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Two de Novo Mutations in the AR Gene Cause the Complete Androgen Insensitivity Syndrome in a Pair of Monozygotic Twins

University Department of Pediatrics, Addenbrooke’s Hospital, University of Cambridge (N.P.M., J.J., K.G., N.S., I.A.H.), Cambridge, United Kingdom CB2 2QQ; Medical Research Council, Laboratory of Molecular Biology (J.W.S.), Cambridge, United Kingdom CB2 2QH; and Great Ormond Street Hospital for Children (M.D.), London, United Kingdom WC1N 3JH

Address all correspondence and requests for reprints to: Nigel P. Mongan, Ph.D., Department of Pharmacology, Room E-409A, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021. E-mail: . n.p.e.mongan.95{at}cantab.net

Abstract

The androgen insensitivity syndrome (AIS) is the most common cause of male undermasculinization and is typically caused by mutations in the AR gene. Affected individuals may exhibit either complete external feminization (complete AIS) or a partial phenotype (partial AIS). Here we describe monozygotic twins diagnosed with complete AIS who each possess two substitutions (CG at position 2930 and TC at position 2955, both in exon 7), leading to Phe⁸⁵⁶Leu and Ser⁸⁶⁵Pro mutations, respectively. Neither parent was found to be a carrier for these mutations, indicating that the double mutation arose de novo. Both mutations were recreated by site-directed mutagenesis and compared functionally with the wild-type receptor. The Phe⁸⁵⁶Leu mutation did not affect androgen binding when expressed in COS-1 cells, nor did this mutation decrease androgen-dependent trans-activation in transfected HeLa cells. However, the Ser⁸⁶⁵Pro mutation completely ablated androgen binding and trans-activation. In this study we demonstrate that the replacement of serine by proline at position 865 is sufficient in itself to cause complete AIS in these twins. Analyses of nuclear receptor structures suggest that this mutation is likely to perturb the conformation of helix 10/11, which plays a role in ligand binding, dimerization, and receptor activation. To our knowledge this is the first confirmed instance of AIS (complete or partial) due to an AR mutation occurring in twins. Furthermore, the phenotype was associated with two mutations that were both novel in nature.

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