Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The etiology of amyotrophic lateral sclerosis remains unknown in the majority of cases. Homozygous SMN1 (survival motor neuron) gene deletion causes spinal muscular atrophy, and SMN2 gene deletions are possible risk factors in lower motor neuron disease. We studied SMN1 and SMN2 genes copy numbers in 167 amyotrophic lateral sclerosis patients and in 167 matched controls. We noted that 16% of amyotrophic lateral sclerosis patients had an abnormal copy number of the SMN1 gene (1 or 3 copies), compared with 4% of controls. An abnormal SMN1 gene locus may be a susceptibility factor for amyotrophic lateral sclerosis.
 ...
PMID:Abnormal SMN1 gene copy number is a susceptibility factor for amyotrophic lateral sclerosis. 1244 45

The presence of the SMN2 deletion in 124 patients with ALS was investigated. Eleven patients had the homozygous deletion of SMN2 (8.8%) in comparison with 20 of 200 (10%) of the healthy control population. No significant differences in sex, age at onset, initial symptoms, form of inheritance, decline in ventilatory function, or survival time were found between patients with and without the deletion. The hypothesis that SMN2 is a prognostic factor in sporadic or familial ALS was not confirmed in this study.
 ...
PMID:Survival and respiratory decline are not related to homozygous SMN2 deletions in ALS patients. 1242 7

About 10 p. cent of amyotrophic lateral sclerosis (ALS) cases are familial. Most of the familial ALS (FALS) cases are clinically homogeneous. Among these families, autosomal dominant, X-linked or autosomal recessive transmission can be observed. Most of the causal mutations have been observed in the SOD1 gene. To date, more than one hundred different mutations have been described, but it remains unclear whether the mutation is always responsible for the phenotype. Penetrance of the mutation depends on age, with almost 90 p. 100 of penetrance at age 70 years. There is no anticipation. Worldwide, the most frequent mutation is A4V with dominant transmission, responsible for a severe, rapid form of the disease. The second most frequent mutation is D90A which is generally transmitted recessively, predominantly in the Scandinavian countries. The phenotype is characterized by a long lasting course (mean: 11 years). Other causal mutations have been described in the Alsine, Apex, NF-H and NAIP genes. Other genes can be considered as risk factors, like SMN2, APO E4, APEX, Dynactine, P-450 D6. Presymptomatic testing for FALS seems difficult because little information can be given to the patient regarding the responsibility of the mutation in the disease, age of onset, and disease trends. The same precautions as for Huntington's disease are needed. Genetic investigations can contribute to better understanding of the pathophysiology of ALS. Other causal genes in the 90 p. 100 of FALS without SOD1 mutation and eventually in the sporadic ALS cases may be disclosed. Genetic investigations also determine the precise role of a given SOD1 mutation because of the large number of potential SOD1 mutations, the variability of the transmission mode and the non-exceptional absence of proven causality for ALS.
 ...
PMID:[Where is the role of the genetic investigations in amyotrophic lateral sclerosis?]. 1712 95

TDP-43 is a highly conserved, 43-kDa RNA-binding protein implicated to play a role in transcription repression, nuclear organization, and alternative splicing. More recently, this factor has been identified as the major disease protein of several neurodegenerative diseases, including frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. For the splicing activity, the factor has been shown to be mainly an exon-skipping promoter. In this study using the survival of motor neuron (SMN) minigenes as the reporters in transfection assay, we show for the first time that TDP-43 could also act as an exon-inclusion factor. Furthermore, both RNA-recognition motif domains are required for its ability to enhance the SMN2 exon 7 inclusion. Combined protein-immunoprecipitation and RNA-immunoprecipitation experiments also suggested that this exon inclusion activity might be mediated by multimeric complex(es) consisting of this protein interacting with other splicing factors, including Htra2-beta1. Our data further evidence TDP-43 as a multifunctional RNA-binding protein for a diverse set of cellular activities.
 ...
PMID:TDP-43 overexpression enhances exon 7 inclusion during the survival of motor neuron pre-mRNA splicing. 1870 4

