Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Androgen activity in the central nervous system, as in other tissues, is mediated by the androgen receptor. We performed the precise localization of the androgen receptor in spinal cord of male and female adult rats by immunohistochemistry using polyclonal antibodies. Light microscopy indicated immunoreactivity in the anterior horn with a strong staining in motoneurons, but staining was also observed in the posterior horn. Electron microscopy showed a predominant nuclear immunostaining. A weaker but significant immunoreactive androgen receptor was also noted in the perinuclear/ intracysternal position. Moreover, no differences were found between male and female rats. Immunoblotting demonstrated that the androgen receptor is expressed in both ventral and dorsal spinal cord, with an apparent molecular mass identical to that noted in other androgen-dependent tissues. The expression of androgen receptor in motoneurons corroborates the role of androgens in motoneuron growth, development and regeneration and underlies the possibility that androgen receptor abnormality leads to the motoneuron degeneration observed in X-linked spinal and bulbar muscular atrophy.
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PMID:Immunohistochemical localization and immunoblotting of androgen receptor in spinal neurons of male and female rats. 866 84

X-linked spinal and bulbar muscular atrophy (SBMA) is a late-onset motor neuron disorder which is caused by an expansion of the trinucleotide repeat (CAG)n in the first exon of the androgen receptor gene. Two cases of prenatal testing for the disease in a Greek family are reported. An affected male died in his late 50s of this disorder and his 30-year-old daughter (an obligate carrier) asked for prenatal testing for SBMA. DNA analysis revealed that she indeed carried an expanded allele of 40 repeats, as well as a normal size allele of 24 repeats. Prenatal diagnosis of SBMA was performed when, on two successive pregnancies, two male fetuses with the expanded (CAG)n allele were found.
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PMID:Prenatal diagnosis of X-linked spinal and bulbar muscular atrophy in a Greek family. 871 Jul 82

Expansion of CAG trinucleotide repeats in androgen receptor gene is present in patients with a rare X-linked inherited form of motor neuron disorder termed Kennedy's disease or spinal and bulbar muscular atrophy (SBMA). This is a late onset progressive disease often associated with mild signs of androgen insensitivity. Defects in androgen receptor (AR) action have been linked to the expansion of the CAG trinucleotide repeats and postulated to be the cause of the disease. We have identified a trinucleotide repeat of 45 in the N-terminus of the AR in two brothers with SBMA and several members in their family (range in the general population is 11-35). Treatment of the patients with androgens failed to improve their clinical symptoms and provided no hint of an anomalous function of the AR. Consistently, functional analysis of the mutant receptor showed hormone binding, transactivation and transrepression potentials identical to that of the wild-type receptor. These results together argue against SBMA being a loss of function mutation of the AR.
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PMID:CAG-repeat expansion in androgen receptor in Kennedy's disease is not a loss of function mutation. 873 74

Kennedy's disease, or spinal and bulbar muscular atrophy (SBMA), is a rare X-linked motoneuron disorder with variable signs of androgen insensitivity. It is associated with the expansion of a trinucleotide CAG repeat within the androgen receptor (AR) gene. We here report our clinical and molecular findings in two Italian families with Kennedy's disease. The increased size of the CAG repeat was demonstrated in four affected males and seven carrier females.
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PMID:Kennedy's disease: clinical and molecular study of two Italian families. 874 4

Expansion of trinucleotide repeats has now been associated with eight inherited diseases: X-linked spinal and bulbar muscular atrophy, two fragile X syndromes, myotonic dystrophy, Huntington's disease, spinocerebellar ataxia type I, dentatorubral pallidoluysian atrophy and Machado-Joseph disease. It has been shown that these expanded DNA repeats are unstable in number when transmitted from parents to offspring ("meiotic instability"), while somatic variation in repeat number has also been found in the fragile X syndrome and myotonic dystrophy. Moderate meiotic instability has been demonstrated in X-linked spinal and bulbar muscular atrophy (SBMA, Kennedy's disease). In order to determine if the expanded CAG repeat in SBMA also shows somatic instability, we compared different tissues from two patients with SBMA. We then examined the in vitro stability of the CAG repeat expansion by analyzing fibroblast cell cultures. Length comparison of expanded CAG repeats from all these materials clearly demonstrates that the CAG trinucleotide repeat in SBMA does not exhibit somatic variation.
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PMID:Somatic stability of the expanded CAG trinucleotide repeat in X-linked spinal and bulbar muscular atrophy. 880 33

Trinucleotide repeat expansion is increasingly recognized as a cause of neurogenetic diseases. To date, seven diseases have been identified as expanded repeat disorders: the fragile X syndrome of mental retardation both FRAXA and FRAXE loci), myotonic dystrophy, X-linked spinal and bulbar muscular atrophy, Huntington's disease, spinocerebellar ataxia type I, dentatorubral-pallidoluysian atrophy, and Machado-Joseph disease. All are neurologic disorders, affecting one or more regions of the neuraxis. Moreover, five of the seven (the last five above) are progressive neurodegenerative disorders whose strikingly similar mutations suggest a common mechanism of neuronal degeneration. In this article we discuss specific characteristics of each trinucleotide repeat disease, review their shared clinical and genetic features, and address possible molecular mechanisms underlying the neuropathology in each disease. Particular attention is paid to the neurodegenerative diseases, all of which are caused by CAG repeats encoding polyglutamine tracts in the disease gene protein.
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PMID:Trinucleotide repeats in neurogenetic disorders. 883 37

