Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026838 (spasticity)
 6,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a genetically heterogeneous disorder characterized by progressive spasticity of the lower limbs. A major locus (SPG4) causing AD-HSP in about 40% of the families was mapped to chromosome 2p. The analysis of six SPG4-linked AD-HSP families using the RED procedure previously showed the expansion of a CAG repeat in affected individuals. To identify the gene responsible for this form of HSP, we have constructed a 3.5-Mb YAC contig flanked by loci D2S400 and D2S367, have subcloned five of these YACs spanning the candidate region into cosmids, and screened these cosmid libraries for the presence of CAG repeat sequences. Four CAG repeats have been identified but none of them is expanded in 26 patients from 13 SPG4-linked AD-HSP families. A gene map comprising 21 transcripts was established using expressed sequence tags (ESTs) assigned previously to this region of 2p21-p22 with radiation hybrid panels GeneBridge 4 and G3. Full-length cDNAs corresponding to the 14 ESTs mapping to the SPG4 interval flanked by loci D2S352 and D2S2347 were isolated and sequenced. None contains a CAG repeat in its coding sequence. Finally, we have assembled a BAC contig composed of 37 clones that were also screened for the presence of CAG repeats; this failed to detect additional repeats to those identified on YACs.
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PMID:A fine integrated map of the SPG4 locus excludes an expanded CAG repeat in chromosome 2p-linked autosomal dominant spastic paraplegia. 1049 30

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.
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PMID:Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. 1061 Jan 78

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.
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PMID:Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia. 1069 87

The autosomal dominant hereditary spastic paraplegias (AD-HSP) are a heterogeneous group of degenerative disorders of the central motor system, characterized by progressive spasticity of the lower limbs. Five loci for pure AD-HSP have been identified to date: SPG3 at 14q, SPG4 at 2p, SPG6 at 15q, SPG8 at 8q, and more recently SPG10 at 12q. We have analyzed a Brazilian family with 16 affected individuals by pure AD-HSP who developed progressive gait disturbance with onset at age 18-26 years. Linkage analysis performed with 13 relatives (6 affected and 7 normal) excluded SPG3, SPG4, and SPG6 as candidate regions. However, positive LOD scores were obtained with markers flanking the candidate region for the SPG8 locus [maximum two point Lod score (Zmax) = 3.3 at theta = 0 for D8S1804]. In this region lies the syntrophin beta 1 gene (SNT2B1), a widely expressed dystrophin-associated protein and therefore a good positional and functional candidate for this disease. Immunohistochemical and Western Blot (WB) studies showed that the distribution, expression, and apparent molecular weight of the beta 1 syntrophin protein were comparable to those of normal control individuals. Therefore, it is unlikely that defects in this protein are related to SPG8, at least in the present family.
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PMID:Brazilian family with pure autosomal dominant spastic paraplegia maps to 8q: analysis of muscle beta 1 syntrophin. 1079 36

Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a genetically heterogeneous neurodegenerative disorder characterised by progressive spasticity of the lower limbs. The SPG4 locus at 2p21-p22 accounts for 40-50% of all AD-HSP families. The SPG4 gene was recently identified. It is ubiquitously expressed in adult and foetal tissues and encodes spastin, an ATPase of the AAA family. We have now identified four novel SPG4 mutations in German AD-HSP families, including one large family for which anticipation had been proposed. Mutations include one frame-shift and one missense mutation, both affecting the Walker motif B. Two further mutations affect two donor splice sites in introns 12 and 16, respectively. RT-PCR analysis of both donor splice site mutations revealed exon skipping and reduced stability of aberrantly spliced SPG4 mRNA. All mutations are predicted to cause loss of functional protein. In conclusion, we confirm in German families that SPG4 mutations cause AD-HSP. Our data suggest that SPG4 mutations exert their dominant effect not by gain of function but by haploinsufficiency. If a threshold level of spastin were critical for axonal preservation, such threshold dosage effects might explain the variable expressivity and incomplete penetrance of SPG4-linked AD-HSP.
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PMID:Hereditary spastic paraplegia caused by mutations in the SPG4 gene. 1103 77

Autosomal-dominant pure hereditary spastic paraplegia (AD-HSP) is characterized by the degeneration of long axons in corticospinal tracts and dorsal columns, resulting in spasticity and difficulty walking. Mutations in the SPG4 gene product spastin are the predominant genetic lesions associated with this inherited disease. In this issue, Orso et al. examine and reconcile existing Drosophila mutants of spastin and generate a new model for HSP by overexpression of a fly spastin transgene that carries a mutation prevalent in human AD-HSP (see the related article beginning on page 3026). Expression of this mutant spastin protein produces pathology in flies reminiscent of the human disease, including adult locomotion defects, in addition to causing aberrant synaptic morphology and altered microtubule stability. Both movement and synaptic defects in fly mutants were ameliorated by treatment with the microtubule-modifying agent vinblastine. The results are consistent with disease-causing mutations in human spastin producing dominant-negative proteins and confirm the usefulness of Drosophila genetic techniques to understand HSP and other neurodegenerative diseases.
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PMID:All neuropathies great and small. 1627 13

