Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The childhood-onset spinal muscular atrophies are a clinically heterogeneous group of autosomal recessive disorders characterized by selective degeneration of the anterior horn cells with subsequent weakness and atrophy of limb muscles. The disease locus has been mapped to a region of chromosome 5q13 characterized by genetic instability and DNA duplication. Among the duplicated genes in this region, SMNT (telomeric copy; survival motor neuron) is thought to be the major disease determining gene since it is missing in the majority of SMA patients and since small, intragenic mutations in the gene have been associated with the disorder. Approximately half of the severely affected SMA I patients are also missing both homologues of a neighboring gene, the neuronal apoptosis inhibitory protein (NAIP). These data indicate that loss of NAIP may affect disease severity and further, that the molecular events underlying the childhood-onset SMAs are complex, possibly involving multiple genes. We report a third multicopy gene in the SMA region, encoding the p44 subunit of basal transcription factor II (BTF2p44). One copy of this transcription-repair gene is deleted in at least 15% of all SMA cases.
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PMID:A multicopy transcription-repair gene, BTF2p44, maps to the SMA region and demonstrates SMA associated deletions. 906 43

Spinal muscular atrophy is an autosomal recessive disease characterized by motor neurone loss, muscle atrophy and weakness. Deletion or mutation of the SMN1 gene reduces intracellular survival motor neurone protein levels causes spinal muscular atrophy, most likely by interfering with spliceosome assembly. A range of clinical severity and corresponding survival motor neurone levels is seen because of the presence of copies of the transcriptionally inefficient SMN2 gene and possibly other modifying genes. The delineation of SMN1 as the gene that causes spinal muscular atrophy and the identification of genes that modify spinal muscular atrophy raise the prospect of gene therapy or in-vivo gene activation treatment for this frequently fatal disorder.
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PMID:Spinal muscular atrophy: molecular pathophysiology. 1022 44

The survival motor neuron gene is present in humans in a telomeric copy, SMN1, and several centromeric copies, SMN2. Homozygous mutation of SMN1 is associated with proximal spinal muscular atrophy (SMA), a severe motor neuron disease characterized by early childhood onset of progressive muscle weakness. To understand the functional role of SMN1 in SMA, we produced mouse lines deficient for mouse Smn and transgenic mouse lines that expressed human SMN2. Smn-/- mice died during the peri-implantation stage. In contrast, transgenic mice harbouring SMN2 in the Smn-/- background showed pathological changes in the spinal cord and skeletal muscles similar to those of SMA patients. The severity of the pathological changes in these mice correlated with the amount of SMN protein that contained the region encoded by exon 7. Our results demonstrate that SMN2 can partially compensate for lack of SMN1. The variable phenotypes of Smn-/-SMN2 mice reflect those seen in SMA patients, providing a mouse model for this disease.
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PMID:A mouse model for spinal muscular atrophy. 1061 30

Spinal muscular atrophy (SMA) is characterized by degeneration of motor neurons in the spinal cord, causing progressive weakness of the limbs and trunk, followed by muscle atrophy. SMA is one of the most frequent autosomal recessive diseases, with a carrier frequency of 1 in 50 and the most common genetic cause of childhood mortality. The phenotype is extremely variable, and patients have been classified in type I-III SMA based on age at onset and clinical course. All three types of SMA are caused by mutations in the survival motor neuron gene (SMN1). There are two almost identical copies, SMN1 and SMN2, present on chromosome 5q13. Only homozygous absence of SMN1 is responsible for SMA, while homozygous absence of SMN2, found in about 5% of controls, has no clinical phenotype. Ninety-six percent of SMA patients display mutations in SMN1, while 4% are unlinked to 5q13. Of the 5q13-linked SMA patients, 96.4% show homozygous absence of SMN1 exons 7 and 8 or exon 7 only, whereas 3. 6% present a compound heterozygosity with a subtle mutation on one chromosome and a deletion/gene conversion on the other chromosome. Among the 23 different subtle mutations described so far, the Y272C missense mutation is the most frequent one, at 20%. Given this uniform mutation spectrum, direct molecular genetic testing is an easy and rapid analysis for most of the SMA patients. Direct testing of heterozygotes, while not trivial, is compromised by the presence of two SMN1 copies per chromosome in about 4% of individuals. The number of SMN2 copies modulates the SMA phenotype. Nevertheless, it should not be used for prediction of severity of the SMA.
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PMID:An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). 1067 38

