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)

Increased length of a protein-coding CAG repeat within the androgen receptor gene appears to be the only type of mutation responsible for spino-bulbal muscular atrophy (SBMA or Kennedy disease). We have analysed a large 4-generation SBMA family and found that the mutant allele was unstable upon transmission from parent to child, with a documented variation from 46 to 53 repeats and a tendency to increase in size (7 increases and a single decrease in 17 events), which appeared stronger upon transmission from a male than from a female. Our results suggest also limited somatic instability of the abnormal allele, with observable variation of up to 2-3 repeats. This indicates that the behavior of the CAG repeat is similar to that observed for small premutations in the fragile X syndrome, or small abnormal alleles in myotonic dystrophy, two diseases which are caused by expansion of an unstable trinucleotide repeat.
Hum Mol Genet 1992 Jul
PMID:Moderate instability of the trinucleotide repeat in spino bulbar muscular atrophy. 130 95

The candidate region for spinal muscular atrophy (SMA) has been defined as a 750 kb interval on 5q13. In this study, we performed allelic association studies in 154 German SMA families with the multicopy markers Ag1-CA (D5S1556); C212 (D5F149S1/S2) and correlated genotype data with deletion of candidate genes. Both multicopy markers recognize 0-3 alleles pro chromosome. Deletions were detected for all copies of the markers Ag1-CA (C272) and C212 in 13 of 88 (15%) type I SMA patients and three of 48 (6%) type II patients. In all informative cases, the deletion was inherited from one parent. In two further cases (one type I and one type III SMA), de novo deletions of only one copy of Ag1-CA and C212 were found. In both cases the patients were homozygously deleted for the survival motor neuron (SMN) gene (exons 7 and 8) but only the type I SMA patient was deleted for the neuronal apoptosis inhibitory protein (NAIP) gene (exons 5 and 6). A third case (type II SMA) showed de novo deletion of SMN, but not of Ag1-CA, C212 and NAIP. Specific alleles of Ag1-CA and C212 showed significant association with SMA, particularly in type I SMA. When the number of marker copies defines genotypes, 1,1 (one allele on each chromosome) is found to be increased in type I SMA (50%) and 1,2 (one allele on one chromosome and two alleles on the other one) in type II SMA (60%). The 2,2 genotype (two alleles on each chromosome) was found in 4% of type I and II patients. By comparison, pooled normal genotype frequencies were 20, 44 and 36%, respectively. These results suggest a strong correlation between genotype and severity of disease. Based on these data we propose a model which indicates that type I SMA patients are composed of two severe alleles, type II of a mild and a severe, and type III of two mild alleles. Correlation of Ag1-CA genotype with deletion of the XS2G3/NAIP genes indicates that most patients with a deletion have a 1,1 genotype. Owing to the physical proximity of these markers, we propose that a large deletion occurs on type I SMA chromosomes that removes DNA between C212 and XS2G3/NAIP and that type II SMA results from compound heterozygosity for mild (small deletion) and severe mutations.
Hum Mol Genet 1995 Aug
PMID:Allelic association and deletions in autosomal recessive proximal spinal muscular atrophy: association of marker genotype with disease severity and candidate cDNAs. 758 64

We have reported that polyglutamine (polyGln)-expanded human androgen receptors (hAR) have reduced transactivational competence in transfected cells. We presumed that maximal hAR transactivation requires a normal-size polyGln tract. Here we report, however, that hAR transactivity and polyGln-tract length are related inversely: n = 0 > 12 > 20 > 40 > 50. Thus, a normal-size polyGln tract represses the transactivational competence of a polyGln-free hAR, and polyGln expansion increases that negative effect. This observation has pathogenetic implications for X-linked spinobular muscular atrophy (Kennedy syndrome), and possibly for the autosomal dominant central neuronopathies associated with (CAG)n expansion in the translated portion of four different genes.
Hum Mol Genet 1995 Apr
PMID:Evidence for a repressive function of the long polyglutamine tract in the human androgen receptor: possible pathogenetic relevance for the (CAG)n-expanded neuronopathies. 763 99

