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)

Patients with Dunnigan-type familial partial lipodystrophy (FPLD) are born with normal fat distribution, but after puberty experience regional and progressive adipocyte degeneration, often associated with profound insulin resistance and diabetes. Recently, the FPLD gene was mapped to chromosome 1q21-22, which harbours the LMNA gene encoding nuclear lamins A and C. Mutations in LMNA were shown to underlie autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD-AD), which is characterized by regional and progressive skeletal muscle wasting and cardiac effects. We hypothesized that the analogy between the regional muscle wasting in EDMD-AD and the regional adipocyte degeneration in FPLD, in addition to its chromosomal localization, made LMNA a good candidate gene for FPLD. DNA sequencing of LMNA in five Canadian FPLD probands indicated that each had a novel missense mutation, R482Q, which co-segregated with the FPLD phenotype and was absent from 2000 normal alleles ( P = 1.1 x 10(-13)). This is the first report of a mutation underlying a degenerative disorder of adipose tissue and suggests that LMNA mutations could underlie other diseases characterized by tissue type- and anatomical site-specific cellular degeneration.
Hum Mol Genet 2000 Jan 01
PMID:Nuclear lamin A/C R482Q mutation in canadian kindreds with Dunnigan-type familial partial lipodystrophy. 1058 85

Spinal and bulbar muscular atrophy (SBMA) is associated with an abnormal expansion of the (CAG)(n)repeat in the androgen receptor (AR) gene. Similar mutations have been reported in other proteins that cause neurodegenerative disorders. The CAG-coded elongated polyglutamine (polyGln) tracts induce the formation of neuronal intracellular aggregates. We have produced a model to study the effects of potentially 'neurotoxic' aggregates in SBMA using immortalized motoneuronal cells (NSC34) transfected with AR containing polyGln repeats of different sizes [(AR.Q(n = 0, 23 or 46)]. Using chimeras of AR.Q(n) and the green fluorescent protein (GFP), we have shown that aggregate formation occurs when the polyGln tract is elongated and AR is activated by androgens. In NSC34 cells co-expressing the AR with the polyGln of pathological length (AR.Q46) and the GFP we have noted the presence of several dystrophic neurites. Cell viability analyses have shown a reduced growth/survival rate in NSC34 expressing the AR.Q46, whereas testosterone treatment partially counteracted both cell death and the formation of dystrophic neurites. These observations indicate the lack of correlation between aggregate formation and cell survival, and suggest that neuronal degeneration in SBMA might be secondary to axonal/dendritic insults.
Hum Mol Genet 2000 Jan 01
PMID:Motoneuronal cell death is not correlated with aggregate formation of androgen receptors containing an elongated polyglutamine tract. 1058 88

Androgen ablation therapy is a primary treatment for advanced prostate cancer, but tumors become refractive to therapy. Consequently, the role of the androgen receptors (ARs) and of mutations in the AR in prostate cancer has been a subject of much concern. In the course of analyzing tumors for mutations, we identified a somatic mutation that substitutes tyrosine for a cysteine at amino acid 619 (C619Y), which is near the cysteines that coordinate zinc in the DNA binding domain in the AR. The mutation was re-created in a wild-type expression vector and functional analyses carried out using transfection assays with androgen-responsive reporters. The mutant is transcriptionally inactive and unable to bind DNA. In response to ligand treatment, AR619Y localizes abnormally in numerous, well circumscribed predominantly nuclear aggregates in the nucleus and cytoplasm. Interestingly, these aggregates also contain the bulk of the coexpressed steroid receptor coactivator SRC-1, suggesting, in analogy to AR in spinal bulbar muscular atrophy, that this mutant may alter cellular physiology through sequestration of critical proteins. Although many inactivating mutations have been identified in androgen insensitivity syndrome patients, to our knowledge, this is the first characterization of an inactivating mutation identified in human prostate cancer.
Mol Endocrinol 1999 Dec
PMID:A C619Y mutation in the human androgen receptor causes inactivation and mislocalization of the receptor with concomitant sequestration of SRC-1 (steroid receptor coactivator 1) 1059 82

Amyotrophic lateral sclerosis (ALS), also referred to as motor neurone disease, is a fatal neurological disease that is characterized clinically by progressive muscle weakness, muscle atrophy, and eventual paralysis. The neuropathology of ALS is primary degeneration of upper (motor cortical) and lower (brainstem and spinal) motor neurons. The amyotrophy refers to the neurogenic atrophy of affected muscle groups, and the lateral sclerosis refers to the hardening of the lateral white matter funiculus in spinal cord (corresponding to degeneration of the corticospinal tract) found at autopsy. Because the mechanisms for the motor neuron degeneration in ALS are not understood, this disease has no precisely known causes and no effective treatments. Very recent studies have identified that the degeneration of motor neurons in ALS is a form of apoptotic cell death that may occur by an abnormal programmed cell death (PCD) mechanism. In order to treat ALS effectively, we need to understand the mechanisms for motor neuron apoptosis more completely. Future studies need to further identify the signals for PCD activation in neurons as they relate to the pathogenesis of ALS and to clarify the molecular pathways leading to motor neuron apoptosis in animal and cell culture model systems. These studies should lead to a better understanding of motor neuron death and to the design of new therapeutic experiments critical for the future treatment of ALS.
Int J Mol Med 2000 Jan
PMID:Mechanisms for neuronal degeneration in amyotrophic lateral sclerosis and in models of motor neuron death (Review). 1060 67

