Hereditary spastic paraplegia. (2002 Nov)
hereditary spastic paraplegia . The hereditary spastic paraplegias are a large group of clinically similar disorders . seventeen different HSP loci have been discovered thus far . different genetic forms of uncomplicated HSP are clinically very similar . except for the average age at which symptoms appear , different genetic types of uncomplicated HSP cannot be distinguished reliably by clinical parameters alone . For most subjects , HSP is a diagnosis of exclusion . The differential diagnosis includes treatable disorders as well as those for which the prognosis is quite different from HSP . Even with the emerging availability of laboratory testing for HSP gene mutations , it is still essential that alternative disorders be excluded by careful history , examination , laboratory studies , neuroimaging , and neurophysiologic evaluation . uncomplicated HSP is due to axonal degeneration at the ends of the longest motor ( corticospinal tract ) and sensory ( dorsal column fibers ) in the spinal cord . The observation that some forms begin in childhood and are essentially nonprogressive while other forms begin in adulthood and are slowly progressive raises the possibility that some forms of HSP ( e . g . ; those associated with licam gene mutations and possibly those due to spg3a mutations ) are neurodevelopmental disorders ; and other forms are truly neurodegenerative disorders . The mechanisms by which spastin , atlastin , and paraplegin mutations cause axonal degeneration that results in clinically similar forms of HSP are not known . nonetheless …

Autosomal dominant hereditary spastic paraplegia : report of a large italian family with r581x spastin mutation. (2007 Aug)
autosomal dominant hereditary spastic paraplegia : report of a large italian family with r581x spastin mutation . We describe a large kindred with a typical pure form of autosomal dominant hereditary spastic paraplegia ( adhsp ) . On the basis of maximum LOD score of 1 . 94 at theta ( max ) 0 with marker d2s367 , we obtained suggestive evidence for linkage of adhsp to SPG4 locus . denaturing high performance liquid chromatography ( dhplc ) and direct sequence analysis allowed us to identify a nonsense mutation ( 1741 C T ) in exon 17 of the spastin gene . This transition , carried by all the affected family members and two apparently healthy individuals , lead to truncation of the last 36 amino acids in the C terminus of the protein . these results confirm the existence of mutation in the SPG4 gene with a reduced penetrance , indicating that other genetic or environmental factors are required to trigger full blown disease .

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 …

Hereditary spastic paraparesis : disrupted intracellular transport associated with spastin mutation. (2003 Dec)
hereditary spastic paraparesis : disrupted intracellular transport associated with spastin mutation . The commonest cause of hereditary spastic paraplegia ( HSP ) is mutation in the spastin gene . Both the normal function of spastin in the central nervous system and the mechanism by which mutation in spastin causes axonal degeneration are unknown . One hypothesis is that mutant spastin disrupts microtubule dynamics , causing an impairment of organelle transport on the microtubule network , which leads to degeneration in the distal parts of long axons . To study this neuronal and non neuronal cells were transfected with either wild type or mutant spastin proteins . We demonstrated evidence of a transient interaction of wild type spastin with microtubules , with resulting disassembly of microtubules , supporting a role for wild type spastin as a microtubule severing protein . mutant spastin demonstrated an abnormal interaction with microtubules , colocalizing with but no longer severing microtubules . The abnormal interaction of mutant spastin with microtubules was demonstrated to be associated with an abnormal perinuclear clustering of mitochondria and peroxisomes , suggestive of an impairment of kinesin mediated intracellular transport . Our findings indicate that an abnormal interaction of mutant spastin with microtubules , which disrupts organelle transport on the microtubule cytoskeleton , is likely to be the primary disease mechanism in HSP caused by missense mutations in the spastin gene .

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 .

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 .

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 .

Spastin gene mutations in bulgarian patients with hereditary spastic paraplegia. (2006 Nov)
spastin gene mutations in bulgarian patients with hereditary spastic paraplegia . hereditary spastic paraplegia ( HSP ) is an extremely heterogeneous group of neurodegenerative disorders affecting the longest axons in the central nervous system . The most common genetic form accounting for about 40 of the autosomal dominant HSP ( adhsp ) cases is spastin gene , SPG4 . We performed mutation screening of the spastin gene on 36 unrelated HSP patients from three different ethnic groups ( bulgarian , turks and gypsies ) and found four new mutations and one already reported . The phenotype genotype correlations in bulgarian SPG4 patients showed a great difference in the age at disease onset between patients with missense mutations and those harboring deletions and splice site mutations . Our study is the first to present corroborative clinical data in favor of the general hypothesis that the clinical course of the disease is related to the type of the spastin mutation . The clinical and genealogical findings in bulgarian SPG4 patients suggest that a positive family history for inheritance as an autosomal dominant trait is a strong indication for spastin mutation screening .

