Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autosomal recessive spinal muscular atrophy is a motor neuron disease which affects about 1 in 10,000 births. Recent evidence shows that the candidate region contains multiple copies of genes and pseudogenes and is characterised by genome instability. We have analysed the frequency of deletions in a recently characterised candidate survival motor neuron (SMN) gene. Our data confirm previous analyses and show that this gene is disrupted by deletion in SMA patients. The same deletion frequency is observed in the milder variants of the disease as in patients with the severe form. In addition, we observed one case of a new mutation in a family previously thought not to be segregating for a chromosome 5 linked form of SMA. This assay is a very good diagnostic for SMA although no direct correlation between phenotype and genotype is apparent and carrier status cannot be determined. The implications for the identification of the gene or genes causing the disease are discussed.
Hum Mol Genet 1995 Apr
PMID:Deletions in the survival motor neuron gene on 5q13 in autosomal recessive spinal muscular atrophy. 763 12

X-linked arthrogryposis Type I (X-linked infantile spinal muscular atrophy) is a rare disorder showing hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and death in infancy. We have studied an X-linked arthrogryposis family using highly polymorphic microsatellite markers throughout the X chromosome. Meiotic breakpoint analysis (concordance analysis) based on shared regions of the founder X chromosome was successful in localizing the X-linked arthrogryposis gene to Xp11.3-q11.2. In this region, the highest two-point lod score was found with DXS991 (Zmax = 2.63, theta = 0.00). In multipoint linkage analysis covering the entire X chromosome, only the region defined by MAOB and DXS991 showed positive lod scores and all other regions showed negative lod scores. These data establish the first gene mapping assignment of an X-linked lethal form of human lower motor neuron disease.
Hum Mol Genet 1995 Jul
PMID:A gene for a severe lethal form of X-linked arthrogryposis (X-linked infantile spinal muscular atrophy) maps to human chromosome Xp11.3-q11.2. 852 11

The mutation gly93-->ala of Cu,Zn superoxide dismutase (SOD) is found in patients with familial amyotrophic lateral sclerosis and causes motor neuron disease when expressed in transgenic mice. The progression of clinical and pathological disease was studied in a line of mice designated G1H. Clinical disease started at 91 +/- 14 days of age with fine shaking of the limbs, followed by paralysis and death by 136 +/- 7 days of age. Pathological changes begin by 37 days of age with vacuoles derived from swollen mitochondria accumulating in motor neurons. At the onset of clinical disease (90 days), significant death of somatic motor neurons innervating limb muscles has occurred; mice at end-stage disease (136 days) show up to 50% loss of cervical and lumbar motor neurons. However, neither thoracic nor cranial motor neurons show appreciable loss despite vacuolar changes. Autonomic motor neurons also are not affected. Mice that express wild-type human Cu,Zn SOD remain free of disease, indicating that mutations cause neuron loss by a gain-of-function. Thus, the age-dependent penetrance of motor neuron disease in this transgenic model is due to the gradual accumulation of pathological damage in select populations of cholinergic neurons.
Mol Cell Neurosci 1995 Aug
PMID:Age-dependent penetrance of disease in a transgenic mouse model of familial amyotrophic lateral sclerosis. 884 4

The wobbler mouse (wr) is an attractive model for studying motor neuron disease but the genetic defect is unknown. The beta-subunit of calmodulin kinase II (beta-CaMK II) is a good candidate for the wr mutation because of its chromosomal localization and tissue distribution. In this report, we found normal levels of CaM KII mRNA and enzyme activity making it highly unlikely that a mutation in the beta-CaM KII gene is the cause of the wr phenotype.
Brain Res Mol Brain Res 1996 Dec 31
PMID:Exclusion of the beta-subunit of type II calmodulin kinase for the wobbler spinal muscular atrophy gene. 903 49