The survival motor neuron genes, SMN1 and SMN2, encode identical proteins; however, only homo- zygous loss of SMN1 correlates with the development of spinal muscular atrophy (SMA). We have previously shown that a single non-polymorphic nucleotide difference in SMN exon 7 dramatically affects SMN mRNA processing. SMN1 primarily produces a full-length RNA whereas SMN2 expresses dramatically reduced full-length RNA and abundant levels of an aberrantly spliced transcript lacking exon 7. The importance of proper exon 7 processing has been underscored by the identification of several mutations within splice sites adjacent to exon 7. Here we show that an AG-rich exonic splice enhancer (ESE) in the center of SMN exon 7 is required for inclusion of exon 7. This region functioned as an ESE in a heterologous context, supporting efficient in vitro splicing of the Drosophila double-sex gene. Finally, the protein encoded by the exon-skipping event, Delta7, was less stable than full-length SMN, providing additional evidence of why SMN2 fails to compensate for the loss of SMN1 and leads to the development of SMA.
Hum Mol Genet 2000 Jan 22
PMID:An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN. 1060 36

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

Spinal muscular atrophy (SMA) is caused by deletion or specific mutations of the telomeric survival motor neuron ( SMN ) gene on human chromosome 5. The human SMN gene, in contrast to the Smn gene in mouse, is duplicated and the centromeric copy on chromosome 5 codes for transcripts which preferentially lead to C-terminally truncated SMN protein. Here we show that a 46% reduction of Smn protein levels in the spinal cord of Smn heterozygous mice leads to a marked loss of the cytoplasmic Smn pool and motor neuron degeneration resembling spinal muscular atrophy type 3. Smn heterozygous mice described here thus represent a model for the human disease. These mice could allow screening for SMA therapies and help in gaining further understanding of the pathophysiological events leading to motor neuron degeneration in SMA.
Hum Mol Genet 2000 Feb 12
PMID:Reduced survival motor neuron (Smn) gene dose in mice leads to motor neuron degeneration: an animal model for spinal muscular atrophy type III. 1065 42

We have analyzed Ca2+ currents in two neuroblastoma-motor neuron hybrid cell lines that expressed normal or glutamine-expanded human androgen receptors (polyGln-expanded AR) either transiently or stably. The cell lines express a unique, low-threshold, transient type of Ca2+ current that is not affected by L-type Ca2+ channel blocker (PN 200-110), N-type Ca2+ channel blocker (omega-conotoxin GVIA) or P-type Ca2+ channel blocker (Agatoxin IVA) but is blocked by either Cd2+ or Ni2+. This pharmacological profile most closely resembles that of T-type Ca2+ channels [1-3]. Exposure to androgen had no effect on control cell lines or cells transfected with normal AR but significantly changed the steady-state activation in cells transfected with expanded AR. The observed negative shift in steady-state activation results in a large increase in the T-type Ca2+ channel window current. We suggest that Ca2+ overload due to abnormal voltage-dependence of transient Ca2+ channel activation may contribute to motor neuron toxicity in spinobulbar muscular atrophy (SBMA). This hypothesis is supported by the additional finding that, at concentrations that selectively block T-type Ca2+ channel currents, Ni2+ significantly reduced cell death in cell lines transfected with polyGln-expanded AR.
Mol Cell Biochem 2000 Jan
PMID:Increased T-type Ca2+ channel activity as a determinant of cellular toxicity in neuronal cell lines expressing polyglutamine-expanded human androgen receptors. 1072 29

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

Childhood onset spinal muscular atrophy (SMA) is a common autosomal recessive disorder primarily characterized by the loss of lower alpha motor neurons. The underlying chromosomal defects causing SMA have been found in the survival motor neuron (SMN) gene. SMN has been shown previously to play a role in both snRNP biogenesis and mRNA processing, although direct evidence for the relationship between SMN and disease pathology has not been elucidated. SMN orthologues have been isolated in many species including Caenorhabditis elegans and Danio rerio. To study the function of SMN, we have identified and characterized the Schizosaccharomyces pombe orthologue of human SMN, smn1 (+). We have demonstrated that smn1 (+) is essential for viability in S.pombe and yeast expressing missense mutations in Smn1p, which mimic mutations in patients with Type I SMA, show significant mislocalization of the protein and a decrease in cell viability. Wild-type Smn1p is localized predominantly in the nucleus whereas yeast expressing Smn1p with missense mutations or deletions of specific domains of the protein accumulate cytoplasmic aggregates. Overexpression of Smn1p results in an increase in the growth rate of cells. Furthermore, mutations within two highly conserved protein interaction domains have a dominant-negative effect on growth, indicating that each domain is of functional significance in S.pombe. These dominant phenotypes can be suppressed by overexpression of murine Smn in the same cell. Given the structural and functional similarities between the protein in fission yeast and higher eukaryotes, S.pombe will be an ideal organism to study the role of SMN in RNA processing.
Hum Mol Genet 2000 Mar 22
PMID:Characterization of the Schizosaccharomyces pombe orthologue of the human survival motor neuron (SMN) protein. 1074 74


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