Nature 352, 77 - 79 (04 July 1991); doi:10.1038/352077a0

Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy

Albert R. La Spada^*, Elizabeth M Wilson^†, Dennis B Lubahn^†, A. E Harding^‡ & Kenneth H Fischbeck^*

^* Neurology Department University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6146, USA
^† Laboratories for Reproductive Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA
^‡ Institute of Neurology, The National Hospital, Queen Square, London WC1N 3BG, UK

X-LINKED spinal and bulbar muscular atrophy (Kennedy's disease) is an adult-onset form of motorneuron disease which may be associated with signs of androgen insensitivity. We have now investigated whether the androgen receptor gene on the proximal long arm of the X chromosome is a candidate gene for this disease. In patient samples we found androgen receptor gene mutations with increased size of a polymorphic tandem CAG repeat in the coding region. These amplified repeats were absolutely associated with the disease, being present in 35 unrelated patients and none of 75 controls. They segregated with the disease in 15 families, with no recombination in 61 meioses (the maximum log likelihood ratio (lod score) is 13.2 at a recombination rate of 0). The association is unlikely to be due to linkage disequilibrium, because 11 different disease alleles were observed. We conclude that enlargement of the CAG repeat in the androgen receptor gene is probably the cause of this disorder.

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