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Evidence That Longer Androgen Receptor Polyglutamine Repeats Are a Causal Factor for Genital Abnormalities

Department of Paediatrics (H.N.L., H.C., I.A.H., J.R.H.), University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom; Medical Research Council Biostatistics Unit (R.M.N.), Institute of Public Health University Forvie Site, Cambridge CB2 2SR, United Kingdom; and Department of Paediatrics (H.C.), Pamela Youde Nethersole Hospital, Chai Wan, Hong Kong, China

Address correspondence and requests for reprints to: Han N. Lim, Ph.D., Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, United Kingdom. E-mail: hl215{at}mole.bio

Abstract

Moderate to severe undermasculinized genitalia was recently shown to be associated with longer polyglutamine repeats within the androgen receptor [AR(Gln)n]. However, it was unknown whether this was because longer AR(Gln)n contributed to the: 1) etiology; 2) severity; and/or 3) testicular maldescent. Therefore, AR(Gln)n length in 175 males with abnormal genitalia were analyzed according to etiology (known or unknown), severity (complete, severe, and moderate), or testis position (abdominal, inguinal, or scrotal). Etiology (P = 0.01) and severity (P = 0.02) but not testis position (P = 0.52) were associated with AR(Gln)n length. The association between the severity of the genital abnormalities and AR(Gln)n length was due to the close association of severity with the etiology (P < 0.0001). A highly selected group with moderate to severe genital abnormalities and multiple criteria to exclude known etiological factors had a greater AR(Gln)n length (mean, 25.33) than all other samples (mean, 23.11; P = 0.0004). The results suggest that AR(Gln)n length does not influence the severity of undermasculinization or testis descent but instead contributes to the causation of genital abnormalities in a subset of patients. These findings, together with a demonstrated relationship between severity and multifactorial etiology, are incorporated into a proposed model for the involvement of AR(Gln)n length in genital abnormalities.

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