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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Some transcription factors contain stretches of polyglutamine encoded by repeats of the trinucleotide CAG. Expansion of the CAG repeat in the androgen receptor (AR) has been correlated with the incidence and severity of X-linked spinal and bulbar muscular atrophy (Kennedy's disease). In order to understand the relationship of this mutation to AR function, we constructed ARs that varied in the position and size of the polyglutamine tract, and assayed for the abilities of these mutant receptors to bind androgen and to activate transcription of several different AR-responsive reporter genes. Elimination of the tract in both human and rat AR resulted in elevated transcriptional activation activity, strongly suggesting that the presence of the polyglutamine tract is inhibitory to transactivation. Progressive expansion of the CAG repeat in human AR caused a linear decrease of transactivation function. Importantly, expansion of the tract did not completely eliminate AR activity. We postulate that this residual AR activity may be sufficient for development of male primary and secondary sex characteristics, but may fall below a threshold level of activity necessary for normal maintenance of motor neuron function. This functional abnormality may be representative of other genetic diseases that are associated with CAG expansion mutations in open reading frames, such as spinocerebellar ataxia type I and Huntington's disease.
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PMID:The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. 806 34

A subgroup of trinucleotide repeat diseases result from abnormal expansions of CAG repeats which are translated into polyglutamine stretches. As yet there is little understanding of how the polyglutamines function either normally, or when expanded. We have investigated these sequences in the Machado-Joseph disease, androgen receptor and spinocerebellar ataxia type 1 genes in humans and other primates. None of the 748 normal chromosomes that were examined had more than 34 uninterrupted glutamine codons in the Machado-Joseph disease gene. Similarly, no normal alleles with more than 39 uninterrupted glutamine codons have been reported for the other disease genes associated with polyglutamine expansions. Sequence analyses of the repeats in primates revealed shorter polyglutamine stretches in some of the non-human primates at all three loci and marked diversions from the expected polyglutamines in the orang-utan Machado-Joseph gene and in the marmoset spinocerebellar ataxia type 1 gene. These data suggest that conservation of these polyglutamine stretches may not always be necessary for normal gene function.
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PMID:Sequence variation and size ranges of CAG repeats in the Machado-Joseph disease, spinocerebellar ataxia type 1 and androgen receptor genes. 854 43

A family history for breast cancer appears to be a major risk factor for breast cancer. It has been estimated that 5% of all breast cancers are hereditary. In the last five years much progress has been made in the identification of genes responsible for breast cancer. Much interest is focused on the BRCA-1 gene, which is associated with early onset breast and ovarian cancers. Heterogeneity within and across families in the pattern of cancer susceptibility has suggested that different susceptibility alleles may exist. The BRCA-1 gene has been cloned but the function of its product has not been determined. BRCA-1 mutations seem not to be involved in sporadic breast cancer. A second breast cancer susceptibility gene, BRCA-2, has been localized to chromosome 13q12-q13 but has not been identified as yet. Loss of heterozygosity of 13q is observed in 25% of sporadic breast tumors, which indicates that BRCA-2 might be a tumor suppressor gene. BRCA-2 confers only a low ovarian cancer risk. The TP53 gene has also been associated with breast cancer but to a much more limited extent than BRCA-1. Germline TP53 mutations have been found in patients with familial breast cancer. Other genes that have been associated with breast cancer risk are the androgen receptor (AR) gene and the ataxia teleangiectasia (AT) gene. The importance of the AR gene appears to be limited but the AT gene might be of considerable importance. It is to be expected that additional breast cancer susceptibility genes will be identified in the near future.
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PMID:Genes responsible for familial breast cancer. 888 Aug 69

X-linked spinal and bulbar muscular atrophy (SBMA) occurs due to an expansion of the trinucleotide repeat (CAG)n in the androgen receptor gene. Anticipation is relatively rare in SBMA in contrast to spinocerebellar ataxia type 1 (SCAl), and dentatorubral and pallidoluysian atrophy (DRPLA) which show obvious paternal anticipation. The differences in the CAG repeat number were compared among sperm, leukocytes and skeletal muscles of SBMA patients. In SBMA, the sperm of most patients and the skeletal muscle of all patients showed the same repeat number as their leukocytes, whereas the increase in the repeat number from leukocytes to sperm was evident in SCA1 and DRPLA patients. The higher mosaicism level in sperm compared with leukocytes was common in SBMA, SCA1 and DRPLA, and the level of sperm was lower in SBMA than in SCA1 and DRPLA. Thus, spermatogenesis was suggested to be strongly associated with paternal anticipation. The mosaicism level was smaller in SBMA than in other (CAG)n expanded disorders, and smallest in the SBMA carrier females. These findings demonstrate that the CAG repeat in SBMA is relatively stable in mitotic and meiotic, processes, and there is a possibility that the lower mosaicism level of the carrier females compared with the SBMA patients is associated with X-linked recessive inheritance.
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PMID:Mitotic and meiotic stability of the CAG repeat in the X-linked spinal and bulbar muscular atrophy gene. 894 11

