Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia. (2000 Apr)
spectrum of SPG4 mutations in autosomal dominant spastic paraplegia . autosomal dominant hereditary spastic paraplegia ( AD HSP ) is a group of genetically heterogeneous neurodegenerative disorders characterized by pro gressive spasticity of the lower limbs . Five AD HSP loci have been mapped to chromosomes 14q , 2p , 15q , 8q and 12q . The SPG4 locus at 2p21 p22 has been shown to account for approximately 40 of all AD HSP families . SPG4 encoding spastin , a putative nuclear AAA protein , has recently been identified . Here , sequence analysis of the 17 exons of SPG4 in 87 unrelated AD HSP patients has resulted in the detection of 34 novel mutations . these SPG4 mutations are scattered along the coding region of the gene and include all types of DNA modification including missense ( 28 ) , nonsense ( 15 ) and splice site point ( 26 . 5 ) mutations as well as deletions ( 23 ) and insertions ( 7 . 5 ) . The clinical analysis of the 238 mutation carriers revealed a high proportion of both asymptomatic carriers ( 14 / 238 ) and patients unaware of symptoms ( 45 / 238 ) , and permitted the redefinition of this frequent form of AD HSP .

Spastin gene mutation in chinese patients with hereditary spastic paraplegia objective : To investigate the mutation characteristics of spastin gene … (2003 Jun)
spastin gene mutation in chinese patients with hereditary spastic paraplegia objective : To investigate the mutation characteristics of spastin gene in chinese patients with hereditary spastic paraplegia ( HSP ) and thus provide a basis for the gene diagnosis of HSP . methods : mutation of spastin gene was screened by polymerase chain reaction single strand conformation polymorphism ( PCR SSCP ) combined with DNA direct sequencing in 31 unrelated affected HSP individuals in china , of whom 22 were from autosomal dominant families and 9 were sporadic HSP patients . Co segregation analysis was carried out after the finding of abnormal SSCP bands . results : Six cases were found to have abnormal SCP bands , and among them , two missense mutations ( t1258a , a1293g in exon 8 ) and one deletion mutation ( 1667delact or 1668delcta or 1669deltac in exon 14 ) were found and all of them were not reported previously . They were all co segregated with the disease and were localized within the functional domain of spastin gene . besides , t1258a was seen in two unrelated families . conclusion : The mutation rate ( 18 . 2 ) in autosomal dominant HSP in chinese patients is comparatively low . point mutation is the major mutation type and exon 8 may be the mutation hot spot .

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 .

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 .

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 .

High frequency of partial spast deletions in autosomal dominant hereditary spastic paraplegia. (2006 Dec)
High frequency of partial spast deletions in autosomal dominant hereditary spastic paraplegia . background : hereditary spastic paraplegia ( HSP ) is a genetically heterogeneous neurodegenerative disease . The most frequent cause of autosomal dominant HSP is mutation of spast ( SPG4 locus ) , but additional pedigrees remain mutation negative by conventional screening despite linkage to SPG4 . objective : To determine the frequency of genomic copy number aberrations of spast in autosomal dominant HSP . methods : We developed and validated a multiplex ligation dependent probe amplification assay targeting spast and spg3a , another gene frequently involved in autosomal dominant HSP . In a multicenter study we subsequently investigated 65 index patients with autosomal dominant HSP , all of whom had previously been screened negative for spast mutations . independent secondary samples , additional family members , and cDNA were analyzed to confirm positive findings . results : aberrant MLPA profiles were identified in 12 cases ( 18 ) . They exclusively affect spast , represent deletions , segregate with the disease , and are largely pedigree specific . internal spast deletions entail expression of correspondingly shortened transcripts , which vary in stability . Age at onset in spast deletion carriers does not differ from that associated with other spast mutations . conclusions : partial spast deletions , but not spast amplifications and spg3a copy number aberrations , represent an underestimated cause of autosomal dominant hereditary spastic paraplegia . partial spast deletions are likely to act via haploinsufficiency …