Mutations in the ubiquitously expressed survival motor neuron 1 (SMN1) and superoxide dismutase 1 (SOD1) genes are selectively lethal to motor neurons in spinal muscular atrophy (SMA) and familial amyotrophic lateral sclerosis (ALS), respectively. Genetic association studies provide compelling evidence that SMN1 and SMN2 genotypes encoding lower SMN protein levels are implicated in sporadic ALS, suggesting that SMN expression is a potential determinant of ALS severity. We therefore sought genetic evidence of SMN involvement in ALS by generating transgenic mutant SOD1 mice on an Smn deficient background. Partial genetic disruption of Smn significantly worsened motor performance and survival in transgenic SOD1(G93A) mice. Furthermore, ALS-linked mutant SOD1 expression severely reduced SMN protein levels, but not transcript, in neuronal culture and mouse models from early presymptomatic disease. SMN protein depletion was linked to the nuclear compartment and a physical interaction between SMN and mutant SOD1 was confirmed in mouse spinal cord. Treatment with the environmental toxin paraquat also depleted SMN protein, implicating oxidative stress in the mechanism underlying SMN deficiency in familial ALS and potentially sporadic disease. In contrast, transgenic SOD1(WT) overexpression in SMA type I mice was incapable of modulating SMN protein levels or disease progression. These data establish that SMN deficiency accelerates phenotypic severity in transgenic familial ALS mice, consistent with an enhancing genetic modifier role. We therefore propose that SMN replacement and upregulation strategies considered for SMA therapy may have protective potential for ALS.
 ...
PMID:Survival motor neuron deficiency enhances progression in an amyotrophic lateral sclerosis mouse model. 1933 22

The human genome contains two SMN (survival motor neuron) genes: SMN1, the telomeric gene whose homozygous deletion causes spinal muscular atrophy (SMA), and SMN2, the centromeric version whose copy number modulates the phenotype of SMA. We performed a Medline search and reviewed all of the publications that focus on SMN1 and SMN2 in amyotrophic lateral sclerosis (ALS) to analyse whether these genes also act as risk factors or phenotypic modulators in ALS. While homozygous deletion of SMN1 was not associated in ALS, abnormal SMN1 copy numbers significantly increased the risk of ALS. The role of the SMN2 gene in ALS needs further clarification. The existence of abnormal SMN1 copy numbers in ALS provides additional evidence that gene copy number variants may contribute to neurodegeneration and might open new approaches to treatment.
 ...
PMID:The importance of the SMN genes in the genetics of sporadic ALS. 1992 37

The association between survivor motor neuron (SMN) gene deletions and motor neuron diseases such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) suggest that sporadic lower motor neuron disease (LMND) may be related to SMN gene deletion. We examined the association between copy numbers of SMN and the risk of LMND among Koreans. We genotyped the copy number of SMN1 and SMN2 in 18 patients diagnosed with sporadic LMND and 100 neurologically healthy subjects using the multiplex ligation-dependent probe amplification (MLPA) method. A total of eight SMN1:SMN2 genotypes (1:1, 1:3, 2:0, 2:1, 2:2, 2:3, 3:2, and 2:2/3:1 of exon7/exon8) were found. We found that homozygous deletion of SMN2 was significantly related to LMND (OR 20.7; 95% CI 2.8-150.5; p = 0.003). There was no significant difference in the distribution of the SMN1 copy number between the LMND patients and controls. In contrast to ALS, the risk of which is influenced by various factors other than SMN copy number itself, the association studies in LMND show a consistent finding that homozygous deletion of SMN2 may be specifically related to LMND, despite the small number of subjects.
 ...
PMID:Association between survivor motor neuron 2 (SMN2) gene homozygous deletion and sporadic lower motor neuron disease in a Korean population. 2094 12

