title: Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome.
abstract: Premature stop codons of the human androgen receptor (AR) gene are usually associated with a complete androgen insensitivity syndrome. We, however, identified an adult patient with a 46,XY karyotype carrying a premature stop codon in exon 1 of the AR gene presenting with signs of partial virilization: pubic hair Tanner stage 4 and clitoral enlargement. No other family members were affected. A point mutation at codon position 172 of the AR gene was detected that replaced the original TTA (Leu) with a premature stop codon TGA (opal). Careful examination of the sequencing gel, however, also identified a wild-type allele, indicating a mosaicism. In addition, elimination of the unique AflII recognition site induced by the mutation was incomplete, thus confirming the coexistence of mutant and wild-type AR alleles in the patient. Normal R1881 binding and a normal 110/112-kDa AR doublet in Western immunoblots consolidated the molecular genetic data by demonstrating the expression of the wild-type AR in the patient's genital skin fibroblasts. Transfection analysis revealed that only relatively high plasmid concentrations carrying the mutated AR complementary DNA lead to expression of a shortened AR due to downstream reinitiation at methionine 189. Thus, reinitiation does not play a role in the presentation of the phenotype; rather, the partial virilization is caused by the expression of the wild-type AR due to a somatic mosaic. We conclude that somatic mosaicism of the AR gene can represent a substantial factor for the individual phenotype by shifting it to a higher degree of virilization than expected from the genotype of the mutant allele alone.
authors.affiliation: Department of Pediatrics, Medical University of Lübeck, Germany.
authors.forename: P M
authors.initials: PM
authors.lastname: Holterhus
authors.forename: H T
authors.initials: HT
authors.lastname: Brüggenwirth
authors.forename: O
authors.initials: O
authors.lastname: Hiort
authors.forename: A
authors.initials: A
authors.lastname: Kleinkauf-Houcken
authors.forename: K
authors.initials: K
authors.lastname: Kruse
authors.forename: G H
authors.initials: GH
authors.lastname: Sinnecker
authors.forename: A O
authors.initials: AO
authors.lastname: Brinkmann
mesh_terms: D000328:Adult; D013734:Androgen-Insensitivity Syndrome / Q000235:genetics*; D001483:Base Sequence; D015153:Blotting, Western; D004247:DNA / Q000032:analysis; D015870:Gene Expression; D006801:Humans; D008297:Male; D015741:Metribolone / Q000378:metabolism; D009030:Mosaicism; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D011944:Receptors, Androgen; D015741:Metribolone; D004247:DNA