Spastin , the most commonly mutated protein in hereditary spastic paraplegia interacts with reticulon 1 an endoplasmic reticulum protein. (2006 May)
spastin , the most commonly mutated protein in hereditary spastic paraplegia interacts with reticulon 1 an endoplasmic reticulum protein . spastin , an atpase belonging to the AAA family of proteins is most commonly mutated in autosomal dominant hereditary spastic paraplegias ( HSP ) . spastin is a multifaceted protein with versatile role in cellular events , principally involved in microtubule dynamics . To gain further insight into the molecular function of spastin , we used the yeast two hybrid approach to identify novel interacting partners of spastin . using spastin as bait , we identified reticulon 1 ( RTN1 ) and reticulon 3 ( RTN3 ) as potential spastin interacting proteins . RTN1 and RTN3 belong to the reticulon ( RTN ) gene family , which are primarily expressed in the endoplasmic reticulum . moreover , RTN1 is known to play a role in vesicular transport processes . using in vitro and in vivo immunoprecipitation experiments , we were able to demonstrate that RTN1 interacts specifically with spastin . intracellular distribution studies using immunostaining and overexpression of epitope tagged protein revealed an obvious colocalization of spastin and RTN1 in discrete vesicles in the cytoplasm . spastin mediates its interaction with RTN1 through its N terminal region containing a microtubule interacting and trafficking domain . It is interesting to note that the aberrant intracellular distribution of a truncated spastin protein was rescued by coexpression with RTN1 , which highlights the physiological significance of this interaction . Our findings strengthen the …

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 .

Investigation of mitochondrial function in hereditary spastic paraparesis. (2003 Mar)
investigation of mitochondrial function in hereditary spastic paraparesis . following the association of hereditary spastic paraparesis ( HSP ) with mutation in the paraplegin gene ( SPG7 ) and mitochondrial dysfunction , we wished to investigate whether mitochondrial dysfunction might be associated with other forms of HSP . Five cases of HSP caused by mutation in the spastin gene ( SPG4 ) and nine cases with HSP with mutation in the spastin and paraplegin genes excluded ( non SPG4 / SPG7 ) , were investigated for mitochondrial dysfunction . muscle tissue from the HSP groups and a control group was analysed histochemically and spectrophotometrically for mitochondrial dysfunction . A significant decrease in mitochondrial respiratory chain complexes I and IV was demonstrated in the non SPG4 / SPG7 group . No abnormality was detected in the SPG4 group . We therefore conclude that there is evidence for mitochondrial dysfunction in non SPG4 / SPG7 HSP . there is no evidence for mitochondrial dysfunction in the pathogenesis of spastin related HSP .

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 .

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 …

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 .

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 …

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 .

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 .

Phenotype of AD HSP due to mutations in the spast gene : comparison with AD HSP without mutations. (2001 Jan)
phenotype of AD HSP due to mutations in the spast gene : comparison with AD HSP without mutations . background : Pure autosomal dominant hereditary spastic paraparesis ( AD HSP ) is clinically and genetically heterogeneous . there are at least seven genetic loci with varying ages at onset and disability . The spast gene at the SPG4 locus on chromosome 2p is the major disease gene for AD HSP . objectives : To investigate whether there are distinct clinical features among families with AD HSP due to spast mutations compared with families excluded from SPG4 . methods : nineteen families with pure AD HSP were identified , and the clinical features of family members were compared using a standard protocol . With use of genetic studies , the families were divided into two groups for comparison : those with mutations in spast , the mutation positive group , and those excluded from SPG4 on the basis of linkage studies , the SPG4 excluded group . results : twenty nine individuals from four families had mutations in spast , whereas 22 individuals from three families comprised the SPG4 excluded group ; in 11 families , the pattern of linkage was unknown . In the one remaining family , no mutations were found despite strong linkage to SPG4 . different mutations were identified in the four spast pedigrees , but the clinical picture was similar in each . comparison of the mutation positive group with the SPG4 excluded group revealed an …

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 …

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 .

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 .

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 .