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 ) …

The identification of a conserved domain in both spartin and spastin , mutated in hereditary spastic paraplegia. (2003 Apr)
The identification of a conserved domain in both spartin and spastin , mutated in hereditary spastic paraplegia . multiple sequence alignment has revealed the presence of a sequence domain of approximately 80 amino acids in two molecules , spartin and spastin , mutated in hereditary spastic paraplegia . The domain , which corresponds to a slightly extended version of the recently described ESP domain of unknown function , was also identified in VPS4 , SKD1 , rpk118 , and snx15 , all of which have a well established and consistent role in endosomal trafficking . recent functional information indicates that spastin is likely to be involved in microtubule interaction . With this new information relating to its likely function , we propose the more descriptive name MIT ( contained within microtubule interacting and trafficking molecules ) for the domain and predict endosomal trafficking as the principal functionality of all molecules in which it is present .

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 .

Early onset autosomal dominant spastic paraplegia caused by novel mutations in spg3a. (2005 Jan)
early onset autosomal dominant spastic paraplegia caused by novel mutations in spg3a . hereditary spastic paraplegia ( HSP ) is a group of neurodegenerative disorders mainly characterized by progressive spasticity of the lower limbs . The major features of HSP are a marked phenotypic variability both among and within families and an extended genetic heterogeneity . More than 20 HSP loci and 10 spastic paraplegia genes ( SPG ) have been identified to date , including the genes responsible for the two most frequent forms of autosomal dominant spastic paraplegia ( AD HSP ) , encoding spastin ( SPG4 ) and atlastin ( spg3a ) , respectively . To date , only eight mutations have been described in the atlastin gene , which was reported to account for about 10 of all AD HSP families . We investigated 15 german and french AD HSP families , including the 3 large pedigrees that allowed the mapping and subsequent refinement of the spg3a locus . three novel mutations were found in exons 4 , 9 , and 12 of the atlastin gene and the common r239c mutation located in exon 7 was confirmed in a 7th family of european origin . overall , the comparison of the clinical data for all spg3a HSP families reported to date failed to reveal any genotype / phenotype correlation as demonstrated for other forms of AD HSP . however , it confirmed the early onset of this form of HSP , which was observed in almost …

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 …

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 …

Zfyve27 ( spg33 ) , a novel spastin binding protein , is mutated in hereditary spastic paraplegia. (2006 Jul)
zfyve27 ( spg33 ) , a novel spastin binding protein , is mutated in hereditary spastic paraplegia . spastin , the most commonly mutated protein in the autosomal dominant form of hereditary spastic paraplegia ( AD HSP ) has been suggested to be involved in vesicular cargo trafficking ; however , a comprehensive function of spastin has not yet been elucidated . To characterize the molecular function of spastin , we used the yeast two hybrid approach to identify new interacting partners of spastin . Here , we report zfyve27 , a novel member of the FYVE finger family of proteins , as a specific spastin binding protein , and we validate the interaction by both in vivo coimmunoprecipitation and colocalization experiments in mammalian cells . More importantly , we report a german family with AD HSP in which zfyve27 ( spg33 ) is mutated ; furthermore , we demonstrate that the mutated zfyve27 protein shows an aberrant intracellular pattern in its tubular structure and that its interaction with spastin is severely affected . We postulate that this specific mutation in zfyve27 affects neuronal intracellular trafficking in the corticospinal tract , which is consistent with the pathology of HSP .

From gene to disease ; spastin and hereditary spastic paraparesis hereditary spastic paraparesis ( HSP ) belongs to a group … (2004 Feb)
From gene to disease ; spastin and hereditary spastic paraparesis hereditary spastic paraparesis ( HSP ) belongs to a group of genetically and clinically heterogeneous disorders characterised by progressive spasticity of the legs and hyperreflexia . A further clinical distinction is drawn between pure and complicated HSP depending on the presence of other neurological and non neurological signs . HSP may be inherited either as autosomal dominant , recessive , or X linked . twenty two loci have been identified and additional ones are envisaged . In autosomal dominant HSP , 11 loci ( five genes ) have been identified , the most prevalent of which is linked to chromosome 2p , coding for spastin , an atpase belonging to the AAA family ( acronym of atpase associated with diverse cellular activities ) . spastin is a nuclear protein , present in neurons , but not in glial cells , and seems to be involved in microtubule dynamics . nonsense and frameshift mutations result in a reduced amount of spastin .

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 …

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 .

The C. (2007 Jun)
The C . elegans homologue of the spastic paraplegia protein , spastin , disassembles microtubules . mutations in human spastin ( SPG4 ) cause an autosomal dominant form of hereditary spastic paraplegia . sequence analysis revealed that spastin contains the AAA ( atpases associated with diverse cellular activities ) domain in the C terminal region . recently , it was reported that spastin interacts dynamically with microtubules and displays microtubule severing activity . A plausible caenorhabditis elegans homologue of spastin ( SPAS 1 ) has been identified by homology search and phylogenetic analyses . To understand the function of the spastin homologue , we characterized the spas 1 deletion mutant and analyzed spas 1 expression regulation in C . elegans . SPAS 1 was localized with cytoskeletons at the perinuclear region . We found that microtubules were intensely stained at the centrosomal region in the deletion mutant . furthermore , overexpression of SPAS 1 caused disassembly of microtubule network in cultured cells , while atpase deficient SPAS 1 did not . these results indicate that C . elegans SPAS 1 plays an important role in microtubule dynamics . We also found that two kinds of products were generated from spas 1 by alternative splicing in a developmental stage dependent manner .

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 …