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 …

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 …

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 .

Isoform specific increase of spastin stability by N terminal missense variants including intragenic modifiers of SPG4 hereditary spastic paraplegia. (2007 Nov)
isoform specific increase of spastin stability by N terminal missense variants including intragenic modifiers of SPG4 hereditary spastic paraplegia . hereditary spastic paraplegia ( HSP ) is a neurodegenerative disorder selectively affecting axons of spinal cord motoneurons . classical mutations in the most frequent HSP gene spast ( spastin protein ) act through haploinsufficiency by abolishing the activity of a C terminal atpase domain or by interfering with expression from the affected allele . N terminal missense variants have been suggested to represent rare polymorphisms , to cause unusually mild phenotypes , and to aggravate the effect of a classical mutation . We confirm these associations for p . S44L but do not detect two other variants ( p . E43Q ; p . P45Q ) in HSP patients and controls . We show that neither of several disease mechanisms associated with classical spast mutations applies to the N terminal variants . instead , all three alterations enhance the stability of one of two alternative spastin isoforms . their phenotypic effect may thus not be mediated by haploinsufficiency but by increasing isoform competition for interacting proteins , substrates or oligomerization partners .

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 .

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 .

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 .

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 .

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 .

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 …

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 .

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 .

Late onset sporadic case of SPG4 ( 1726t C mutant ) accompanied by polyneuropathy with diabetes mellitus We report a … (2007 Jul)
Late onset sporadic case of SPG4 ( 1726t C mutant ) accompanied by polyneuropathy with diabetes mellitus We report a 73 year old man with SPG4 . From aged 53 he had diabetes mellitus and at 64 he developed spastic paraparesis and urinary disturbance . At 70 years , he began to walk with a stick and noted abnormal sensations in bilateral feet . there was no relevant family history . moderate spasticity with mild muscle weakness , markedly brisk tendon reflex with pathological reflexes , and mildly abnormal sensation in bilateral lower extremities , and markedly spastic gait were found . MRI showed mild C4 C7 spondylosis and L4 5 disk protrusion but no abnormality of the corpus callosum . nerve conduction and needle EMG studies revealed various abnormalities in distal ( MCV , SCV ) and proximal ( F wave ) peripheral nerves , but no neurogenic changes in limb muscles . We found a missense spastin gene mutation ( 1726t C ) that causes leu534pro substitution . This spastin gene mutation was novel in japanese , but has been reported in an italian family . The present case s neuropathy might be related to diabetes mellitus , because SPG4 is generally not associated with neuropathy . however , recent studies suggest that SPG4 patients sometimes have subclinical neuropathy , and longer disease duration may contribute to peripheral neuropathy . further study of clinical characteristics associated with the leu534pro mutation will be necessary .

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 .

Spastin mutations in sporadic adult onset upper motor neuron syndromes. (2005 Dec)
spastin mutations in sporadic adult onset upper motor neuron syndromes . mutation of the spastin gene is the single most common cause of pure hereditary spastic paraparesis . In patients with an unexplained sporadic upper motor neuron ( UMN ) syndrome , clinical distinction between primary lateral sclerosis and sporadic hereditary spastic paraparesis may be problematic . To investigate whether spastin mutations are present in patients with primary lateral sclerosis and sporadic hereditary spastic paraparesis , we screened the spastin gene in 99 dutch patients with an unexplained , apparently sporadic , adult onset UMN syndrome . We found 6 mutations , of which 4 were novel , in the subgroup of 47 patients with UMN symptoms restricted to the legs ( 13 ) . another novel spastin mutation was found in a patient with a rapidly progressive spinal and bulbar UMN syndrome that progressed to amyotrophic lateral sclerosis . In the patients with arm or bulbar UMN symptoms and slow progression , no spastin mutations were found . Our study shows that spastin mutations are a frequent cause of apparently sporadic spastic paraparesis but not of primary lateral sclerosis .

