X-linked muscular atrophy and the androgen receptor

X-linked muscular atrophy is a form of adult-onset, usually slowly progressive spinal and bulbar motor neuron degenerative disease that is uniquely associated with male hypogonadism. The mutation responsible for this syndrome is expansion of the trinucleotide repeat—cytosine (C), adenine (A), guanine (G)—in a 5′-translated portion of the androgen receptor (AR) gene from a normal, polymorphic length of n = 11–31 to n ≥ 40. The resulting androgen receptor (AR) protein has an expanded polyglutamine tract in its NH₂-terminal modulatory domain, and is postulated to lose a basic, intrinsic function that causes a mild form of androgen insensitivity; however, almost certainly, it also gains a novel, extrinsic function that is selectively neuronotoxic. The unexplained mechanism that culminates in this form of neuronspecific death is the prototype for three different adult-onset neuronopathies that are caused by (CAG)_n expansions in other genes.