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration and loss of motor neurons of the anterior horn of the spinal cord. The clinical manifestations include proximal symmetric weakness and progressive atrophy of muscle. SMA is classified by age of onset, severity of symptoms, and evolution in three groups: type I, severe or Werdnig-Hoffmann disease, type II or intermediate and type III, moderate-mild, Kugelberg-Welander disease. The identification of the SMN1 gene as determinant of SMA opened new alternatives to study the disease. Most of the patients have deletions and conversion of SMN1 and in a small number of cases, point mutations were detected. There is no obvious genotype-phenotype correlation because homozygous absence of SMN1 was associated to a wide spectrum of manifestations from congenital disease to non symptomatic cases. Modifier factors, such as the number of copies of SMN2, could influence the phenotype. Other possible modifier genes are under study. The SMN gene is expressed in various neuronal populations. However, only motor neurons are responsible for the manifestations of the disease. The SMN protein is part of a complex with various proteins involved in the splicing reaction. This apparent essential function for all cells could be critical in motor neurons. When SMN1 is absent or dysfunctional, the motor neurons could be more sensitive because they have an increased transcription activity. In this situation, other cells and tissues could be protected by genetic or cellular factors still undiscovered.
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PMID:[Molecular basis of spinal muscular atrophy: th SMN gene]. 1119 46

The human genome has two homologous survival motor neuron genes, SMN1 and SMN2. Although deletions of SMN1 are frequently reported in childhood-onset spinal muscular atrophy (SMA), SMN2 have been found to be intact in patients with the disorder. We report on a 5-year-old boy with childhood-onset SMA who has a homozygous deletion of SMN2. He had wasting, weakness, and hyporeflexia, predominantly in the distal muscles. The muscles involved showed chronic neurogenic changes on electromyogram. There was no sensory involvement. A nerve conduction study showed near normal conduction velocity with reduction in the amplitude of the compound muscle action potential. Analysis of polymerase chain reaction-restriction fragment length polymorphism as well as single-strand conformation polymorphism on exons 7 and 8 of the SMN genes revealed the SMN2-deletion. Base sequencing and densitometric analysis of the critical region (exon 7) did not show any microdeletion or duplication of SMN1, but confirmed the deletion of SMN2. We conclude that a deletion of SMN2 may also result in the SMA phenotype.
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PMID:SMN2-deletion in childhood-onset spinal muscular atrophy. 1197 91

Spinal muscular atrophy is an autosomal recessive neurodegenerative disorder with progressive weakness and atrophy of voluntary muscles. The survival motor neuron gene (SMN) is present in two highly homologous copies (SMN1 and SMN2) on chromosome 5q13. Homozygous deletion of exons 7 and 8 of SMN1 is responsible for spinal muscular atrophy. In spinal muscular atrophy patients, SMN2 partially compensates for the lack of SMN1. Previously, we reported the relatively high incidence of a large deletion including the SMN1 region in Japanese spinal muscular atrophy type I patients. In order to further establish the genetic background of Japanese spinal muscular atrophy type I patients, we investigated the SMN1/SMN2 ratio in the carriers. In normal individuals, there is one copy of each gene on the chromosome (the SMN1/SMN2 ratio was 1). Among 15 carriers (14 parents and one carrier sibling of Japanese type I spinal muscular atrophy patients with homozygous deletion of exons 7 and 8 of SMN1), we found that the SMN1/SMN2 ratio was 0.5 or 1 in 11 (73.3%) carriers. The remaining four carriers had an SMN1/SMN2 ratio of 1/3. This finding supports the idea that deletion rather than conversion is the main genetic event in type I spinal muscular atrophy. In addition, the ratio of SMN1/SMN2 among Japanese carriers, which was thought to be higher than that of the Western population, was compatible with the results obtained in Western populations. For further insight into the characteristic genetic background of spinal muscular atrophy in Japanese, determination of the gene copy number is essential.
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PMID:The gene copy ratios of SMN1/SMN2 in Japanese carriers with type I spinal muscular atrophy. 1150 4