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

Myotonic dystrophy (DM) is the most common form of inherited neuromuscular disease in adults and is characterized by progressive muscle wasting and myotonia. The mutation responsible for DM has been identified as the amplification of a polymorphic (CTG)n repeat in the 3' untranslated region of a gene encoding a serine/threonine kinase (DMK). We have produced a polyclonal rabbit antibody preparation against a fusion protein encoding the C-terminal amino acids 471-629 of the human DMK gene. This antibody specifically detects products of both full length and truncated human DMK genes expressed in bacteria and in insect cells. On immunoblots, we observed protein species of approximately 74 and 82 kDa in cardiac muscle, skeletal muscle, ependyma and choroid plexus. By immunofluorescence, DMK was found to localize post-synaptically at the neuromuscular junction of skeletal muscle, at intercalated discs of cardiac tissue and at the apical membrane of the ependyma and choroid plexus. We have also detected two to three species (approximately 45-50 kDa) in other regions of the brain. Synaptic localization of DMK in the cerebellum, hippocampus, midbrain and medulla was noted. These results suggest that DMK plays a specialized role in intercellular communication.
Hum Mol Genet 1995 Jun
PMID:Characterization of myotonic dystrophy kinase (DMK) protein in human and rodent muscle and central nervous tissue. 765 60

The gene for the common recessive neuromuscular disorder spinal muscular atrophy (SMA) has been previously mapped to chromosome 5q. We report here linkage disequilibrium analyses of two polymorphic simple tandem repeat (STR) sequences which map into the critical region of 5q13 containing the SMA gene. The polymorphisms presented are constituents of CATT-1, a complex STR which is present in as many as four or more copies per chromosome 5. The PCR can amplify as many as eight CATT-1 products of different sizes from genomic DNA samples due to differing numbers of CA dinucleotides at each STR location (sublocus). Oligonucleotide primers for two of these subloci have been developed for specific PCR assays; a variety of allele sizes can be generated with each assay and, in some cases, no amplification products are detected due to null alleles. The genotyping of 149 SMA Type 1 chromosomes and 142 normal chromosomes from Canadian and American kindreds reveals the presence of significant linkage disequilibrium between the null allele of the sublocus referred to as CATT-40G1 and mutation(s) causing SMA Type 1 (Werdnig-Hoffmann disease). Allele 2 of the second sublocus, CATT-192F7, is also in linkage disequilibrium with SMA Type 1 although the degree of this association is less than that found for CATT-40G1. The proximal and distal STRs from the critical region, D5S435 and D5S351, showed no linkage disequilibrium with SMA. The data presented here will serve as a framework for future linkage disequilibrium analyses, expediting the final stage of the search for the SMA gene.
Hum Mol Genet 1994 Nov
PMID:Two 5q13 simple tandem repeat loci are in linkage disequilibrium with type 1 spinal muscular atrophy. 787 11

Muscle weakness in glucocorticoid myopathy results mainly from muscle atrophy, the reason for which is the accelerated catabolism of muscle proteins. As the content of lysosomes in skeletal muscle, particularly in fast-twitch glycolytic fibers, is relatively low the non-lysosomal pathway makes a particularly significant contribution and has special importance in the initial rate-limiting steps in the catabolism of contractile proteins and in the regulation of their turnover rate. The turnover rate of actin and the myosin heavy chain is decreased in all types of muscle fibers, and more rapid turnover of the myosin light chain is registered in the fast-twitch glycolytic and oxidative-glycolytic fibers. Exercise and simultaneous glucocorticoid treatment is an effective measure in retarding skeletal muscle atrophy and provides protection against muscle wasting.
J Steroid Biochem Mol Biol 1994 Jul
PMID:Turnover of skeletal muscle contractile proteins in glucocorticoid myopathy. 804 26

DNA was recovered from sections of muscle biopsies of 20 spinal muscular atrophy (SMA) patients fixed on microscopic slides and stored from one to 20 years at room temperature. Microsatellite DNA markers tightly linked to the SMA locus were amplified using the polymerase chain reaction (PCR) to obtain specific amplified products. The procedure was successful in all cases, and allowed prenatal diagnosis in one at-risk pregnancy. In our hands this procedure is quick, sensitive and reproducible.
Mol Cell Probes 1993 Jun
PMID:A tool for the molecular analysis of an early lethal disease: slide-PCR in spinal muscular atrophy patients. 836 67