Six inherited neurodegenerative diseases are caused by a CAG/polyglutamine expansion, including spinal and bulbar muscular atrophy (SBMA), Huntington's disease (HD), spinocerebellar ataxia type 1 (SCA1), dentatorubral pallidoluysian atrophy (DRPLA) Machado-Joseph disease (MJD or SCA3) and SCA2. Normal and expanded HD allele sizes of 6-39 and 35-121 repeats have been reported, and the allele distributions for the other diseases are comparable. Intergenerational instability has been described in all cases, and repeats tend to be more unstable on paternal transmission. This may present as larger increases on paternal inheritance as in HD, or as a tendency to increase on male and decrease on female transmission as in SCA1 (ref. 15). Somatic repeat instability is also apparent and appears most pronounced in the CNS. The major exception is the cerebellum, which in HD, DRPLA, SCA1 and MJD has a smaller repeat relative to the other brain regions tested. Of non-CNS tissues, instability was observed in blood, liver, kidney and colon. A mouse model of CAG repeat instability would be helpful in unravelling its molecular basis although an absence of CAG repeat instability in transgenic mice has so far been reported. These studies include (CAG) in the androgen receptor cDNA, (CAG) in the HD cDNA, (CAG) in the SCA1 cDNA, (CAG) in the SCA3 cDNA and as an isolated (CAG) tract.
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PMID:Instability of highly expanded CAG repeats in mice transgenic for the Huntington's disease mutation. 902 Aug 32

In the past few years, a new type of genetic mutation, expansion of trinucleotide repeats, has been shown to cause neurologic disease. This new class of mutations was first identified in 1991 as the underlying genetic defect in spinal and bulbar muscular atrophy and the fragile X syndrome, and in recent years, trinucleotide repeat expansions have been found to be the causative mechanism in 10 other neurologic diseases. These mutations are produced by heritable unstable DNA and are termed "dynamic mutations" because of changes in the number of repeat units inherited from generation to generation. In the normal population, these repeat units, although polymorphic, are stably inherited. To date four types of trinucleotide repeat expansions have been identified: (1) long cytosine-guanine-guanine (CGG) repeats in the two fragile X syndromes (FRAXA and FRAXE), (2) long cytosine-thymine-guanine (CTG) repeat expansions in myotonic dystrophy, (3) long guanine-adenine-adenine repeat expansions in Friedreich's ataxia and (4) short cytosine-adenine-guanine repeat expansions (CAG) which are implicated in eight neurodegenerative disorders and are the focus of this review. Diseases that are caused by trinucleotide repeat expansions exhibit a phenomenon called anticipation that can not be explained by conventional Mendelian genetics. Anticipation is defined as increase in the severity of disease with an earlier age of onset of symptoms in successive generations. Anticipation is often influenced by the sex of the transmitting parent, and for most CAG repeat disorders, the disease is more severe when paternally transmitted. The severity and the age of onset of the disease have been correlated with the size of the repeats on mutant alleles, with the age of onset being inversely correlated with the size of the expansion. In all eight disorders caused by CAG repeat expansion, the repeat is located within the coding region of the gene involved and in all cases it is translated into a stretch of polyglutamines in the respective proteins. All the proteins are unrelated outside of the polyglutamine stretch and most are novel with exception of the androgen receptor and the voltage gated alpha 1A calcium channel, which are mutated in spinal and bulbar muscular atrophy and spinocerebellar ataxia type 6. It is intriguing that the proteins are ubiquitously expressed in both peripheral and nervous tissue but in each disorder only a select population of nerve cells are targeted for degeneration as a consequence of the expanded CAG repeat. Current thinking among scientists working on the molecular mechanisms of neurodegeneration in these diseases is that the presence of an expanded polyglutamine confers a gain of function onto the involved protein. To understand the mechanisms underlying the pathogenesis of these diseases, investigators have turned to generating transgenic mice which recapitulate some of the features of the human disease and hence are excellent model systems to study the progression of the disease in vivo.
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PMID:The CAG/polyglutamine tract diseases: gene products and molecular pathogenesis. 921 76

