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 .

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 .

Recent advances in hereditary spastic paraplegia. (2001 Jul)
recent advances in hereditary spastic paraplegia . The hereditary spastic paraplegias are a group of rare disorders that are characterized by great clinical and genetic heterogeneity . there has been an exponential increase in the number of HSP loci mapped in recent years , with nine out of the 17 loci reported during the past 2 years . eight loci have now been identified for the autosomal dominant form , and seven of these are associated with pure HSP . spastic paraplegia 4 remains the most frequent locus , and is usually associated with a pure phenotype . although the corresponding spastin gene was only recently identified , over 50 mutations have been described to date , which renders molecular diagnosis difficult . Five loci are known for autosomal recessive HSP , and four of these are associated with complex forms , all with different phenotypes . Two genes have been identified : paraplegin and sacsin . finally , three loci have been identified in X linked HSP , two of which are complex forms . The genes that encode L1 and PLP were the first to be identified in HSP disorders . surprisingly , the five genes encode proteins of different families , making understanding and diagnosis of HSP even more difficult . The discovery of new genes should hopefully help to clarify the pathophysiology of these disorders .

Subtle cognitive impairment but no dementia in patients with spastin mutations. (2003 Aug)
subtle cognitive impairment but no dementia in patients with spastin mutations . background : The most frequent form of autosomal dominant hereditary spastic paraparesis is associated with the SPG4 locus , described originally as a pure form of the disease . mutations of the SPG4 gene have been increasingly associated with reports of cognitive impairment . objective : To investigate cognitive function in 10 families with hereditary spastic paraparesis due to mutations in the SPG4 gene , using intrafamilial control subjects . patients AND methods : neuropsychological examinations , including the cambridge cognitive evaluation , were conducted in 29 carriers with identified SPG4 mutations and 29 intrafamilial controls . results : carriers were not demented but had a subclinical cognitive impairment primarily affecting executive functions . The dysfunction was more severe in those carriers older than 50 years , but was correlated with the progression of the disease , not with age . disease progression and cognitive impairment appeared to be more severe in the carriers of missense mutations than in those with truncating mutations . conclusion : asymptomatic cognitive impairment mostly affecting executive functions is present in SPG4 mutation carriers and is more frequent in those with missense mutations .

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 .

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 .

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

Spg20 is mutated in troyer syndrome , an hereditary spastic paraplegia. (2002 Jul)
spg20 is mutated in troyer syndrome , an hereditary spastic paraplegia . troyer syndrome ( TRS ) is an autosomal recessive complicated hereditary spastic paraplegia ( HSP ) that occurs with high frequency in the Old order amish . We report mapping of the TRS locus to chromosome 13q12 . 3 and identify a frameshift mutation in spg20 , encoding spartin . comparative sequence analysis indicates that spartin shares similarity with molecules involved in endosomal trafficking and with spastin , a molecule implicated in microtubule interaction that is commonly mutated in HSP .

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 .

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 .

Three novel spastin ( SPG4 ) mutations in families with autosomal dominant hereditary spastic paraplegia. (2002 Aug)
three novel spastin ( SPG4 ) mutations in families with autosomal dominant hereditary spastic paraplegia . hereditary spastic paraplegia ( HSP ) is a clinically and genetically heterogeneous condition , characterised principally by progressive spasticity of the lower limbs . forty percent of autosomal dominant ( AD ) pedigrees show linkage to the SPG4 locus on chromosome 2 , which encodes spastin , an atpase associated with diverse cellular activities ( AAA ) protein . We have performed a clinical and genetic study of three AD HSP families linked to SPG4 . sequencing revealed three novel causative mutations . Two of the mutations were located in exon 5 ( a 1 base pair ( bp ) insertion and a 5 bp deletion ) , resulting in frameshift and premature termination of translation , with the predicted protein lacking the entire AAA functional domain . The 5 bp deletion was associated with a later onset and mild cerebellar features . The third mutation was a 3 bp deletion in exon 9 , resulting in the loss of a highly conserved phenylalanine residue within the AAA cassette and an apparently milder phenotype . This is the first example of a deletion of an amino acid in spastin .

Motor system abnormalities in hereditary spastic paraparesis type 4 ( SPG4 ) depend on the type of mutation in the … (2003 Jul)
motor system abnormalities in hereditary spastic paraparesis type 4 ( SPG4 ) depend on the type of mutation in the spastin gene . background : hereditary spastic paraparesis ( HSP ) denotes a group of inherited neurological disorders with progressive lower limb spasticity as their clinical hallmark ; a large proportion of autosomal dominant HSP belongs to HSP type 4 , which has been linked to the SPG4 locus on chromosome 2 . A variety of mutations have been identified within the SPG4 gene product , spastin . objective : correlation of genotype and electrophysiological phenotype . material : Two large families with HSP linked to the SPG4 locus with a very similar disease with respect to age of onset , progression , and severity of symptoms . methods : mutation analysis was performed by PCR from genomic DNA and cDNA , and direct sequencing . The motor system was evaluated using transcranial magnetic stimulation . results : patients differ in several categories depending on the type of mutation present . conclusions : For the first time in hereditary spastic paraparesis , a phenotypic correlate of a given genetic change in the spastin gene has been shown .

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 …

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 .

Infantile onset of hereditary spastic paraplegia poorly predicts the genotype. (2007 Jun)
infantile onset of hereditary spastic paraplegia poorly predicts the genotype . Age of symptom onset of hereditary spastic paraplegia varies from infancy to the eighth decade . infantile onset of hereditary spastic paraplegia without a positive family history may cause difficulties in reaching the correct diagnosis and misdiagnosis as a diplegic form of cerebral palsy is particularly common . infantile onset of hereditary spastic paraplegia caused by mutations in the spastin gene ( spast ) is very rare and previously was mostly associated with codominant mutations in this gene . We present a kindred with infantile onset of spastic paraplegia in three successive generations caused by confirmed de novo novel mutation 1537g A ( g471d ) in spast . several family members were previously diagnosed as having cerebral palsy . infantile onset of hereditary spastic paraplegia may be caused by mutations in multiple genes , and this phenotype does not reliably predict the genotype . pediatric neurologists need to be aware of relatively frequent de novo mutations in hereditary spastic paraplegia genes and a possibility that this condition presents in infancy without a positive family history .

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 .

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 of a novel mutation in the spastin gene ( SPG4 ) in an italian family with hereditary spastic paresis. (2006 Nov)
identification of a novel mutation in the spastin gene ( SPG4 ) in an italian family with hereditary spastic paresis . hereditary spastic paraparesis ( HSP ) includes a heterogeneous group of neurodegenerative diseases characterised by progressive spasticity and hyper reflexia of the lower limbs . autosomal dominant HSP type 4 is the most common clinical form , accounting for about 40 50 of autosomal dominant HSP families . This form is due to mutation of the gene encoding spastin ( SPG4 ) , an ATP ase associated with a variety of cellular function ( AAA ) . Here we describe a novel missense mutation ( 1297t C ; 391L P ) in exon 8 of SPG4 gene , identified in 2 members ( mother and son ) of an italian family with autosomal dominant HSP , clinically pure in the mother and complicated in the son . The mutation lies in a highly conserved AAA box domain between amino acids 342 and 599 in spastin sequence . In both patients , this novel mutation was associated with the absence of relatively common clinical characteristics , such as vibratory sensory deficit and loss of sphincter control , and partial temporal epilepsy , particularly in the son , with infantile onset , secondarily generalised and moderately severe neuropsychiatric symptoms .

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 …

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 .