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 .

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

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 …

Hereditary spastic paraplegia : clinical genetic study of 15 families. (2004 Jun)
hereditary spastic paraplegia : clinical genetic study of 15 families . background : autosomal dominant hereditary spastic paraplegia ( adhsp ) is mainly caused by mutations in the SPG4 gene , which encodes a new member of the AAA ( adenosine triphosphatases associated with diverse cellular activities ) protein family ( spastin ) . accumulation of genotype phenotype correlation is important for better understanding of SPG4 linked hereditary spastic paraplegia . objectives : To perform a clinical and genetic study of families with adhsp and to perform the functional analysis of the founder mutation discovered in the SPG4 gene . design : genetic and clinical study . patients fifteen unrelated families with adhsp originating from southern scotland . MAIN outcome measures : clinical assessment , linkage analysis , haplotype study , expression of mutant spastin protein in cultured cells . results : Nine families with adhsp were linked to the SPG4 locus at 2p21 p24 . sequence analysis of spg4showed a novel n386s mutation in all 9 of these families . expression of mutant spastin showed aberrant distribution in cultured cells . haplotype analysis suggested the existence of a common founder . clinical examination of the affected members carrying the mutation showed phenotypic variations including broad range of age at onset and disease duration and additional neurologic features such as mental retardation . magnetic resonance imaging demonstrated unique features , including thin corpus callosum and atrophy of the cerebellum in 2 patients . linkage and sequence analyses showed no evidence …

The drosophila homologue of the hereditary spastic paraplegia protein , spastin , severs and disassembles microtubules. (2005 Apr)
The drosophila homologue of the hereditary spastic paraplegia protein , spastin , severs and disassembles microtubules . hereditary spastic paraplegias ( HSPs ) , a group of neurodegenerative disorders characterized by lower extremity spasticity and weakness , are most commonly caused by mutations in the spastin gene , which encodes a AAA atpase related to the microtubule severing protein katanin . A drosophila homolog of spastin ( D spastin ) was identified recently , and D spastin RNAi treated or genetic null flies show neurological defects , and protein overexpression decreases the density of cellular microtubules . elucidating spastin s function and disease mechanism will require a more detailed understanding of its structure and biochemical mechanism . Here , we have investigated the effects of D spastin , individual D spastin domains , and D spastin proteins bearing disease mutations on microtubules in cellular and in vitro assays . We show that D spastin , like katanin , displays atpase activity and uses energy from ATP hydrolysis to sever and disassemble microtubules ; disease mutations abolish or partially interfere with these activities .

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 .

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 .

Spinal cord magnetic resonance imaging in autosomal dominant hereditary spastic paraplegia. (2005 Oct)
spinal cord magnetic resonance imaging in autosomal dominant hereditary spastic paraplegia . hereditary spastic paraplegia ( HSP ) is a genetically heterogeneous group of neurodegenerative disorders characterized by progressive lower extremity weakness and spasticity . HSP pathology involves axonal degeneration that is most pronounced in the terminal segments of the longest descending ( pyramidal ) and ascending ( dorsal columns ) tracts . In this study , we compared spinal cord magnetic resonance imaging ( MRI ) in 13 HSP patients with four different types of autosomal dominant hereditary spastic paraplegia ( spg3a , SPG4 , SPG6 , and SPG8 ) with age matched control subjects . The cross section area of HSP subjects at cervical level C2 was 59 . 42 / 12 . 57 mm2 and at thoracic level T9 was 28 . 58 / 5 . 25 mm2 . Both of these values were less than in the healthy controls ( p 0 . 001 ) . The degree of cord atrophy was more prominent in patients with SPG6 and SPG8 who had signs of severe cord atrophy ( 47 . 60 / 6 . 58 mm2 at C2 , 21 . 40 / 2 . 4 mm2 at T9 ) than in subjects with SPG3 and SPG4 ( 66 . 0 / 8 . 94 mm2 at C2 , p 0 . 02 ; 31 . 75 / 2 . 76 mm2 at T9 , p 0 . 001 ) . these observations indicate that spinal …