Spinal muscular atrophy (SMA), which is caused by inactivating mutations in the survival motor neuron 1 (SMN1) gene, is characterized by loss of lower motor neurons in the spinal cord. The gene encoding SMN is very highly conserved in evolution, allowing the disease to be modeled in a range of species. The similarities in anatomy and physiology to the human neuromuscular system, coupled with the ease of genetic manipulation, make the mouse the most suitable model for exploring the basic pathogenesis of motor neuron loss and for testing potential treatments. Therapies that increase SMN levels, either through direct viral delivery or by enhancing full-length SMN protein expression from the SMN1 paralog, SMN2, are approaching the translational stage of development. It is therefore timely to consider the role of mouse models in addressing aspects of disease pathogenesis that are most relevant to SMA therapy. Here, we review evidence suggesting that the apparent selective vulnerability of motor neurons to SMN deficiency is relative rather than absolute, signifying that therapies will need to be delivered systemically. We also consider evidence from mouse models suggesting that SMN has its predominant action on the neuromuscular system in early postnatal life, during a discrete phase of development. Data from these experiments suggest that the timing of therapy to increase SMN levels might be crucial. The extent to which SMN is required for the maintenance of motor neurons in later life and whether augmenting its levels could treat degenerative motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), requires further exploration.
 ...
PMID:The contribution of mouse models to understanding the pathogenesis of spinal muscular atrophy. 2170 1

Abnormal survival motor neuron 1 (SMN1)-copy number has been associated with an increased risk of amyotrophic lateral sclerosis (ALS) in French and Dutch population studies. The aim of this study was to determine whether SMN gene copy number increases the risk of ALS or modulates its phenotype in a cohort of Swedish sporadic ALS (SALS) patients. In all, 502 Swedes with SALS and 502 Swedish controls matched for gender and age were enrolled. SMN1 and SMN2 gene copy numbers were studied by a semi-quantitative PCR method. A genotype-phenotype comparison was performed in order to determine whether SMN genes modulate the phenotype of ALS. The results were also compared with our previously reported French cohort of ALS patients. There was no difference between Swedish patients and controls in the frequency of SMN1 and SMN2 copy numbers. The frequency of SMN1 gene copies differed significantly between the French and Swedish ALS populations. The duration of the disease was significantly longer in the Swedish cohort with homozygous deletions of SMN2 when compared with the French cohort. Abnormal SMN1 gene copy number cannot be considered as a universal genetic susceptibility factor for SALS and this result underlines the importance of reproducing association gene studies in groups from different origins. We also suggest that SMN2 gene copy number might have different effects on ALS progression in disparate human populations.
 ...
PMID:Homozygous SMN2 deletion is a protective factor in the Swedish ALS population. 2227 80

Survival Motor Neuron 1 (SMN1) is a causative gene for autosomal recessive infantile and juvenile proximal spinal muscular atrophy. SMN1 duplications have recently been found to increase susceptibility to amyotrophic lateral sclerosis. The role of centromeric SMN copy (SMN2) has been postulated in progressive muscular atrophy (PMA). The aim of this study was to analyse the SMN1 and SMN2 copy number variations in patients with PMA. SMN1 and SMN2 genotype was studied in 87 patients with PMA, diagnosed at the Department of Neurology, Medical University of Warsaw, between 1992 and 2012 and in 600 healthy controls. Results demonstrated that three copies of SMN1 were found in 8.1% of PMA patients and in 24% of PMA patients with disease duration above 48 months compared to 4.6% of the general population. Patients with three SMN1 copies had a limb onset, lower median age of onset and longer disease duration compared to patients with two SMN1 copies. There were no significant differences in the SMN2 copy numbers. In conclusion, the increased copy number of SMN1 may be a susceptibility factor to PMA and influence the clinical phenotype.
 ...
PMID:SMN1 gene duplications are more frequent in patients with progressive muscular atrophy. 2347 10


1 2 Next >>