Kennedy's disease (spinal and bulbar muscular atrophy) is an X-linked form of motor neuron disease that affects adult men. The syndrome is characterized by progressive atrophy of the limb muscles, pelvic and shoulder girdles and dysphagia and dysarthria, and is caused by the degeneration of spinal and bulbar motor neurons. Kennedy's disease is caused by a trinucleotide repeat expansion of a CAG repeat in exon A of the androgen receptor gene, and is one of a group of neurological diseases caused by trinucleotide repeat expansions in different genes. The mutation in Kennedy's disease involves an increased number of glutamine residues in the amino-terminal domain of the receptor. Point mutations and deletions in the androgen receptor gene cause androgen insensitivity syndrome, however subjects with Kennedy's disease have normal virilization, although progressive gynaecomastia, testicular atrophy and infertility may occur. Androgen receptors are expressed widely in the normal brain, and in the anterior horn cells of the spinal cord; however, their role in neuronal tissue is not known, nor is it known how the androgen receptor gene mutation causes neuronal degeneration. Kennedy's disease is likely to be a 'gain of function' abnormality, so that the presence of the receptor with an increased number of glutamines is toxic to motor neurons. It is possible that the mutation alters interaction of the receptor with other neuronal transcription factors, or neuronotoxicity may occur because of a non-specific effect caused by the presence of a protein with a large homoglutamine domain. Studies of patients with Kennedy's disease have shown that expression of androgen receptor mRNA and protein in spinal cord may be decreased, as can be the affinity of the mutant receptor for androgen. In vitro studies have shown impaired transcription activation ability of the mutant androgen receptor. The age at onset of Kennedy's disease may correlate with the size of the CAG repeat, however there is a large degree of variability of age at onset between subjects with the same number of repeats. Further study of the effect of the Kennedy's disease mutation on androgen receptor function in motor neurons will allow us to increase our understanding of the pathogenesis of this disease.
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PMID:Spinal and bulbar muscular atrophy: androgen receptor dysfunction caused by a trinucleotide repeat expansion. 886 71

We analyzed the polymorphic (CAG)n and (GGC)n repeats of the androgen receptor gene in 113 unrelated X-linked spinal and bulbar muscular atrophy (SBMA) X chromosomes and 173 control X chromosomes in Japanese males. The control chromosomes had an average CAG repeat number of 21 +/- 3 with a range from 14-32 repeat units, and SBMA chromosomes had a range from 40-55 with a median of 47 +/- 3 copies. The control chromosomes had seven different alleles of the (GGC)n repeat with the range of 11 to 17; the most frequent size of (GGC)n was 16 (79%), while (GGC)17 was very rare (1%). However, in SBMA chromosomes only two alleles were seen; the most frequent size of (GGC)n was 16 (61%) followed by 17 (39%). (GGC)n size distribution was significantly different between SBMA and control chromosomes (P < 0.0001), indicating the presence of linkage disequilibrium. There was no allelic association between the (CAG)n and (GGC)n microsatellites among control subjects as well as SBMA patients, which suggests that a founder effect makes a more significant contribution to generation of Japanese SBMA chromosomes than new mutations.
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PMID:Founder effect in spinal and bulbar muscular atrophy (SBMA). 887 64

Osteopetrosis is an inherited disorder characterized by bone sclerosis due to reduced bone resorption. Here we report that human osteopetrotic osteoblast-like (Ob) cells express a defective phenotype in primary cultures in vitro, and that bone marrow transplant (BMT) corrects osteoblast function. DNA analysis at polymorphic short-tandem repeat loci from donor, recipient, and primary Ob-like cells pre-BMT and 2 yr post-BMT revealed that Ob were still of recipient origin post-BMT. Osteopetrotic Ob-like cells obtained pre-BMT showed normal and abnormal 1,25(OH)2D3-induced alkaline phosphatase (ALPase) and osteocalcin production, respectively, and failed to produce macrophage colony-stimulating factor (M-CSF) in response to IL-1a and TNF-alpha. These parameters were all normalized in primary Ob-like cells prepared 2 yr post-BMT. X-linked clonality analysis at the human androgen receptor (HUMARA) locus revealed that osteoblasts showed a polyclonal and an oligoclonal derivation pre- and post-BMT respectively, indicating that a limited number of progenitor reconstituted this population. Because osteoblasts were still of recipient origin post-BMT, this suggests that functional osteoclasts, due to the replacement of hematopoeitic cells, provided a local microenvironment in vivo triggering the differentiation and/or recruitment of a limited number of functional osteoblasts.
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PMID:Demonstration of an osteoblast defect in two cases of human malignant osteopetrosis. Correction of the phenotype after bone marrow transplant. 887 17

Polyglutamine tracts encoded by trinucleotide CAG repeats have been found in some transcription factors. Expansion of the polyglutamine tracts in the androgen receptor (AR) has been recognized as a cause of X-linked spinal and bulbar muscular atrophy (SBMA). To study the role of AR as a transcription factor in SBMA, we constructed AR genes encoding expanded polyglutamine tracts (repeat numbers = 52, 92, 132, and 212), and analyzed AR-induced transcriptional activation in NG108-15 cells. We found that AR-induced transcriptional activation gradually decreased with increasing glutamine repeat numbers, and polyglutamine expansion caused a specific reduction in transcription activity in motor neurons. However, the degree of reduction was slight in comparison with the normal AR gene and that of SBMA. Thus, subtle disorders of transcriptional control may occur in SBMA.
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PMID:Transcriptional activation by the androgen receptor in X-linked spinal and bulbar muscular atrophy. 890 13


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