The 38 kDa survival motor neuron (SMN) protein is encoded by two ubiquitously expressed genes: telomeric SMN (SMN(T)) and centromeric SMN (SMN(C)). Mutations in SMN(T), but not SMN(C), cause proximal spinal muscular atrophy (SMA), an autosomal recessive disorder that results in loss of motor neurons. SMN is found in the cytoplasm and nucleus. The nuclear form is located in structures termed gems. Using a panel of anti-SMN antibodies, we demonstrate that the SMN protein is expressed from both the SMN(T) and SMN(C) genes. Western blot analysis of fibroblasts from SMA patients with various clinical severities of SMA showed a moderate reduction in the amount of SMN protein, particularly in type I (most severe) patients. Immunocytochemical analysis of SMA patient fibroblasts indicates a significant reduction in the number of gems in type I SMA patients and a correlation of the number of gems with clinical severity. This correlation to phenotype using primary fibroblasts may serve as a useful diagnostic tool in an easily accessible tissue. SMN is expressed at high levels in brain, kidney and liver, moderate levels in skeletal and cardiac muscle, and low levels in fibroblasts and lymphocytes. In SMA patients, the SMN level was moderately reduced in muscle and lymphoblasts. In contrast, SMN was expressed at high levels in spinal cord from normals and non-SMA disease controls, but was reduced 100-fold in spinal cord from type I patients. The marked reduction of SMN in type I SMA spinal cords is consistent with the features of this motor neuron disease. We suggest that disruption of SMN(T) in type I patients results in loss of SMN from motor neurons, resulting in the degeneration of these neurons.
Hum Mol Genet 1997 Aug
PMID:The survival motor neuron protein in spinal muscular atrophy. 925 65

IgM antibodies directed against neuronal gangliosides GM1, GM2, GD1a, GD1b and GT1b occur in normal individuals and their level significantly decreases with age. Patients with lower motor neuron disease (LMND) produce high levels of these autoantibodies. AntiGM1 IgM is selectively augmented. In these patients, the CD5+ (B1) and CD5- (B2) subsets of B cells are not distinct entities but range from those without detectable CD5 marker to those with high CD5+ expression. B1 B cells were sorted to homogeneity, but B2 B cell cannot be isolated to homogeneity because of the presence of B1 cells with low CD5 expression. In short term cultures both the subsets produced IgM antibodies, but the antibodies reacted better with desialylated GM1 than with GM1. Cycloheximide (Cx) (0.35 mM) largely blocked IgM synthesis of the B1 B cells but inhibition of the B2 B cells was incomplete, possibly due to shedding of cytophilic antibodies as well as to the presence of B1 phenotype with loss of CD5 expression. CD5+ B cells may be involved in the production of antiglycolipid IgM.
Cell Mol Life Sci 1997 Sep
PMID:Augmentation of natural antiganglioside IgM antibodies in lower motor neuron disease (LMND) and role of CD5+ B cells. 936 72

Motor neurone disease is a rapidly progressive neurodegenerative disorder, characterized by muscular weakness and wasting with fasciculation and by spasticity. While most cases are sporadic, approximately 10% are inherited in an autosomal dominant mode. Recently, mutations in the gene encoding the free-radical scavenging enzyme superoxide dismutase-1 have been found to segregate with the disorder in 20% of familial cases. This is an exciting development, as free radical damage has long been implicated in the pathogenesis of motor neurone disease and it raises the possibility of novel therapeutic approaches in this otherwise fatal condition.
Mol Med Today 1995 Jul
PMID:Mechanisms in motor neurone disease: clues from genetic studies. 941 57

