metribolone and Muscular-Atrophy--Spinal

To investigate androgen receptor (AR) function in spinal and bulbar muscular atrophy (SBMA).. A kindred was identified with five individuals carrying the AR gene CAG repeat expansion that causes SBMA. Androgen binding was measured in cultured genital skin fibroblasts from three affected individuals. One newborn, pre-symptomatic, individual showed normal androgen binding, but two older, symptomatic individuals showed a decrease in androgen binding affinity. This difference was not related to AR CAG repeat size, as all affected individuals in this kindred had 49 repeats (normal range 6-35). Post-mortem analysis in one subject confirmed the signs of androgen insufficiency in the testis, with marked seminiferous tubule atrophy, and the absence of germinal cells. The characteristic neuronal depletion in the anterior horn gray matter was also observed.. This report raises the possibility that age- or puberty-related changes in androgen binding could occur, which could potentially contribute to the progressive development of androgen resistance in affected men.

Topics: Adult; Aged; Aging; Blotting, Southern; Family Health; Female; Humans; Male; Metribolone; Middle Aged; Muscular Atrophy, Spinal; Polymerase Chain Reaction; Postmortem Changes; Protein Binding; Radioligand Assay; Receptors, Androgen; Testis; Trinucleotide Repeats; Tritium

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.

Topics: Animals; Base Sequence; Binding, Competitive; Blotting, Western; Choline O-Acetyltransferase; COS Cells; Gene Expression Regulation; Genetic Linkage; Glutamine; Hybrid Cells; Metribolone; Mice; Molecular Sequence Data; Muscular Atrophy, Spinal; Mutagenesis; Neuroblastoma; Receptors, Androgen; Repetitive Sequences, Nucleic Acid; Testosterone Congeners; Transcription, Genetic; X Chromosome