Androgen receptor abnormality in X‐linked spinal and bulbar muscular atrophy

Matsuura, Tetsuya; Demura, Takayoshi; Aimoto, Yasuharu; Mizuno, T.; Moriwaka, Fumio; Tashiro, Kunio

doi:10.1212/wnl.42.9.1724

Cited by 34 publications

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“…Our findings resemble those reported recently from one other BSN family [43]. AR abnormality in scrotal skin of BSN patients has also been demonstrated by failure to stain with a specific antibody [26].…”

Section: Discussionsupporting

confidence: 91%

Decrease in androgen binding and effect of androgen treatment in a case of X-linked bulbospinal neuronopathy

et al. 1994

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X-linked recessive bulbospinal neuronopathy is a motoneuron disorder to be distinguished from amyotrophic lateral sclerosis, Effective treatment is not known. Patients with X-linked recessive bulbospinal neuronopathy may show gynecomastia and testicular atrophy, and a mutation in the androgen receptor gene has been found associated with the disease. Intermediate steps leading from the androgen receptor abnormality to the clinical syndrome have not yet been elucidated. Therefore, binding of androgen ([3H]dihydrotestosterone) to its specific receptor by genital skin fibroblasts cultured from a patient with X-linked recessive bulbospinal neuronopathy and confirmed androgen receptor mutation was studied. Markedly decreased binding capacity was found. We treated the patient for 6 months with nandrolone-decanoate. No effect on his neuromuscular status was observed during 2 years of follow-up.

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Section: Discussionsupporting

confidence: 91%

Decrease in androgen binding and effect of androgen treatment in a case of X-linked bulbospinal neuronopathy

et al. 1994

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“…Huntington's disease, SCA1, and Kennedy's disease share several features: (1) the diseases are late-onset, neurological disorders, with larger repeats correlated with earlier age of onset; (2) the CAG repeats are present in putative open reading frames and encode polyglutamine; and (3) the size range of the repeat in affected individuals is approximately twice the range in the normal population. In Kennedy's disease, a degenerative neuromuscular syndrome (18,19), the expanded CAG trinucleotide repeat is in the AR N-terminal domain, and the size of the repeat is inversely correlated with the severity of the symptoms (20)(21)(22)(23)(24). Because the mutations associated with these three diseases are so similar, it is possible that studying the effect of CAG expansion on AR function may reveal a common underlying mechanism that results in the disease phenotypes in Huntington's disease and SCA1 (25,26).…”

Section: Introductionmentioning

confidence: 99%

The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function

Chamberlain

Driver²,

Miesfeld³

1994

Nucl Acids Res

1,047

733

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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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“…The abnormal gene was localized on the proximal part of the long arm of the X chromosome in 1986 (4) and subsequently an increased size of a polymorphic tandem CAG repeat in the androgen receptor gene was found, probably being the cause of the disorder (5). Recently androgen receptor abnormality in the scrota1 skin was demonstrated (6).…”

mentioning

confidence: 99%

X-linked recessive bulbospinal neuronopathy (Kennedy's syndrome): a neurophysiological study

Trojaborg

Wulff

2009

Acta Neurologica Scandinavica

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We examined 8 men with X‐linked recessive bulbospinal neuronopathy. Quantitative electromyography showed large amplitude motor unit action potentials of prolonged duration and increased polyphasia. There was a pronounced loss of motor units in all but one muscle at maximal volition even in muscles with normal or only mildly decreased force. Denervation activity was present in 53% sampled limb muscles, and fasciculation was recorded in 33% of limb muscles. Nerve conduction studies showed small amplitude sensory action potentials in 6 out of 8 patients. The motor and sensory conduction velocity was normal or borderline slow. The electrophysiologic findings were consistent with chronic partial denervation (motor axonopathy) combined with large fibre sensory axonopathy.

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Androgen receptor abnormality in X‐linked spinal and bulbar muscular atrophy

Abstract: X-linked spinal and bulbar muscular atrophy (SBMA) is usually associated with feminization and hypogonadism. We were unable to find androgen receptor (AR) in the scrotal skin of three patients with SBMA, and propose that AR abnormality is the cause of the disease.

Cited by 34 publications

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Decrease in androgen binding and effect of androgen treatment in a case of X-linked bulbospinal neuronopathy

Decrease in androgen binding and effect of androgen treatment in a case of X-linked bulbospinal neuronopathy

The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function

X-linked recessive bulbospinal neuronopathy (Kennedy's syndrome): a neurophysiological study

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