Human amyotrophic lateral sclerosis (ALS), a typical motor neuron disease, is characterized pathologically by selective degenerative loss of motoneurons in the CNS. We have demonstrated significant reductions of neurotransmitter-related factors, such as acetylcholine-(ACh)-synthesizing enzyme activity and glutamate and aspartate contents in the ALS, compared to the non-ALS spinal cord obtained at autopsy. We have also shown considerable reductions in activities of cytochrome-c oxidase (CO), an enzyme contributing to aerobic energy production, and transglutaminase (TG), a Ca(2+)-dependent marker enzyme for tissue degeneration, in the ALS spinal cord. We found marked increases in fragmented glial fibrillary acidic protein (GFAP), a filamentous protein specifically associated with reactive astrocytes, in the ALS spinal cord relative to non-ALS tissue. These biochemical results corresponded well to pathomor-phological neuronal degenerative loss and reactive proliferation of astroglial components in the ALS spinal cord tissue. However, these results only indicate the final pathological and biochemical outcomes of ALS, and it is difficult to follow up cause and process in the ALS spinal cord during progression of the disease. Therefore, we used an animal model closely resembling human ALS, motor neuron degeneration (Mnd) mutant mice, a subline of C57BL/6 that shows late-onset progressive degeneration of lower motor neurons with paralytic gait beginning around 6.5 mo of age, to follow the biochemical and pathological alterations during postnatal development. We detected significant decreases in CO activity during early development and in activity of superoxide dismutase (SOD), an antioxidant enzyme, in later stages in Mnd mutant spinal cord tissue. TG activity in the Mnd spinal cord showed gradual increases during early development reaching a maximum at 5 mo, and then tending to decrease thereafter. Amounts of fragmented GFAPs increased continuously during postnatal development in Mnd spinal cord. These biochemical changes were observed prior to the appearance of clinical motor dysfunctions in the Mnd mutant mice. Such biochemical analyses using appropriate animal models will be useful for inferring the origin and progression of human ALS.
Mol Chem Neuropathol 1998 Apr
PMID:Neurochemical changes in the spinal cord in degenerative motor neuron diseases. 964 76

Proximal spinal muscular atrophy (SMA) is a common motor neuron disease in humans and in its most severe form causes death by the age of 2 years. It is caused by defects in the telomeric survival motor neuron gene ( SMN1 ), but patients retain at least one copy of a highly homologous gene, centromeric SMN ( SMN2 ). Mice possess only one survival motor neuron gene ( Smn ) whose loss is embryonic lethal. Therefore, to obtain a mouse model of SMA we created transgenic mice that express human SMN2 and mated these onto the null Smn (-/-)background. We show that Smn (-/-); SMN2 mice carrying one or two copies of the transgene have normal numbers of motor neurons at birth, but vastly reduced numbers by postnatal day 5, and subsequently die. This closely resembles a severe type I SMA phenotype in humans and is the first report of an animal model of the disease. Eight copies of the transgene rescues this phenotype in the mice indicating that phenotypic severity can be modulated by SMN2 copy number. These results show that SMA is caused by insufficient SMN production by the SMN2 gene and that increased expression of the SMN2 gene may provide a strategy for treating SMA patients.
Hum Mol Genet 2000 Feb 12
PMID:The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(-/-) mice and results in a mouse with spinal muscular atrophy. 1065 41

The motor neuron disease spinal muscular atrophy (SMA) is caused by reduced levels of functional survival of motor neurons (SMN) protein. Previous studies have shown that SMN binds to the SMN-interacting protein SIP1 and mediates the assembly of spliceosomal U snRNPs in the cytoplasm. In addition, a nuclear function for SMN in pre-mRNA splicing has recently been proposed. Here, we describe the analysis of the Schizo-saccharomyces pombe protein Yab8p and provide evidence that it is structurally and functionally related to SMN found in higher eukaryotes. We show that Yab8p interacts via its N-terminus with a novel protein termed Yip1p. Importantly, Yip1p exhibits homology to SIP1, and the mode of binding to Yab8p is remarkably similar to the SMN-SIP1 interaction. Hence, Yip1p is likely to be the homologue of SIP1 in S.pombe. Yab8p and Yip1p localize predominantly in the nucleus. Genetic studies demonstrate that Yab8p is essential for viability. Strikingly, suppression of YAB8 expression in a conditional knock-out strain causes nuclear accumulation of poly(A) mRNA and inhibition of splicing. These data identify Yab8p as a novel factor involved in splicing and suggest that Yab8p exerts a function similar or identical to the nuclear pool of SMN. Our studies provide a model system to study the cellular function of SMN in yeast, and should help in understanding the molecular events leading to SMA.
Hum Mol Genet 2000 Mar 22
PMID:The Schizosaccharomyces pombe protein Yab8p and a novel factor, Yip1p, share structural and functional similarity with the spinal muscular atrophy-associated proteins SMN and SIP1. 1074 73


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