Clinical characteristics and spastin gene mutation analysis on an autosomal dominant kindred with hereditary spastic paraplegia objective : To investigate … (2007 Apr)
clinical characteristics and spastin gene mutation analysis on an autosomal dominant kindred with hereditary spastic paraplegia objective : To investigate the clinical characteristics and analyze spastin gene mutation on a kindred with hereditary spastic paraplegia ( HSP ) . methods : All family members were studied through clinical examinations . The proband and another two patients in this kindred were subjected to electromyography ( EMG ) examinations . The proband was subjected to thoracic MRI examination too . mutation analysis of spastin gene was screened by polymerase chain reaction combined with DNA sequencing in the proband and his father . results : All patients in the kindred manifested as classical HSP . thoracic MRI revealed atrophies of the spinal cord in the proband . No abnormal spastin gene mutation was detected in these two patients . conclusion : This kindred has typical clinical manifestations of HSP . The pathogenesis has no association with mutation of the exons of spastin gene .

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 ) …

Thin corpus callosum and amyotrophy in spastic paraplegia case report and review of literature. (2006 Sep)
Thin corpus callosum and amyotrophy in spastic paraplegia case report and review of literature . We report the clinical , structural , functional and genetic characterization of a 37 year old caucasian female , presenting as a sporadic case of complicated spastic paraplegia with thin corpus callosum ( CC ) , cognitive impairment , amyotrophy of the hand muscles and a sensorimotor neuropathy and review the literature for spastic paraplegia with thin CC . magnetic resonance imaging ( MRI ) examination revealed a thin CC with fronto parietal cortical atrophy . 18fluordesoxyglucose positron emission tomography ( FDG PET ) showed reduced cortical and thalamic metabolism . By transcranial magnetic stimulation , we delineated a severe impairment of transcallosal inhibition . sequence analysis did not reveal disease causing mutations in the genes slc12a6 ( andermann ) , spastin ( SPG 4 ) , bscl2 ( SPG 17 ) and spartin ( SPG 20 ) . We reviewed the literature for HSP with thin CC and found 113 HSP patients with thin CC previously described ( 35 with linkage to chromosome 15q13 15 ) . Thin CC and peripheral neuropathy often appear together in spastic paraplegia and might be indicative for combined degeneration mechanism of central and peripheral axons .

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 .

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 .

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 .

The hereditary spastic paraplegia protein spastin interacts with the escrt III complex associated endosomal protein chmp1b. (2004 Dec)
The hereditary spastic paraplegia protein spastin interacts with the escrt III complex associated endosomal protein chmp1b . Pure hereditary spastic paraplegia is characterized by length dependent degeneration of the distal ends of long axons . mutations in spastin are the most common cause of the condition . We set out to investigate the function of spastin using a yeast two hybrid approach to identify interacting proteins . using full length spastin as bait , we identified chmp1b , a protein associated with the escrt ( endosomal sorting complex required for transport ) III complex , as a binding partner . several different approaches confirmed the physiological relevance of the interaction in mammalian cells . epitope tagged chmp1b and spastin showed clear cytoplasmic co localization in Cos 7 and PC12 cells . chmp1b and spastin interacted specifically in vitro and in vivo in beta lactamase protein fragment complementation assays , and spastin co immunoprecipitated with chmp1b . The interaction was mediated by a region of spastin lying between residues 80 and 196 and containing a microtubule interacting and trafficking domain . expression of epitope tagged chmp1b in mammalian cells prevented the development of the abnormal microtubule phenotype associated with expression of atpase defective spastin . these data point to a role for spastin in intracellular membrane traffic events and provide further evidence to support the emerging recognition that defects in intracellular membrane traffic are a significant cause of motor neuron pathology .

Spastin and microtubules : functions in health and disease. (2007 Sep)
spastin and microtubules : functions in health and disease . SPG4 , the gene encoding for spastin , a member of the atpases associated with various cellular activities ( AAA ) family , is mutated in around 40 of cases of autosomal dominant hereditary spastic paraplegia ( AD HSP ) . This group of neurodegenerative diseases is characterized by a progressive spasticity and lower limb weakness with degeneration of terminal axons in cortico spinal tracts and dorsal columns . spastin has two main domains , a microtubule interacting and endosomal trafficking ( MIT ) domain at the N terminus and the C terminus AAA domain . early studies suggested that spastin interacts with microtubules similarly to katanin , a member of the same subgroup of AAA . recent evidence confirmed that spastin possesses microtubule severing activity but can also bundle microtubules in vitro . understanding the physiologic and pathologic involvement of these activities and their regulation is critical in the study of HSP .

Large deletion involving the 5 UTR in the spastin gene caused mild phenotype of autosomal dominant hereditary spastic paraplegia. (2005 Feb)
large deletion involving the 5 UTR in the spastin gene caused mild phenotype of autosomal dominant hereditary spastic paraplegia . hereditary spastic paraplegia ( HSP ) due to mutations in the spastin gene ( SPG4 ) located to 2p22 p21 is the most common form of autosomal dominant ( AD ) HSP . We performed PCR based direct sequencing of SPG4 , followed by a linkage analysis and subsequent southern blot analysis in large japanese kindred where 20 of 33 members were evaluated neurologically , and consequently 6 were affected with HSP . clinical evaluation showed that the mean age at disease onset of the patients was older and the disability was less severe than those of previously reported typical patients with SPG4 mutations . direct sequencing of genomic DNA and RT PCR product did not show a SPG4 mutation despite of a strong linkage to the SPG4 locus at 2p . southern blot analysis suggested a deletion involving the 5 UTR of SPG4 . further sequence analysis confirmed a heterozygous 2307 bp deletion spanning from the 5 UTR to intron 1 of SPG4 . The results suggested that transcription of the mutated allele starts from an authentic initiation site , but lacks an authentic translational start site of exon 1 because of a deficient splice donor site and coding region . The abnormal transcripts may result in rapid RNA decay . The novel refractory mutation we identified widens the spectrum of SPG4 mutations . these findings suggest that structural …

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 .