SPG4, the gene encoding for spastin, a member of the ATPases associated with various cellular activities (AAA) family, is mutated in around 40% of cases of autosomal dominant hereditary spastic paraplegia (AD-HSP). This group of neurodegenerative diseases is characterized by a progressive spasticity and lower limb weakness with degeneration of terminal axons in cortico-spinal tracts and dorsal columns. Spastin has two main domains, a microtubule interacting and endosomal trafficking (MIT) domain at the N-terminus and the C-terminus AAA domain. Early studies suggested that spastin interacts with microtubules similarly to katanin, a member of the same subgroup of AAA. Recent evidence confirmed that spastin possesses microtubule-severing activity but can also bundle microtubules in vitro. Understanding the physiologic and pathologic involvement of these activities and their regulation is critical in the study of HSP.
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PMID:Spastin and microtubules: Functions in health and disease. 1734 41

Spastic paraplegias (HSPs) and dystonias (DYTs) typically localize to different neuroanatomic systems. We report clinical and genetic data from large Ohio kindred with autosomal dominant (AD) HSP and DYT. Single and multipoint linkage using microsatellite and single nucleotide polymorphism array genotyping were performed on a large, multigenerational family with a novel, AD, highly penetrant neurological disease causing spasticity and DYT. Age of onset of spasticity and weakness is from the first year to the sixth decade, and age of onset of DYT from the first to third decade. There is no ataxia or apparent cognitive involvement. Neuroimaging and peripheral neurophysiology are normal. Generalized DYT improved markedly with deep brain stimulation in 1 child. The disease locus was mapped to a region on chromosome 2q 24-31, flanked by markers rs1424937-rs1559510, proximal to SPG13, in a region where there are no known HSP or DYT genes. A secondary analysis for candidate genes segregating with the DYT phenotype revealed two candidate regions with parametric lod scores above 2.0. On the basis of clinical presentation and linkage results, we conclude that this disease is a novel neurological disorder. Identifying the causative gene may elucidate an important pathway for pyramidal and extrapyramidal disorders.
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PMID:A novel hereditary spastic paraplegia with dystonia linked to chromosome 2q24-2q31. 1900 92

The hereditary spastic paraplegias (HSPs or SPGs) are clinically and genetically highly heterogeneous neurodegenerative disorders mainly characterized by progressive spasticity and weakness in the lower limbs. The inheritance mode includes autosomal dominant(AD-HSP), autosomal recessive(AR-HSP) and X-linked recessive(XR-HSP). Thirty-five loci have been mapped with 17 disease-associated genes identified. SPG4 and SPG7 are the common subtypes in the AD-HSP and AR-HSP, respectively. The authors briefly review the function of spastin (SPG4) and paraplegin (SPG7), both of which belong to AAA ATPases family, and the recent progress of the study on the pathogenesis of HSPs.
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PMID:[AAA ATPases and hereditary spastic paraplegia]. 1950 43

The Japan Spastic Paraplegia Research Consortium (JASPAC) is conducting a nationwide clinical and genetic survey of patients with HSP in Japan. To date (July 20, 2011), 375 index patients with HSP from 42 prefectures in Japan have been registered. In 148 Japanese ADHSP families, SPG4 was the most common form, accounting for 47%, followed by SPG31 (4%), SPG3A (3%), SPG8 (1%), and SPG10 (1%). Meanwhile, preliminary data showed that SPG11 and ARSACS were common in Japanese ARHSP families. Since the genes in approximately 40% of ADHSP and 80% of ARHSP cases remain unknown, we aim to identify the new genes responsible for HSP. We are now searching for a novel gene responsible for ARHSP with optic atrophy and neuropathy. To date, non-Quebec patients with ARSACS have been found in the Mediterranean area, Europe and Japan. Although Quebec patients show a homogeneous phenotype, Japanese patients exhibit some atypical clinical features, as follows: slightly later onset than that in Quebec patients, absence of retinal hypermyelination, intellectual impairment, and lack of spasticity. Recently, we found characteristic MRI findings in eight Japanese ARSACS patients, who all exhibited linear hypointensity in the pons and a hypointense area in the middle cerebellar peduncles in T(2) weighted and FLAIR images.
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PMID:[Hereditary spastic paraplegia in Japan]. 2227 6


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