Thyroid hormones are essential for the normal growth and development of many tissues. In the rat, hypothyroidism is associated with growth impairment, and hyperthyroidism with the development of a hypercatabolic state and skeletal muscle wasting but, paradoxically, cardiac hypertrophy. The mechanism by which thyroid hormone produces cardiac hypertrophy and myosin isoenzyme changes remains unclear. The role of IGF-I, an anabolic hormone with both paracrine and endocrine actions, in producing cardiac hypertrophy was investigated during this study in hyperthyroid, hypothyroid and control rats. A treated hypothyroid group was also included in order to assess the effect of acute normalization of thyroid function. Body weight was significantly lower in the hyperthyroid (mean +/- S.E.M.; 535.5 +/- 24.9 g, P < 0.05), hypothyroid (245.3 +/- 9.8 g, P < 0.001) and treated hypothyroid (265.3 +/- 9.8 g, P < 0.001) animals when compared with controls (618.5 +/- 28.6 g). Heart weight/body weight ratios were, however, significantly increased in the hyperthyroid (2.74 +/- 0.11 x 10(-3), P < 0.01) and treated hypothyroid (2.87 +/- 0.07 x 10(-3), P < 0.001) animals when compared with controls (2.26 +/- 0.03 x 10(-3). Serum IGF-I concentrations were similar in the control and hyperthyroid rats (0.91 +/- 0.07 vs 0.78 +/- 0.04 U/ml, P = 0.26), but bioactivity was reduced by 70% in hyperthyroid serum, suggesting a circulating inhibitor of IGF. Serum IGF-I levels (0.12 +/- 0.03 U/ml, P < 0.001) and bioactivity (0.12 +/- 0.04 U/ml, P < 0.001) were significantly lower in the hypothyroid group. Liver IGF-I mRNA levels were not statistically different in the control and hyperthyroid animals, but were significantly reduced in the hypothyroid animals (P < 0.05 vs control). Heart IGF-I mRNA levels were similar in the control and hypothyroid rats, but were significantly increased in the hyperthyroid and treated hypothyroid animals (increased by 32% in hyperthyroidism, P < 0.05; increased by 57% in treated hypothyroidism, P < 0.01). Cardiac IGF-I was significantly elevated in hyperthyroidism (0.16 +/- 0.01 U/mg heart tissue, P < 0.01), was low in hypothyroidism (0.08 +/- 0.01 U/mg, P < 0.01) and was normalized in the treated hypothyroid group (0.11 +/- 0.01 U/mg vs control, 0.13 +/- 0.01 U/mg). Low body mass during both hypothyroidism and hyperthyroidism is therefore associated with reduced systemic IGF bioactivity. In hypothyroidism there is a primary defect in the endocrine function of IGF-I, while in hyperthyroidism serum IGF bioactivity is reduced in the presence of normal endocrine production of this anabolic hormone.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Endocrinol 1993 Jun
PMID:Endocrine and cardiac paracrine actions of insulin-like growth factor-I (IGF-I) during thyroid dysfunction in the rat: is IGF-I implicated in the mechanism of heart weight/body weight change during abnormal thyroid function? 837 15

We have constructed a contig of non-chimaeric yeast artificial chromosomes (YACs) across the candidate region for childhood autosomal recessive spinal muscular atrophy (SMA) in 5q13. A novel microsatellite reduces the candidate region to approximately 400kb of DNA distal to D5S435. The candidate region contains blocks of chromosome 5 specific repeats which have copies on 5p as well as elsewhere on 5q. Restriction mapping of the YACs reveals at least one CpG island in the SMA gene region. The YAC maps indicate that the contig contains minimal rearrangements or deletions. The data show the value of screening several YAC libraries simultaneously in order to construct a set of overlapping sequences suitable for candidate gene searches and direct genomic sequencing.
Hum Mol Genet 1993 Aug
PMID:A contig of non-chimaeric YACs containing the spinal muscular atrophy gene in 5q13. 840 97


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