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 .

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 .

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 .

Recognition of C terminal amino acids in tubulin by pore loops in spastin is important for microtubule severing. (2007 Mar)
recognition of C terminal amino acids in tubulin by pore loops in spastin is important for microtubule severing . spastin , an AAA atpase mutated in the neurodegenerative disease hereditary spastic paraplegia , severs microtubules . Many other AAA proteins form ring shaped hexamers and contain pore loops , which project into the ring s central cavity and act as ratchets that pull on target proteins , leading , in some cases , to conformational changes . We show that spastin assembles into a hexamer and that loops within the central pore recognize C terminal amino acids of tubulin . Key pore loop amino acids are required for severing , including one altered by a disease associated mutation . We also show that spastin contains a second microtubule binding domain that makes a distinct interaction with microtubules and is required for severing . given that spastin engages the MT in two places and that both interactions are required for severing , we propose that severing occurs by forces exerted on the C terminal tail of tubulin , which results in a conformational change in tubulin , which releases it from the polymer .

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 subcellular localization is regulated through usage of different translation start sites and active export from the nucleus. (2005 Sep)
spastin subcellular localization is regulated through usage of different translation start sites and active export from the nucleus . Most cases of autosomal dominant hereditary spastic paraplegia are linked to mutations in SPG4 encoding spastin , a protein involved in microtubule dynamics and membrane trafficking . In pyramidal neurons of the motor cortex and in immortalized motor neurons , spastin is localized to the synaptic terminals and growth cones . however , in other neurons and in proliferating cells spastin is prevalently nuclear . The mechanisms that determine targeting of spastin to the nucleus or the cytoplasm are unknown . We show here that the SPG4 mRNA is able to direct synthesis of two spastin isoforms , 68 and 60 kDa , respectively , through usage of two different translational start sites . Both isoforms are imported into the nucleus , but the 68 kDa isoform contains two nuclear export signals that efficiently drive export to the cytoplasm . nuclear export is leptomycin B sensitive . The cytoplasmic 68 kDa spastin isoform is more abundant in the brain and the spinal cord than in other tissues . Our data indicate that spastin function is modulated through usage of alternative translational start sites and active nuclear import and export , and open new perspectives for the pathogenesis of hereditary spastic paraplegia .

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 ) …

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 …

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 .

Isoform specific increase of spastin stability by N terminal missense variants including intragenic modifiers of SPG4 hereditary spastic paraplegia. (2007 Nov)
isoform specific increase of spastin stability by N terminal missense variants including intragenic modifiers of SPG4 hereditary spastic paraplegia . hereditary spastic paraplegia ( HSP ) is a neurodegenerative disorder selectively affecting axons of spinal cord motoneurons . classical mutations in the most frequent HSP gene spast ( spastin protein ) act through haploinsufficiency by abolishing the activity of a C terminal atpase domain or by interfering with expression from the affected allele . N terminal missense variants have been suggested to represent rare polymorphisms , to cause unusually mild phenotypes , and to aggravate the effect of a classical mutation . We confirm these associations for p . S44L but do not detect two other variants ( p . E43Q ; p . P45Q ) in HSP patients and controls . We show that neither of several disease mechanisms associated with classical spast mutations applies to the N terminal variants . instead , all three alterations enhance the stability of one of two alternative spastin isoforms . their phenotypic effect may thus not be mediated by haploinsufficiency but by increasing isoform competition for interacting proteins , substrates or oligomerization partners .

Spastin and atlastin , two proteins mutated in autosomal dominant hereditary spastic paraplegia , are binding partners. (2006 Jan)
spastin and atlastin , two proteins mutated in autosomal dominant hereditary spastic paraplegia , are binding partners . The pure hereditary spastic paraplegias ( HSPs ) are a group of conditions in which there is a progressive length dependent degeneration of the distal ends of the corticospinal tract axons , resulting in spastic paralysis of the legs . Pure HSPs are most frequently inherited in an autosomal dominant pattern and are commonly caused by mutations either in the SPG4 gene spastin or in the spg3a gene atlastin . To identify binding partners for spastin , we carried out a yeast two hybrid screen on a brain cDNA library , using spastin as bait . remarkably , nearly all of the positive interacting prey clones coded for atlastin . We have verified the physiological relevance of this interaction using co immunoprecipitation , glutathione S transferase pull down and intracellular co localization experiments . We show that the spastin domain required for binding to atlastin lies within the N terminal 80 residues of the protein , a region that is only present in the predominantly cytoplasmic , full length spastin isoform . these data suggest that spastin and atlastin function in the same biochemical pathway and that it is the cytoplasmic function of spastin which is important for the pathogenesis of HSP . They also provide further evidence for a physiological and pathological role of spastin in membrane dynamics .

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 .

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 .

Subcellular localization of spastin : implications for the pathogenesis of hereditary spastic paraplegia. (2005 Oct)
subcellular localization of spastin : implications for the pathogenesis of hereditary spastic paraplegia . hereditary spastic paraplegia ( HSP ) is a group of clinically and genetically heterogeneous diseases characterized by neuronal degeneration that is maximal at the distal ends of the longest axons of the central nervous system . The most common cause of autosomal dominant HSP is mutation of a novel gene encoding spastin , a protein whose function is still being elucidated . One clue concerning spastin function is its intracellular localization . Here , we describe a novel anti spastin antiserum designed to a unique epitope contained within all splicing isoforms . The antiserum exhibits specific immunostaining of recombinant spastin in intact , fixed cells . using this reagent , we find that endogenous spastin is located at the centrosome in a variety of cell types at all points in the cell cycle . This localization is resistant to microtubule disruption , suggesting that spastin may be an integral centrosomal protein . In addition to the centrosome , spastin also localizes at discrete focal regions along the axons of primary cultured neurons . these data lend additional support to the emerging hypothesis that spastin plays a role in microtubule dynamics , with a crucial role in microtubule organization .

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 .

Hereditary spastic paraplegia : spastin phenotype and function. (2004 Jun)
hereditary spastic paraplegia : spastin phenotype and function .

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 .

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 .

Spastic paraplegia caused by a novel mutation in the spastin gene ( 1207c G , p361r ) clinical features of … (2008 Feb)
spastic paraplegia caused by a novel mutation in the spastin gene ( 1207c G , p361r ) clinical features of a patient without family history A 52 year old man with no apparent family history of neurodegenerative diseases developed gait disturbance at age 47 . neurological examination at aged 52 revealed spastic paraplegia , generalized hyperreflexia , decreased of vibration sense in the lower limbs , and pollakisuria . ocular symptoms , deafness , cerebellar ataxia , extrapyramidal signs , mental deterioration , dementia , peripheral neuropathy , retinal pigment degeneration , ichthyosis and syndactyly were absent . MRI of the brain was normal . A pure form of hereditary spastic paraplegia was diagnosed . genetic analysis revealed a novel missense mutation in the spastin gene ( 1207c G , p361r ) . The clinical features of this patient were consistent with those of patient with the pure form of SPG4 . Gene analysis should be considered for patients with spastic paraplegia even in the absence of any family history .