Proximal spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans caused by degeneration of alpha motor neurons in the anterior horns of the spinal cord. This affects voluntary movements, leading to muscle weakness and atrophy. SMA is caused by homozygous deletions/mutations in the survival motor neuron gene 1 (SMN1). The severity of the phenotype is modulated by the copy number of SMN2 and by other yet unknown factors. SMN2 is affected by a critical non-translational nucleotide exchange in exon 7 that disrupts an exonic splicing enhancer. In consequence SMN2 produces mainly alternatively spliced mRNA that lacks exon 7. Trans-activating factors such as Htra2-beta1, as well as various drugs like sodium butyrate or aclarubicin, are able to restore the full-length SMN2 RNA to large amounts. Since each SMA patient carries at least one SMN2 copy, reconstitution of full-length SMN2 protein is an exciting strategy for somatic gene therapy in SMA patients.
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PMID:Spinal muscular atrophy: state-of-the-art and therapeutic perspectives. 1221 30

Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder that is characterized by degeneration of the anterior horn cells of the spinal cord, which leads to the axial and limb weakness associated with muscle atrophy. SMA is classified into three groups based on the clinical severity: type I (severe), type II (intermediate) and type III (mild). All three clinical subtypes of SMA are caused by mutations of the SMN1 gene. More than 95 % of SMA patients show homozygous deletion of SMN1. It is thought that SMN2, which is a highly homologous gene of SMN1, compensates for the SMN1 deletion to some degree. To clarify the relationship between SMN2 and the disease severity of SMA, we performed fluorescence-based quantitative polymerase chain reaction assay of the copy number of SMN2 in 27 patients (11 type I and 16 type II-III) homozygous for SMN1 deletion. The SMN2 copy number in type II-III patients was 3.1 +/- 0.3 (mean +/- SD), which is significantly higher than that observed in type I patients, 2.2 +/- 0.6 (P < 0.01). However, three of the 11 type I patients carried 3 SMN2 copies. A type I patient with 3 SMN2 copies was studied further. RT-PCR analysis of the patient showed a trace of full-length SMN2 mRNA species, but a large amount of the truncated SMN2 mRNA species lacking exon 7. In conclusion, SMN2 alleles are not functionally equivalent among SMA patients, although in general the SMN2 copy number is correlated with the severity of SMA. Genetic background influencing splicing mechanisms of the SMN2 gene may be more critical in some SMA patients.
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PMID:Correlation between SMN2 copy number and clinical phenotype of spinal muscular atrophy: three SMN2 copies fail to rescue some patients from the disease severity. 1224 41

A hereditary form of spinal muscular atrophy (SMA) caused by an autosomal recessive gene has been reported for American Brown-Swiss cattle and in advanced backcrosses between American Brown-Swiss and many European brown cattle breeds. Bovine SMA (bovSMA) bears remarkable resemblance to the human SMA (SMA1). Affected homozygous calves also show progressive symmetric weakness and neurogenic atrophy of proximal muscles. The condition is characterized by severe muscle atrophy, quadriparesis, and sternal recumbency as result of neurogenic atrophy. We report on the localization of the gene causing bovSMA within a genomic interval between the microsatellite marker URB031 and the telomeric end of bovine Chromosome (Chr) 24 (BTA24). Linkage analysis of a complex pedigree of German Braunvieh cattle revealed a recombination fraction of 0.06 and a three-point lod score of 11.82. The results of linkage and haplotyping analysis enable a marker-assisted selection against bovSMA based on four microsatellite markers most telomeric on BTA24 to a moderate accuracy of 89-94%. So far, this region is not orthologous to any human chromosome segments responsible for twelve distinct disease phenotypes of autosomal neuropathies. Our results indicate the apoptosis-inhibiting protein BCL2 as the most promising positional candidate gene causing bovSMA. Our findings offer an attractive animal model for a better understanding of human forms of SMA and for a probable anti-apoptotic synergy of SMN-BCL2 aggregates in mammals.
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PMID:Mapping of the bovine spinal muscular atrophy locus to Chromosome 24. 1287 60


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