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

Herein we describe a family with X-linked spinal and bulbar muscular atrophy (SBMA or Kennedy's disease), an adult onset neuromuscular disease characterized by slow progression, predominant proximal and bulbar muscle weakness. One frequent association is the appearance of gynecomastia. This disorder was previously shown to be linked to the locus DXYS1 on the proximal long arm of the X chromosome. Recently, a report implicated a mutation at the N-terminus of the androgen receptor gene involving amplification of CAG repeats as the cause of X-linked SBMA. We studied this region of the androgen receptor in a kindred clinically suspected but not confirmed of having X-linked SBMA by the polymerase chain reaction (PCR) followed by Southern analysis and DNA sequencing. The mutated allele was found to have an increased number of 51 CAG repeats confirming the clinical diagnosis of SBMA. Normal individuals revealed 23 repeat numbers within the normal range, while another unrelated X-linked SBMA patient had an enlarged CAG repeat region. The carrier or disease status could be established or confirmed in 12 individuals of this family on the basis of detecting normal and disease alleles reflected by the number of CAG repeats.
 ...
PMID:Analysis of the CAG repeat region of the androgen receptor gene in a kindred with X-linked spinal and bulbar muscular atrophy. 146 23

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.
 ...
PMID:Somatic stability of the expanded CAG trinucleotide repeat in X-linked spinal and bulbar muscular atrophy. 880 33

We describe a patient with X-linked spinal and bulbar muscular atrophy (X-SBMA) and myasthenic symptoms. The diagnosis of X-SBMA was established by demonstration of the increased number of CAG repeats in the androgen receptor gene on the X chromosome. This patient was characterized by the clinical symptoms of fatigability, decremental motor responses to repetitive nerve stimulation, and improvement of the myasthenic symptoms with oral administration of pyridostigmine. No serum antibody to acetylcholine receptor was detected. It is suggested that, in the process of chronic denervation and reinnervation of X-SBMA, reinnervated motor endplates may be associated with the defect of neuromuscular transmission.
 ...
PMID:X-linked spinal and bulbar muscular atrophy with myasthenic symptoms. 907 16

A female patient with the karyotype 45,X/46, X, r(X)(p11.2 q13) and severe developmental delay, prominent fingertip pads, long palpebral fissures, short stature, and history of hypotonia had a phenotype reminiscent of Kabuki syndrome. We hypothesized that overexpression of X chromosome-derived sequences might be associated with the Kabuki-like phenotype observed. The nature and parental origin of this small-ring X were ascertained using a combination of genotyping with microsatellite markers and quantitative Southern blotting. PCR-based genotyping demonstrated heterozygosity at X-linked loci SBMA (Xq11-q12) and DXS227 (Xq13.1). Hemizygosity was observed at several loci: DMD STR-49 (Xp21.2), DXS1003 (Xp11.23), DXS988 (Xp11.21), DXS101 (Xq21.3), FMR-1 (Xq27.3), and DXYS64 (Xq28). This ring X chromosome is paternally derived since only maternal alleles are inherited at three informative microsatellite loci. Results of FISH and RT-PCR experiments indicate that the XIST locus is missing in the ring X chromosome and not expressed. These data indicated a large deletion of the X chromosome consistent with a small-ring X chromosome with approximate breakpoints near p11.2 and q13. These results are comparable to the observation of others where an atypically severe phenotype has been associated with the presence of an r(X), or small mar(X).
 ...
PMID:Ring chromosome X in a child with manifestations of Kabuki syndrome. 912 39

The androgen receptor (AR) is a ligand-dependent transcription factor involved in various biological processes such as sex differentiation, sexual maturation and spermatogenesis. Disorders of AR function cause a wide spectrum of androgen insensitivity syndromes. The phenotypes vary from women with female external genitalia through patients with genital ambiguity to men with normal male genitalia but infertile. The CAG repeat in exon A is important for transactivation function of the AR and consequently for many androgen-dependent processes. Expansion of this repeat is the cause of the X-linked spinal and bulbar muscular atrophy (SBMA, Kennedy's disease). Mutations of the AR gene occur commonly in prostate cancers and are significant for prognosis of the disease.
 ...
PMID:Clinical and molecular aspects of androgen receptor defects. 1007 22

We report on a case of genetically proven X-linked spinal and bulbar muscular atrophy (X-SBMA) with prominent distal muscle atrophy and without proximal muscle involvement. The patient was a 35-year-old man who had a history of slow progressive hand and distal leg muscle weakness and wasting for 10 years. Motor nerve conduction velocities were normal with reduced compound muscle action potential amplitudes of hand and foot muscles. Sensory action potential amplitudes were small. Needle EMG revealed a chronic partial denervation with reduced interference in hand and distal leg muscles but with normal heading in all tested proximal muscles. Genetic studied showed an expansion of CAG repeat in the first exon of the androgen receptor gene, which suggests diagnosis of X-SBMA. The importance of genetic studies in this patient with unusual clinical presentation is emphasized.
 ...
PMID:X-linked spinal and bulbar muscular atrophy without proximal atrophy. 1244 17

