title: Two de novo mutations in the AR gene cause the complete androgen insensitivity syndrome in a pair of monozygotic twins.
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 (C-->G at position 2930 and T-->C at position 2955, both in exon 7), leading to Phe(856)Leu and Ser(865)Pro 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 Phe(856)Leu 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 Ser(865)Pro 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.
authors.affiliation: University Department of Pediatrics, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom CB2 2QQ. n.p.e.mongan.95@cantab.net
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Mongan
authors.forename: Jarmo
authors.initials: J
authors.lastname: Jääskeläinen
authors.forename: Katherine
authors.initials: K
authors.lastname: Green
authors.forename: John W
authors.initials: JW
authors.lastname: Schwabe
authors.forename: Naoto
authors.initials: N
authors.lastname: Shimura
authors.forename: Mehul
authors.initials: M
authors.lastname: Dattani
authors.forename: Ieuan A
authors.initials: IA
authors.lastname: Hughes
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D013734:Androgen-Insensitivity Syndrome / Q000235:genetics*; D000728:Androgens / Q000502:physiology*; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D019556:COS Cells; D004200:Diseases in Twins; D006801:Humans; D007231:Infant, Newborn; D008024:Ligands; D008297:Male; D009154:Mutation / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics*; D014430:Twins, Monozygotic
chemical_list: D000728:Androgens; D008024:Ligands; D011944:Receptors, Androgen