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Spinal-Bulbar Muscular Atrophy (SBMA)


MDA researchers first identified the genetic defect underlying spinal-bulbar muscular atrophy (SBMA) in the early 1990s. Since then, many MDA-supported research groups have worked to understand the disease and develop treatments for it.

SBMA is caused by mutation in the gene for the androgen receptor (AR). The androgen receptor is a protein that binds to the male sex hormone, testosterone. When testosterone binds to the AR, the testosterone/AR complex can enter the cell nucleus. Like many other hormones, testosterone exerts its effects by controlling the expression of a range of genes in the nucleus, and the AR is critical for this purpose.

The mutation that causes SBMA is called a trinucleotide repeat expansion. Genes are made of DNA; DNA is composed of subunits, called nucleotides, strung together. The AR gene includes a segment of nucleotides in which the three DNA “letters” C-A-G repeat multiple times. The normal gene contains up to CAG 36 repeats. In people with SBMA, the AR gene contains 38 or more CAG repeats. This trinucleotide CAG sequence causes the amino acid glutamine to be incorporated into the AR protein. When the mutant gene is translated, the resulting protein contains too many glutamine amino acids. The extra glutamines causes the protein to misfold, taking on the wrong shape and making the resulting protein molecule “sticky,” causing it to clump together. It is not clear how this leads to loss of motor neurons, and discovering the steps in the disease pathogenesis is a major focus of research.

Many MDA-supported projects are focused on understanding how the downstream effects of mutations in the androgen receptor gene affect cells, and developing methods to overcome or compensate for these effects.

Recently, some MDA researchers have been looking into the possibility of using a new class of drugs called selective androgen receptor modulators (SARMs) to treat SBMA.

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