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 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 .

Clinical and pathologic findings in hereditary spastic paraparesis with spastin mutation. (2000 Aug)
clinical and pathologic findings in hereditary spastic paraparesis with spastin mutation . objective : To describe a family with chromosome 2p linked hereditary spastic paraparesis ( HSP ) associated with dementia and illustrate the cerebral pathology associated with this disorder . background : HSP comprises a heterogeneous group of inherited disorders in which the main clinical feature is severe , progressive lower limb spasticity . nongenetic classification relies on characteristics such as mode of inheritance , age at onset , and the presence or absence of additional neurologic features . several loci have been identified for autosomal dominant pure HSP . The most common form , which links to chromosome 2p ( SPG4 ) , has recently been shown to be due to mutations in spastin , the gene encoding a novel AAA containing protein . results : The authors report four generations of a british family with autosomal dominant HSP in whom haplotype analysis indicates linkage to chromosome 2p . In addition , a missense mutation has been identified in exon 10 of the spastin gene ( a1395g ) . dementia was documented clinically in one member of the family , two other affected family members were reported to have had late onset memory loss , and a younger affected individual showed evidence of memory disturbance and learning difficulties . autopsy of the demented patient confirmed changes in the spinal cord typical of HSP and also demonstrated specific cortical pathology . there was neuronal depletion and tau immunoreactive neurofibrillary …

Mutation analysis of the spastin gene ( SPG4 ) in patients with hereditary spastic paraparesis. (2000 Oct)
mutation analysis of the spastin gene ( SPG4 ) in patients with hereditary spastic paraparesis . background : hereditary spastic paraparesis is a genetically heterogeneous condition . recently , mutations in the spastin gene were reported in families linked to the common SPG4 locus on chromosome 2p21 22 . objectives : To study a population of patients with hereditary spastic paraparesis for mutations in the spastin gene ( SPG4 ) on chromosome 2p21 22 . methods : DNA from 32 patients ( 12 from families known to be linked to SPG4 ) was analysed for mutations in the spastin gene by single strand conformational polymorphism analysis and sequencing . All patients were also examined clinically . results : thirteen SPG4 mutations were identified , 11 of which are novel . these mutations include missense , nonsense , frameshift , and splice site mutations , the majority of which affect the AAA cassette . We also describe a nucleotide substitution outside this conserved region which appears to behave as a recessive mutation . conclusions : recurrent mutations in the spastin gene are uncommon . This reduces the ease of mutation detection as a part of the diagnostic work up of patients with hereditary spastic paraparesis . Our findings have important implications for the presumed function of spastin and schemes for mutation detection in HSP patients .

Hereditary spastic paraplegia caused by mutations in the SPG4 gene. (2001 Jan)
hereditary spastic paraplegia caused by mutations in the SPG4 gene . autosomal dominant hereditary spastic paraplegia ( AD HSP ) is a genetically heterogeneous neurodegenerative disorder characterised by progressive spasticity of the lower limbs . The SPG4 locus at 2p21 p22 accounts for 40 50 of all AD HSP families . The SPG4 gene was recently identified . It is ubiquitously expressed in adult and foetal tissues and encodes spastin , an atpase of the AAA family . We have now identified four novel SPG4 mutations in german AD HSP families , including one large family for which anticipation had been proposed . mutations include one frame shift and one missense mutation , both affecting the walker motif B . Two further mutations affect two donor splice sites in introns 12 and 16 , respectively . RT PCR analysis of both donor splice site mutations revealed exon skipping and reduced stability of aberrantly spliced SPG4 mRNA . All mutations are predicted to cause loss of functional protein . In conclusion , we confirm in german families that SPG4 mutations cause AD HSP . Our data suggest that SPG4 mutations exert their dominant effect not by gain of function but by haploinsufficiency . If a threshold level of spastin were critical for axonal preservation , such threshold dosage effects might explain the variable expressivity and incomplete penetrance of SPG4 linked AD HSP .

Novel mutations in spastin gene and absence of correlation with age at onset of symptoms. (2000 Nov)
novel mutations in spastin gene and absence of correlation with age at onset of symptoms . autosomal dominant hereditary spastic paraplegia is genetically heterogeneous , with at least five loci identified by linkage analysis . recently , mutations in spastin were identified in SPG4 , the most common locus for dominant hereditary spastic paraplegia that was previously mapped to chromosome 2p22 . We identified five novel mutations in the spastin gene in five families with SPG4 mutations from north america and tunisia and showed the absence of correlation between the predicted mutant spastin protein and age at onset of symptoms .

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 …

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 large japanese SPG4 family with a novel insertion mutation of the SPG4 gene : a clinical and genetic study. (2001 Mar)
A large japanese SPG4 family with a novel insertion mutation of the SPG4 gene : a clinical and genetic study . We studied a large japanese family with autosomal dominant pure hereditary spastic paraplegia ( adphsp ) clinically and genetically . To date , seven loci causing adphsp have been mapped to chromosomes 14q , 2p , 15q , 8q , 12q , 2q , and 19q . among these loci , the SPG4 locus on chromosome 2p21 p22 has been shown to account for approximately 40 of all autosomal dominant hereditary spastic paraplegia ( adhsp ) families . Very recently , hazan et al . identified the SPG4 gene encoding a new member of the AAA ( atpases associated with diverse cellular activities ) protein family , named spastin . We found a novel insertion mutation ( nt1272 1273insa ) in exon 8 of the SPG4 gene in the present family . Our study is the first to confirm the causative mutation of the SPG4 gene in japanese . clinically , it is noteworthy that the disease progression in the patients of this family was slow in spite of the late onset , and more than half of the patients showed severe constipation in addition to pure spastic paraplegia .