Toxicity associated with abnormal protein folding and protein aggregation are major hypotheses for neurodegeneration. This article comparatively reviews the experimental and human tissue-based evidence for the involvement of such mechanisms in neuronal death associated with the motor system disorders of X-linked spinobulbar muscular atrophy (SBMA; Kennedy's disease) and amyotrophic lateral sclerosis (ALS), especially disease related to mutations in the superoxide dismutase (SOD1) gene. Evidence from transgenic mouse, Drosophila and cell culture models of SBMA, in common with other trinucleotide repeat expansion disorders, show protein aggregation of the mutated androgen receptor, and intraneuronal accumulation of aggregated protein, to be obligate mechanisms. Strong experimental data link these phenomena with downstream biochemical events involving gene transcription pathways (CREB-binding protein) and interactions with protein chaperone systems. Manipulations of these pathways are already established in experimental systems of trinucleotide repeat disorders as potential beneficial targets for therapeutic activity. In contrast, the evidence for the role of protein aggregation in models of SOD1-linked familial ALS is less clear-cut. Several classes of intraneuronal inclusion body have been described, some of which are invariably present. However, the lack of understanding of the biochemical basis of the most frequent inclusion in sporadic ALS, the ubiquitinated inclusion, has hampered research. The toxicity associated with expression of mutant SOD1 has been intensively studied however. Abnormal protein aggregation and folding is the only one of the four major hypotheses for the mechanism of neuronal degeneration in this disorder currently under investigation (the others comprise oxidative stress, axonal transport and cytoskeletal dysfunctions, and glutamatergic excitotoxicity). Whilst hyaline inclusions, which are strongly immunoreactive to SOD1, are linked to degeneration in SOD1 mutant mouse models, the evidence from human tissue is less consistent and convincing. A role for mutant SOD1 aggregation in the mitochondrial dysfunction associated with ALS, and in potentially toxic interactions with heat shock proteins, both leading to apoptosis, are supported by some experimental data. Direct in vitro data on mutant SOD1 show evidence for spontaneous oligomerization, but the role of such oligomers remains to be elucidated, and therapeutic strategies are less well developed for this familial variant of ALS.
 ...
PMID:Protein aggregation in motor neurone disorders. 1463 60

Motor neuron diseases may be divided into three categories: those with lower motor neuron involvement--spinal muscular atrophy (SMA) and spinobulbar muscular atrophy (SBMA or Kennedy's disease); those with upper motor neuron involvement--primary lateral sclerosis (PLS) and the spastic paraplegias; and those with combined upper and lower motor neuron involvement--amyotrophic lateral sclerosis (ALS). Other familial motor neuron disorders include hereditary neuronopathies, GM2 gangliosidosis, and possibly the ALS/PD syndrome of Guam. The contribution of genetics to the etiopathogenesis of motor neuron considerably, accounting for a high percentage of spinal muscular atrophies, but only a small fraction of cases of ALS. The mode of inheritance also varies, with examples of autosomal dominant (AD), autosomal recessive (AR), or X-linked kindreds. (Tables 1 and 2).
 ...
PMID:The genetics of motor neuron diseases. 1475 56

X-linked spinal and bulbar muscular atrophy (SBMA; Kennedy's disease) is a polyglutamine (polyQ) disease in which the affected males suffer progressive motor neuron degeneration accompanied by signs of androgen insensitivity, such as gynecomastia and reduced fertility. SBMA is caused by CAG repeat expansions in the androgen receptor (AR) gene resulting in the production of AR protein with an extended glutamine tract. SBMA is one of nine polyQ diseases in which polyQ expansion is believed to impart a toxic gain-of-function effect upon the mutant protein, and initiate a cascade of events that culminate in neurodegeneration. However, whether loss of a disease protein's normal function concomitantly contributes to the neurodegeneration remains unanswered. To address this, we examined the role of normal AR function in SBMA by crossing a highly representative AR YAC transgenic mouse model with 100 glutamines (AR100) and a corresponding control (AR20) onto an AR null (testicular feminization; Tfm) background. Absence of endogenous AR protein in AR100Tfm mice had profound effects upon neuromuscular and endocrine-reproductive features of this SBMA mouse model, as AR100Tfm mice displayed accelerated neurodegeneration and severe androgen insensitivity in comparison to AR100 littermates. Reduction in size and number of androgen-sensitive motor neurons in the spinal cord of AR100Tfm mice underscored the importance of AR action for neuronal health and survival. Promoter-reporter assays confirmed that AR transactivation competence diminishes in a polyQ length-dependent fashion. Our studies indicate that SBMA disease pathogenesis, both in the nervous system and the periphery, involves two simultaneous pathways: gain-of-function misfolded protein toxicity and loss of normal protein function.
 ...
PMID:Loss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X-linked spinal and bulbar muscular atrophy. 1677 30

X-linked spinal and bulbar muscular atrophy (SBMA or Kennedy's disease) has a variable prognosis. Most male carriers are affected by their fourth or fifth decade of life, while some remain asymptomatic lifelong. Elevations of serum creatine kinase are well known to occur in clinically manifesting SBMA patients. Elevations prior to the onset of the clinical syndrome have not been reported. Here we report two cases of SBMA presenting with 'idiopathic' elevations of serum transaminases and creatine kinase a decade in advance of their symptomatic onset. These cases emphasize the need to consider SBMA and genetic testing for the androgen receptor trinucleotide CAG expansion in males otherwise healthy with 'idiopathic' elevated creatinine kinase.
 ...
PMID:Elevated creatine kinase and transaminases in asymptomatic SBMA. 1736 38


1 2 Next >>