpus callosum and amyotrophy in spastic paraplegia case report and review of literature . We report the clinical , structural , functional and genetic characterization of a 37 year old caucasian female , presenting as a sporadic case of complicated spastic paraplegia with thin corpus callosum ( CC ) , cognitive impairment , amyotrophy of the hand muscles and a sensorimotor neuropathy and review the literature for spastic paraplegia with thin CC . magnetic resonance imaging ( MRI ) examination revealed a thin CC with fronto parietal cortical atrophy . 18fluordesoxyglucose positron emission tomography ( FDG PET ) showed reduced cortical and thalamic metabolism . By transcranial magnetic stimulation , we delineated a severe impairment of transcallosal inhibition . sequence analysis did not reveal disease causing mutations in the genes slc12a6 ( andermann ) , spastin ( SPG 4 ) , bscl2 ( SPG 17 ) and spartin ( SPG 20 ) . We reviewed the literature for HSP with thin CC and found 113 HSP patients with thin CC previously described ( 35 with linkage to chromosome 15q13 15 ) . Thin CC and peripheral neuropathy often appear together in spastic paraplegia and might be indicative for combined degeneration mechanism of central and peripheral axons .

Spastin , a new AAA protein , is altered in the most frequent form of autosomal dominant spastic paraplegia. (1999 Dec)
spastin , a new AAA protein , is altered in the most frequent form of autosomal dominant spastic paraplegia . autosomal dominant hereditary spastic paraplegia ( AD HSP ) is a genetically heterogeneous neurodegenerative disorder characterized by progressive spasticity of the lower limbs . among the four loci causing AD HSP identified so far , the SPG4 locus at chromosome 2p2 1p22 has been shown to account for 40 50 of all AD HSP families . using a positional cloning strategy based on obtaining sequence of the entire SPG4 interval , we identified a candidate gene encoding a new member of the AAA protein family , which we named spastin . sequence analysis of this gene in seven SPG4 linked pedigrees revealed several DNA modifications , including missense , nonsense and splice site mutations . Both SPG4 and its mouse orthologue were shown to be expressed early and ubiquitously in fetal and adult tissues . The sequence homologies and putative subcellular localization of spastin suggest that this atpase is involved in the assembly or function of nuclear protein complexes .

Mutations of SPG4 are responsible for a loss of function of spastin , an abundant neuronal protein localized in the … (2002 Dec)
mutations of SPG4 are responsible for a loss of function of spastin , an abundant neuronal protein localized in the nucleus . mutations of spastin are responsible for the most common autosomal dominant form of hereditary spastic paraplegia ( AD HSP ) , a disease characterized by axonal degeneration of corticospinal tracts and posterior columns . generation of polyclonal antibodies specific to spastin has revealed two isoforms of 75 and 80 kDa in both human and mouse tissues with a tissue specific variability of the isoform ratio . spastin is an abundant protein in neural tissues and immunolabeling experiments have shown that spastin is expressed in neurons but not in glial cells . these data indicate that axonal degeneration linked to spastin mutations is caused by a primary defect of neurons . protein and transcript analyses of patients carrying either nonsense or frameshift spastin mutations revealed neither truncated protein nor mutated transcripts , providing evidence that these mutations are responsible for a loss of spastin function . identifying agents able to induce the expression of the non mutated spastin allele should represent an attractive therapeutic strategy in this disease .

The hereditary spastic paraplegia gene , spastin , regulates microtubule stability to modulate synaptic structure and function. (2004 Jul)
The hereditary spastic paraplegia gene , spastin , regulates microtubule stability to modulate synaptic structure and function . background : hereditary spastic paraplegia ( HSP ) is a devastating neurological disease causing spastic weakness of the lower extremities and eventual axonal degeneration . Over 20 genes have been linked to HSP in humans ; however , mutations in one gene , spastin ( SPG4 ) , are the cause of 40 of all cases . spastin is a member of the atpases associated with diverse cellular activities ( AAA ) protein family , and contains a microtubule interacting and organelle transport ( MIT ) domain . previous work in cell culture has proposed a role for spastin in regulating microtubules . results : employing drosophila transgenic methods for overexpression and RNA interference ( RNAi ) , we have investigated the role of spastin in vivo . We show that drosophila spastin ( D spastin ) is enriched in axons and synaptic connections . At neuromuscular junctions ( NMJ ) , dspastin RNAi causes morphological undergrowth and reduced synaptic area . moreover , dspastin overexpression reduces synaptic strength , whereas dspastin RNAi elevates synaptic currents . By using antibodies against posttranslationally modified alpha tubulin , we find that dspastin regulates microtubule stability . functional synaptic defects caused by dspastin RNAi and overexpression were pharmacologically alleviated by agents that destabilize and stabilize microtubules , respectively . conclusions : Loss of dspastin in drosophila causes an aberrantly stabilized microtubule cytoskeleton in neurons and …

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 …