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 .

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 .

Mutations in a newly identified gtpase gene cause autosomal dominant hereditary spastic paraplegia. (2001 Nov)
mutations in a newly identified gtpase gene cause autosomal dominant hereditary spastic paraplegia . The hereditary spastic paraplegias ( HSPs ; strümpell lorrain syndrome , MIM number 18260 ) are a diverse class of disorders characterized by insidiously progressive lower extremity spastic weakness ( reviewed in refs . 1 3 ) . eight autosomal dominant HSP ( adhsp ) loci have been identified , the most frequent of which is that linked to the SPG4 locus on chromosome 2p22 ( found in approximately 42 ) , followed by that linked to the spg3a locus on chromosome 14q11 q21 ( in approximately 9 ) . Only SPG4 has been identified as a causative gene in adhsp . Its protein ( spastin ) is predicted to participate in the assembly or function of nuclear protein complexes . Here we report the identification of mutations in a newly identified gtpase gene , spg3a , in adhsp affected individuals .

A large family with hereditary spastic paraparesis due to a frame shift mutation of the spastin ( SPG4 ) gene … (2001 Nov)
A large family with hereditary spastic paraparesis due to a frame shift mutation of the spastin ( SPG4 ) gene : association with multiple sclerosis in two affected siblings and epilepsy in other affected family members . hereditary spastic paraparesis ( HSP ) is a clinically and genetically heterogeneous neurodegenerative disorder characterised by progressive lower limb spasticity and weakness . Some forms have been associated with white matter lesions and complex phenotypes . This study was prompted by the diagnosis of multiple sclerosis ( MS ) in two sisters from a large pedigree with hereditary spastic paraparesis . twelve affected members of the extended family were examined ( MRI and EEG were carried out and evoked potentials measured in five ) , and historical information was obtained from six affected deceased persons . The inherited disease phenotype was confirmed as autosomal dominant hereditary spastic paraparesis associated with epilepsy in four affected persons . None of the extended family had evidence of MS . genetic analysis of the family has shown linkage to chromosome 2p and sequencing of the spastin gene has identified a 1406delt frameshift mutation in exon 10 . This kindred demonstrates the clinical heterogeneity of HSP associated with spastin mutations . The possible relevance of the concurrence of HSP and MS in the sib pair is discussed .

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 …

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 …

Missense and splice site mutations in SPG4 suggest loss of function in dominant spastic paraplegia. (2002 May)
missense and splice site mutations in SPG4 suggest loss of function in dominant spastic paraplegia . We studied nine italian families with a pure form of autosomal dominant spastic paraplegia ( adhsp ) to assess the frequency of mutations in the SPG4 gene . We observed marked intrafamilial variability in both age at onset and clinical severity , ranging from severe congenital presentation to mild involvement after age 55 years to healthy carriers of the mutation after age 70 . Four of nine probands harboured SPG4 mutations , We identified three new SPG4 mutations , all predicting a loss of func tion with apparently important consequences for spastin function . RT PCR studies predict loss of function as a possible mechanism leading to spastin related HSP . The current study expands the spectrum of allelic variants in SPG4 , confirming their pathological significance in pure AD HSP and suggesting implications for the presumed function of spastin .

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 .

Mutation analysis of the spastin gene ( SPG4 ) in patients in germany with autosomal dominant hereditary spastic paraplegia. (2002 Jul)
mutation analysis of the spastin gene ( SPG4 ) in patients in germany with autosomal dominant hereditary spastic paraplegia . hereditary spastic paraplegias ( HSP ) comprise a genetically and clinically heterogeneous group of neurodegenerative disorders characterized by progressive spasticity and hyperreflexia of the lower limbs . autosomal dominant hereditary spastic paraplegia 4 linked to chromosome 2p ( SPG4 ) is the most common form of autosomal dominant hereditary spastic paraplegia . It is caused by mutations in the SPG4 gene encoding spastin , a member of the AAA protein family of atpases . In this study the spastin gene of HSP patients from 161 apparently unrelated families in germany was analyzed . The authors identified mutations in 27 out of the 161 HSP families ; 23 of these mutations have not been described before and only one mutation was found in two families . among the detected mutations are 14 frameshift , four nonsense , and four missense mutations , one large deletion spanning several exons , as well as four mutations that affect splicing . Most of the novel mutations are located in the conserved AAA cassette encoding region of the spastin gene . The relative frequency of spastin gene mutations in an unselected group of german HSP patients is approximately 17 . frameshift mutations account for the majority of SPG4 mutations in this population . The proportion of splice mutations is considerably lower than reported elsewhere .

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 .