Linking axonal degeneration to microtubule remodeling by spastin mediated microtubule severing. (2005 Feb)
linking axonal degeneration to microtubule remodeling by spastin mediated microtubule severing . mutations in the AAA adenosine triphosphatase ( atpase ) spastin ( SPG4 ) cause an autosomal dominant form of hereditary spastic paraplegia , which is a retrograde axonopathy primarily characterized pathologically by the degeneration of long spinal neurons in the corticospinal tracts and the dorsal columns . using recombinant spastin , we find that six mutant forms of spastin , including three disease associated forms , are severely impaired in atpase activity . In contrast to a mutation designed to prevent adenosine triphosphate ( ATP ) binding , an ATP hydrolysis deficient spastin mutant predicted to remain kinetically trapped on target proteins decorates microtubules in transfected cells . analysis of disease associated missense mutations shows that some more closely resemble the canonical hydrolysis mutant , whereas others resemble the ATP binding mutant . using real time imaging , we show that spastin severs microtubules when added to permeabilized , cytosol depleted cells stably expressing GFP tubulin . using purified components , we also show that spastin interacts directly with microtubules and is sufficient for severing . these studies suggest that defects in microtubule severing are a cause of axonal degeneration in human disease .

Exon deletions of SPG4 are a frequent cause of hereditary spastic paraplegia. (2007 Apr)
Exon deletions of SPG4 are a frequent cause of hereditary spastic paraplegia . background : point mutations in SPG4 , the gene encoding spastin , are a frequent cause of autosomal dominant hereditary spastic paraplegia ( AD HSP ) . however , standard methods for genetic analyses fail to detect exonic microdeletions . methods : 121 mutation negative probands were screened for rearrangements in SPG4 by multiplex ligation dependent probe amplification . results : 24 patients with 16 different heterozygotic exon deletions in SPG4 ( 20 ) were identified , ranging from one exon to the whole coding sequence . comparison with 78 patients with point mutations showed a similar clinical picture but an earlier age at onset . conclusions : Exon deletions in SPG4 are as frequent as point mutations , and SPG4 is responsible for 40 of AD HSP .

Two novel mutations in the spastin gene ( SPG4 ) found by dhplc mutation analysis. (2004 Oct)
Two novel mutations in the spastin gene ( SPG4 ) found by dhplc mutation analysis . The most common form of autosomal dominant hereditary spastic paraplegia is caused by mutations in the gene encoding spastin ( SPG4 ) , a member of the AAA family of atpases . In the current study , we designed a denaturing high performance liquid chromatography based protocol for the analysis of the SPG4 gene . using this method , we detected two novel missense mutations , 1375a G ( r459g ) and 1378c T ( r460c ) , one previously described five bases deletion ( 1215 1219del ) and three polymorphic changes . This study suggests that denaturing high performance liquid chromatography would be a fast and reliable tool in the investigation of the molecular defects in the SPG4 gene .

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 .

Spastin interacts with the centrosomal protein NA14 , and is enriched in the spindle pole , the midbody and the … (2004 Aug)
spastin interacts with the centrosomal protein NA14 , and is enriched in the spindle pole , the midbody and the distal axon . hereditary spastic paraplegia ( HSP ) is characterized by the specific retrograde degeneration of the longest axons in the central nervous system , the corticospinal tracts . The gene most frequently involved in autosomal dominant cases of this disease , SPG4 , encodes spastin , an atpase belonging to the AAA family . AAA proteins are thought to exert their function by the energy dependent rearrangement of protein complexes . The composite function of these proteins is directed by their binding to regulatory factors and adaptor proteins that target their activity into specific pathways in vivo . We previously found that overexpressed spastin interacts dynamically with microtubules and displays microtubule severing activity . Here , we demonstrate that spastin is enriched in cell regions containing dynamic microtubules . during cell division spastin is found in the spindle pole , the central spindle and the midbody , whereas in immortalized motoneurons it is enriched in the distal axon and the branching points . furthermore , spastin interacts with the centrosomal protein NA14 , and co fractionates with gamma tubulin , a centrosomal marker . deletion of the region required for binding to NA14 disrupts spastin interaction with microtubules , suggesting that NA14 may be an important adaptor to target spastin activity at the centrosome . these data strongly argue that spastin plays a role in cytoskeletal rearrangements and …

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 …

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 .

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 .

Characterization of a novel spg3a deletion in a french canadian family. (2007 Jul)
characterization of a novel spg3a deletion in a french canadian family . hereditary spastic paraplegias ( HSPs ) are characterized by progressive lower limb spasticity and weakness . mutations in the spg3a gene , which encodes the large guanosine triphosphatase atlastin , are the second most common cause of autosomal dominant hereditary spastic paraplegia . In a large spg3a screen of 70 hereditary spastic paraplegia subjects , a novel in frame deletion , p . del436n , was identified . characterization of this deletion showed that it affects neither the guanosine triphosphatase activity of atlastin nor interactions between atlastin and spastin . interestingly , immunoblot analysis of lymphoblasts from affected patients demonstrated a significant reduction in atlastin protein levels , supporting a loss of function disease mechanism .

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 .