Non-specific X-linked mental retardation is a heterogeneous group of disorders with an incidence of approximately 1 in 500 males. A recently identified gene in Xq12, encoding a Rho-GTPase-activating protein, was found to be mutated in individuals with mental retardation. We describe here two sisters with a 46,XY karyotype and a microdeletion of the oligophrenin-1 gene and 1.1 Mb of flanking DNA. We have characterised the molecular interval defining this microdeletion syndrome with the fibre-FISH technique. A visual physical map of 1.2 Mb was constructed which spans the oligophrenin-1 gene and the androgen receptor gene. The analysis of the patients revealed a deletion which extended from the 5' end of the AR gene to a region approximately 80 kb proximal to the EPLG2 gene. The clinical manifestations of the two sisters include psychomotor retardation, seizures, ataxia, hypotonia and complete androgen insensitivity. Cranial MRI scans show enlargement of the cerebral ventricles and cerebellar hypoplasia. Our findings give further support for the involvement of the oligophrenin-1 gene in specific morphological abnormalities of the brain which is of importance in the investigation of male patients presenting with mental retardation. In combination with our results from physical mapping we suggest that a region around the oligophrenin-1 locus is relatively bereft of vital genes.
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PMID:Deletion including the oligophrenin-1 gene associated with enlarged cerebral ventricles, cerebellar hypoplasia, seizures and ataxia. 1043 59

We generated transgenic mice that expressed a highly expanded 239 polyglutamine (polyQ) repeat under the control of the human androgen receptor promoter. These transgenic mice developed progressive neurological phenotypes of muscular weakness and ataxia, small body size and short life-span. PolyQ nuclear inclusions (NIs) were remarkable and widespread but found in selective regions of the central nervous system (CNS) such as the spinal cord, cerebrum and cerebellum as well as in selective peripheral visceral organs. This distribution pattern resembled that of spinal and bulbar muscular atrophy somewhat, but was more widespread. In neuronal tissues, NIs were present in astrocytes as well as neurons. Cytoplasmic and axonal inclusions were not observed. In the CNS regions with abundant NIs, neuronal populations were well-preserved, and neither neuronal cell death, reactive astrogliosis nor microglial invasions were detected. These findings suggest that polyQ alone can induce the neuronal dysfunction that precedes gross neuronal degeneration and provides a clue for investigating molecular mechanisms that underly the pathway to neuronal dysfunction from polyQ expansion.
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PMID:Transgenic mice with an expanded CAG repeat controlled by the human AR promoter show polyglutamine nuclear inclusions and neuronal dysfunction without neuronal cell death. 1133 14

The androgen receptor is a member of the nuclear receptor superfamily, and regulates gene expression in response to the steroid hormones testosterone and dihydrotestosterone. Mutations in the receptor have been correlated with a diverse range of clinical conditions, including androgen insensitivity, prostate cancer and spinal bulbar muscular atrophy, a neuromuscular degenerative condition. The latter is caused by expansion of a polyglutamine repeat within the N-terminal domain of the receptor. Thus the androgen receptor is one of a growing number of neurodegenerative disease-associated proteins, including huntingtin (Huntington's disease), ataxin-1 (spinocerebellar ataxia, type 1) and ataxin-3 (spinocerebellar ataxia, type 3), which show expansion of CAG triplet repeats. Although widely studied, the functions of huntingtin, ataxin-1 and ataxin-3 remain unknown. The androgen receptor, which has a well-recognized function in gene regulation, provides a unique opportunity to investigate the functional significance of poly(amino acid) repeats in normal and disease states.
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PMID:Structural and functional alterations in the androgen receptor in spinal bulbar muscular atrophy. 1135 58

Partington et al. [1988] described a three-generation family (MRXS1, MIM *309510, PRTS) with a syndromic form of X-linked mental retardation (XLMR). The clinical features in 10 affected males included mild to moderate MR, dystonic movements of the hands, and dysarthria. After refinement, the PRTS locus was mapped to marker DXS989 (with maximum LOD score of 3.1) with flanking markers DXS365 and DXS28. Since then, no other patients with a similar phenotype have been described. We present a detailed description of the neurological symptoms and the disease history of two brothers with the clinical features of PRTS. Psychomotor development was delayed in both, and neurological features included mild to moderate mental retardation, dysarthria, facial muscle weakness, severe dysdiadochokinesis, slow dystonic movements, and mild spasticity of the hands, without ataxia or spasticity of the legs. The symptoms were nonprogressive and extrapyramidal, and without cerebellar involvement. In general, behavior of the two brothers was friendly and quiet, although the elder brother had periods of depressed mood and outbursts of anger. Karyotypes and subsequent investigation of the subtelomeres as well as DNA analysis of the FMR1 gene, the androgen receptor gene, and the DM locus did not reveal a genetic abnormality. Haplotype analysis showed that the affected brothers share the PRTS region at Xp22.1. Mutation screening of the PDH-E1alpha gene did not reveal a pathogenic mutation.
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PMID:Clinical study and haplotype analysis in two brothers with Partington syndrome. 1237 38


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