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 …

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 ) …

Infantile onset of hereditary spastic paraplegia poorly predicts the genotype. (2007 Jun)
infantile onset of hereditary spastic paraplegia poorly predicts the genotype . Age of symptom onset of hereditary spastic paraplegia varies from infancy to the eighth decade . infantile onset of hereditary spastic paraplegia without a positive family history may cause difficulties in reaching the correct diagnosis and misdiagnosis as a diplegic form of cerebral palsy is particularly common . infantile onset of hereditary spastic paraplegia caused by mutations in the spastin gene ( spast ) is very rare and previously was mostly associated with codominant mutations in this gene . We present a kindred with infantile onset of spastic paraplegia in three successive generations caused by confirmed de novo novel mutation 1537g A ( g471d ) in spast . several family members were previously diagnosed as having cerebral palsy . infantile onset of hereditary spastic paraplegia may be caused by mutations in multiple genes , and this phenotype does not reliably predict the genotype . pediatric neurologists need to be aware of relatively frequent de novo mutations in hereditary spastic paraplegia genes and a possibility that this condition presents in infancy without a positive family history .

Three novel spastin ( SPG4 ) mutations in families with autosomal dominant hereditary spastic paraplegia. (2002 Aug)
three novel spastin ( SPG4 ) mutations in families with autosomal dominant hereditary spastic paraplegia . hereditary spastic paraplegia ( HSP ) is a clinically and genetically heterogeneous condition , characterised principally by progressive spasticity of the lower limbs . forty percent of autosomal dominant ( AD ) pedigrees show linkage to the SPG4 locus on chromosome 2 , which encodes spastin , an atpase associated with diverse cellular activities ( AAA ) protein . We have performed a clinical and genetic study of three AD HSP families linked to SPG4 . sequencing revealed three novel causative mutations . Two of the mutations were located in exon 5 ( a 1 base pair ( bp ) insertion and a 5 bp deletion ) , resulting in frameshift and premature termination of translation , with the predicted protein lacking the entire AAA functional domain . The 5 bp deletion was associated with a later onset and mild cerebellar features . The third mutation was a 3 bp deletion in exon 9 , resulting in the loss of a highly conserved phenylalanine residue within the AAA cassette and an apparently milder phenotype . This is the first example of a deletion of an amino acid in spastin .

Mutations of SPG4 are responsible for a loss of function of spastin , an abundant neuronal protein localized in the … (2002 Dec)
mutations of SPG4 are responsible for a loss of function of spastin , an abundant neuronal protein localized in the nucleus . mutations of spastin are responsible for the most common autosomal dominant form of hereditary spastic paraplegia ( AD HSP ) , a disease characterized by axonal degeneration of corticospinal tracts and posterior columns . generation of polyclonal antibodies specific to spastin has revealed two isoforms of 75 and 80 kDa in both human and mouse tissues with a tissue specific variability of the isoform ratio . spastin is an abundant protein in neural tissues and immunolabeling experiments have shown that spastin is expressed in neurons but not in glial cells . these data indicate that axonal degeneration linked to spastin mutations is caused by a primary defect of neurons . protein and transcript analyses of patients carrying either nonsense or frameshift spastin mutations revealed neither truncated protein nor mutated transcripts , providing evidence that these mutations are responsible for a loss of spastin function . identifying agents able to induce the expression of the non mutated spastin allele should represent an attractive therapeutic strategy in this disease .

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 .

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 .

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 .

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 .

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

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 .

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 .

Spastin mutations in sporadic adult onset upper motor neuron syndromes. (2005 Dec)
spastin mutations in sporadic adult onset upper motor neuron syndromes . mutation of the spastin gene is the single most common cause of pure hereditary spastic paraparesis . In patients with an unexplained sporadic upper motor neuron ( UMN ) syndrome , clinical distinction between primary lateral sclerosis and sporadic hereditary spastic paraparesis may be problematic . To investigate whether spastin mutations are present in patients with primary lateral sclerosis and sporadic hereditary spastic paraparesis , we screened the spastin gene in 99 dutch patients with an unexplained , apparently sporadic , adult onset UMN syndrome . We found 6 mutations , of which 4 were novel , in the subgroup of 47 patients with UMN symptoms restricted to the legs ( 13 ) . another novel spastin mutation was found in a patient with a rapidly progressive spinal and bulbar UMN syndrome that progressed to amyotrophic lateral sclerosis . In the patients with arm or bulbar UMN symptoms and slow progression , no spastin mutations were found . Our study shows that spastin mutations are a frequent cause of apparently sporadic spastic paraparesis but not of primary lateral sclerosis .

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 .

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 .

Unexpected pathogenic mechanism of a novel mutation in the coding sequence of SPG4 ( spastin ). (2006 Feb)
unexpected pathogenic mechanism of a novel mutation in the coding sequence of SPG4 ( spastin ) . The authors report a nucleotide substitution ( c . 1216a G ) in SPG4 ( spastin ) causing hereditary spastic paraplegia . This apparent missense mutation in the atpase domain confers aberrant , in frame splicing and results in destabilization of mutated transcript . mutated protein is deficient in microtubule severing activity but , unlike neighboring mutations , shows regular subcellular localization . The authors data point to haploinsufficiency rather than a dominant negative effect as the disease causing mechanism for this mutation .

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 …

Neurophysiological findings in SPG4 patients differ from other types of spastic paraplegia. (2003 May)
neurophysiological findings in SPG4 patients differ from other types of spastic paraplegia . The authors examined 12 families with autosomal dominant hereditary spastic paraplegia for phenotypic characteristics predicting the underlying genotype . They found no clinical differences between patients with or without mutations in the spastin gene ( SPG4 ) . motor evoked potentials and nerve conduction studies were almost normal in those with SPG4 . In contrast , non SPG4 families had prolonged central motor conduction times or marked peripheral neuropathy , or both .

The hereditary spastic paraplegia gene , spastin , regulates microtubule stability to modulate synaptic structure and function. (2004 Jul)
The hereditary spastic paraplegia gene , spastin , regulates microtubule stability to modulate synaptic structure and function . background : hereditary spastic paraplegia ( HSP ) is a devastating neurological disease causing spastic weakness of the lower extremities and eventual axonal degeneration . Over 20 genes have been linked to HSP in humans ; however , mutations in one gene , spastin ( SPG4 ) , are the cause of 40 of all cases . spastin is a member of the atpases associated with diverse cellular activities ( AAA ) protein family , and contains a microtubule interacting and organelle transport ( MIT ) domain . previous work in cell culture has proposed a role for spastin in regulating microtubules . results : employing drosophila transgenic methods for overexpression and RNA interference ( RNAi ) , we have investigated the role of spastin in vivo . We show that drosophila spastin ( D spastin ) is enriched in axons and synaptic connections . At neuromuscular junctions ( NMJ ) , dspastin RNAi causes morphological undergrowth and reduced synaptic area . moreover , dspastin overexpression reduces synaptic strength , whereas dspastin RNAi elevates synaptic currents . By using antibodies against posttranslationally modified alpha tubulin , we find that dspastin regulates microtubule stability . functional synaptic defects caused by dspastin RNAi and overexpression were pharmacologically alleviated by agents that destabilize and stabilize microtubules , respectively . conclusions : Loss of dspastin in drosophila causes an aberrantly stabilized microtubule cytoskeleton in neurons and …