Subtle cognitive impairment but no dementia in patients with spastin mutations. (2003 Aug)
subtle cognitive impairment but no dementia in patients with spastin mutations . background : The most frequent form of autosomal dominant hereditary spastic paraparesis is associated with the SPG4 locus , described originally as a pure form of the disease . mutations of the SPG4 gene have been increasingly associated with reports of cognitive impairment . objective : To investigate cognitive function in 10 families with hereditary spastic paraparesis due to mutations in the SPG4 gene , using intrafamilial control subjects . patients AND methods : neuropsychological examinations , including the cambridge cognitive evaluation , were conducted in 29 carriers with identified SPG4 mutations and 29 intrafamilial controls . results : carriers were not demented but had a subclinical cognitive impairment primarily affecting executive functions . The dysfunction was more severe in those carriers older than 50 years , but was correlated with the progression of the disease , not with age . disease progression and cognitive impairment appeared to be more severe in the carriers of missense mutations than in those with truncating mutations . conclusion : asymptomatic cognitive impairment mostly affecting executive functions is present in SPG4 mutation carriers and is more frequent in those with missense mutations .

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 .

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

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 .

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

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 …

An atypical intronic deletion widens the spectrum of mutations in hereditary spastic paraplegia. (2001 Jun)
An atypical intronic deletion widens the spectrum of mutations in hereditary spastic paraplegia . objective : To identify the genetic mutation responsible for autosomal dominant spastic paraplegia ( HSP ) in a large family with a pure form of the disorder . background : The disease locus in most families with HSP is genetically linked to the SPG4 locus on chromosome 2p21 p22 . Some of these families have mutations in the splice site or coding regions of the spastin gene ( spast ) . methods : linkage and mutational analyses were used to identify the location and the nature of the genetic defect causing the disorder in a large family . after the disease phenotype was linked to the SPG4 locus , all 17 coding regions and flanking intronic sequences of spast were analyzed by single strand conformation polymorphism analysis ( SSCP ) and compared between affected and normal individuals . direct sequencing and subcloning methods were used to investigate incongruous mobility shifts . results : The genomic sequence of spast showed a heterozygous four base pair deletion ( deltaat ) near the 3 splice site of exon three in all 11 affected individuals but not in 21 normal family members or in 50 unrelated controls ( 100 chromosomes ) . conclusions : This study identifies an atypical intronic microdeletion in spast that causes HSP and widens the spectrum of genetic abnormalities that cause the disorder .

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 .

Spastin , a new AAA protein , is altered in the most frequent form of autosomal dominant spastic paraplegia. (1999 Dec)
spastin , a new AAA protein , is altered in the most frequent form of autosomal dominant spastic paraplegia . autosomal dominant hereditary spastic paraplegia ( AD HSP ) is a genetically heterogeneous neurodegenerative disorder characterized by progressive spasticity of the lower limbs . among the four loci causing AD HSP identified so far , the SPG4 locus at chromosome 2p2 1p22 has been shown to account for 40 50 of all AD HSP families . using a positional cloning strategy based on obtaining sequence of the entire SPG4 interval , we identified a candidate gene encoding a new member of the AAA protein family , which we named spastin . sequence analysis of this gene in seven SPG4 linked pedigrees revealed several DNA modifications , including missense , nonsense and splice site mutations . Both SPG4 and its mouse orthologue were shown to be expressed early and ubiquitously in fetal and adult tissues . The sequence homologies and putative subcellular localization of spastin suggest that this atpase is involved in the assembly or function of nuclear protein complexes .

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 .

A novel missense mutation ( i344k ) in the spg4gene in a korean family with autosomal dominant hereditary spastic paraplegia. (2002 Aug)
A novel missense mutation ( i344k ) in the spg4gene in a korean family with autosomal dominant hereditary spastic paraplegia . hereditary spastic paraplegia ( HSP ) is a group of clinically and genetically heterogeneous neurodegenerative disorders characterized by slowly progressive spasticity and weakness of the lower extremities . among eight loci linked with autosomal dominant ( AD ) HSP , the SPG4 locus on chromosome 2p22 accounts for about 40 of all patients . recently , mutations in a new member of the AAA protein family , called spastin , have been identified as responsible for SPG4 linked AD HSP . Here , we describe a novel missense mutation ( c . 1031t A ; i344k ) in exon 7 of the SPG4 gene identified in a korean family with typical clinical features of pure AD HSP . The mutation affects the third amino acid of the highly conserved AAA cassette domain , which is the most fore part of the domain altered by a missense mutation reported so far . clinical presentations of affected individuals carrying the i344k mutation were not different from those of pure AD HSP with SPG4 mutations reported previously . however , it is noteworthy that neither urinary dysfunction nor involvement of upper extremities was noticed in this family . To our knowledge , this is the first report of genetically confirmed AD HSP in korea .

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 .