Seven novel mutations and four exon deletions in a collection of norwegian patients with SPG4 hereditary spastic paraplegia. (2007 Jun)
seven novel mutations and four exon deletions in a collection of norwegian patients with SPG4 hereditary spastic paraplegia . To establish the phenotypic variation and frequency of spast mutations or deletions in norwegian patients with hereditary spastic paraplegia ( HSP ) , we examined 59 unrelated patients with HSP and screened for DNA point mutations and microdeletions in SPG4 . forty one had a familial history , 35 had a clear dominant inheritance , six had other affected sibs and 18 were sporadic . We found 12 mutations in SPG4 , seven of them novel , and four different heterozygous exon deletions , two of them novel . mutations were found in 16 families showing autosomal dominant ( AD ) inheritance , and in one sporadic case . In two non SPG4 families the S44L polymorphism / modifier was found in both affected and unaffected individuals . This is the first study of norwegian patients with HSP since the 1970s , and the first report on SPG4 in norway . Our results show that SPG4 mutations and deletions are a significant cause of HSP in our population and warrant SPG4 screening in AD families and selected sporadic cases .

Molecular basis of inherited spastic paraplegias. (2001 May)
molecular basis of inherited spastic paraplegias . recently , paraplegin and spastin have been found to be mutated in two autosomal forms of hereditary spastic paraplegia . Both proteins harbour a common atpase domain that expresses a chaperone function . paraplegin is a nuclear encoded mitochondrial metalloprotease , while the exact role and subcellular localisation of spastin are still unclear .

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 .

Novel spastin mutations and their expression analysis in two italian families. (2003 Aug)
novel spastin mutations and their expression analysis in two italian families . mutations in spastin cause the most common form of pure autosomal dominant hereditary spastic paraparesis ( SPG4 ) . Here , we report two italian families affected with SPG4 linked HSP harboring two novel spastin mutations . SSCP / sequencing analysis of the spastin gene showed a single base pair deletion causing a frame shift in one family ( 1442delt ) and a missense mutation ( 1726t C ) resulting in a leucine to proline amino acid change ( l534p ) in the other family . total RNA from the mutant and the wild type spastin allele in muscle biopsies from patients from the two affected families was quantitated . RNA expression was almost absent from the spastin allele harboring the single base pair deletion , while it was nearly normal for the spastin allele harboring the missense mutation . these data suggest that varying spastin RNA levels are found in out of frame and missense spastin mutations and imply different mechanisms involved in the molecular pathology of SPG4 linked HSP .

Atlastin1 mutations are frequent in young onset autosomal dominant spastic paraplegia. (2004 Dec)
atlastin1 mutations are frequent in young onset autosomal dominant spastic paraplegia . background : hereditary spastic paraplegias are disorders that are very heterogeneous , both clinically and genetically . The atlastin1 gene has recently been implicated in spg3a , a form of autosomal dominant pure spastic paraplegia . atlastin1 mutations have been identified in 8 families so far . objectives : To determine the relative frequency , phenotype , and mutation spectrum of spg3a in patients with pure autosomal dominant spastic paraplegia and onset before age 20 years . patients AND methods : We sequenced the atlastin1 gene in a large series of patients ( 31 families ) in which mutations in the spastin gene , corresponding to the frequent SPG4 locus , had previously been excluded . The phenotype was compared with 126 SPG4 patients . results : We identified 12 families ( 39 ) including 34 patients with 9 different missense atlastin1 mutations , 7 of which are newly described . The main clinical characteristic of these spg3a patients was pure spasticity with very young onset of symptoms ( mean age , 4 . 6 / 3 . 9 years ) and slow progression . however , additional signs such as decreased vibration sense and wasting in lower limbs , sphincter disturbances , and scoliosis were found in a minority of patients . In addition , several gene carriers were clinically affected but still asymptomatic ( n 5 ) or had no clinical signs ( n 2 ) …