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 .

High frequency of partial spast deletions in autosomal dominant hereditary spastic paraplegia. (2006 Dec)
High frequency of partial spast deletions in autosomal dominant hereditary spastic paraplegia . background : hereditary spastic paraplegia ( HSP ) is a genetically heterogeneous neurodegenerative disease . The most frequent cause of autosomal dominant HSP is mutation of spast ( SPG4 locus ) , but additional pedigrees remain mutation negative by conventional screening despite linkage to SPG4 . objective : To determine the frequency of genomic copy number aberrations of spast in autosomal dominant HSP . methods : We developed and validated a multiplex ligation dependent probe amplification assay targeting spast and spg3a , another gene frequently involved in autosomal dominant HSP . In a multicenter study we subsequently investigated 65 index patients with autosomal dominant HSP , all of whom had previously been screened negative for spast mutations . independent secondary samples , additional family members , and cDNA were analyzed to confirm positive findings . results : aberrant MLPA profiles were identified in 12 cases ( 18 ) . They exclusively affect spast , represent deletions , segregate with the disease , and are largely pedigree specific . internal spast deletions entail expression of correspondingly shortened transcripts , which vary in stability . Age at onset in spast deletion carriers does not differ from that associated with other spast mutations . conclusions : partial spast deletions , but not spast amplifications and spg3a copy number aberrations , represent an underestimated cause of autosomal dominant hereditary spastic paraplegia . partial spast deletions are likely to act via haploinsufficiency …

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 .

Novel spastin ( SPG4 ) mutations in italian patients with hereditary spastic paraplegia. (2006 Jun)
novel spastin ( SPG4 ) mutations in italian patients with hereditary spastic paraplegia . spastic paraplegia type 4 is caused by mutations in the gene that encodes spastin ( SPG4 ) , a member of the AAA protein family . A cohort of 34 unrelated italian patients with pure spastic paraplegia , of which 18 displayed autosomal dominant inheritance and 16 were apparently sporadic , were screened for mutations in the SPG4 gene by denaturing high performance liquid chromatography . We identified a previously reported mutation in a sporadic patient with pure hereditary spastic paraplegia . We also identified eight unrelated patients with pure autosomal dominant hereditary spastic paraplegia carrying five novel mutations in the SPG4 gene ( one missense mutation , c . 1304 C T ; one nonsense mutation , c . 807C A ; two frameshift mutations , c . 1281dupt , c . 1514 1515insata ; and one splicing mutation , c . 1322 2A C ) . The frequency for SPG4 mutations detected in autosomal dominant hereditary spastic paraplegia was 44 . 4 . This study contributes to expand the spectrum of SPG4 mutations in italian population .

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 .

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 .

Four mutations of the spastin gene in japanese families with spastic paraplegia. (2006 Aug)
Four mutations of the spastin gene in japanese families with spastic paraplegia . hereditary spastic paraplegia ( HSP ) is a group of genetically heterogeneous neurodegenerative disorders characterized by slowly progressive spasticity and weakness of the lower limbs . HSP is caused by failure of development or selective degeneration of the corticospinal tracts , which contain the longest axons in humans . The most common form of HSP is caused by mutations of the spastin gene ( spast ) , located on chromosome 2p21 p22 , which encodes spastin , one of the atpases associated with diverse cellular activities ( AAA ) . In this study , we detected four causative mutations of spast among 14 unrelated patients with spastic paraplegia . Two missense mutations ( 1447a G , 1207c G ) and two deletion mutations ( 1465delt , 1475 1476delaa ) were located in the AAA cassette region . three of these four mutations were novel . previous reports and our results suggest that the frequency of spast mutations is higher among japanese patients with autosomal dominant HSP , although spast mutations are also observed in patients with sporadic spastic paraplegia .

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 .

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 .

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 .

A de novo spast mutation leading to somatic mosaicism is associated with a later age at onset in HSP. (2007 Jul)
A de novo spast mutation leading to somatic mosaicism is associated with a later age at onset in HSP . SPG4 / spast , the gene encoding spastin , is responsible for the most frequent form of autosomal dominant hereditary spastic paraplegia ( HSP ) . SPG4 HSP is a heterogeneous disorder characterized by both interfamilial and intrafamilial variation , especially regarding the severity and the age at onset . In this study , we investigated the origin of the mutation and the factors involved in intra familial heterogeneity in a family with a SPG4 mutation . We demonstrated that the mutation occurred de novo and show evidence of somatic mosaicism in the grandfather , who was the only affected member of six siblings . His disease began at age 55 , much later than in his daughter , who had onset at age 18 , and his grandson , in whom onset was at age 5 . these observations indicate that de novo mutations can occur in SPG4 , and that somatic mosaicism might account for intra familial variation in SPG4 linked HSP .

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 .

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 .

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 .

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 ) …

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 .

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 .

Phenotype of AD HSP due to mutations in the spast gene : comparison with AD HSP without mutations. (2001 Jan)
phenotype of AD HSP due to mutations in the spast gene : comparison with AD HSP without mutations . background : Pure autosomal dominant hereditary spastic paraparesis ( AD HSP ) is clinically and genetically heterogeneous . there are at least seven genetic loci with varying ages at onset and disability . The spast gene at the SPG4 locus on chromosome 2p is the major disease gene for AD HSP . objectives : To investigate whether there are distinct clinical features among families with AD HSP due to spast mutations compared with families excluded from SPG4 . methods : nineteen families with pure AD HSP were identified , and the clinical features of family members were compared using a standard protocol . With use of genetic studies , the families were divided into two groups for comparison : those with mutations in spast , the mutation positive group , and those excluded from SPG4 on the basis of linkage studies , the SPG4 excluded group . results : twenty nine individuals from four families had mutations in spast , whereas 22 individuals from three families comprised the SPG4 excluded group ; in 11 families , the pattern of linkage was unknown . In the one remaining family , no mutations were found despite strong linkage to SPG4 . different mutations were identified in the four spast pedigrees , but the clinical picture was similar in each . comparison of the mutation positive group with the SPG4 excluded group revealed an …

Possible anticipation in hereditary spastic paraplegia type 4 ( SPG4 ). (2007 Jun)
possible anticipation in hereditary spastic paraplegia type 4 ( SPG4 ) . objective : We report a multigenerational family with uncomplicated hereditary spastic paraplegia type 4 and apparent anticipation . genetic analysis of the proband revealed a frame shift mutation ( 5 base pair deletion ) in exon 9 of the SPG4 gene encoding the spastin protein . We hypothesized that this deletion mutation may be dynamic and variability in the size of the deletion could account for the anticipation . methods : clinical and genetic analysis of this family and the deletion mutation . results : In this family , the age of onset , which ranges from 3 to 50 years shows an average decrease in the age of onset of 21 . 8 years per transmission over three generations . genetic analysis of multiple family members indicates that all affected members carry the same c . 1340 1344deltataa mutation and that it is not dynamic . conclusion : In this family , other molecular mechanisms may contribute to development of anticipation .

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 …