title: Extreme androgen resistance in a kindred with a novel insertion/deletion mutation in exon 5 of the androgen receptor gene.
abstract: Androgen insensitivy syndrome (AIS) is the most frequent cause of male pseudohermaphroditism resulting from target-organ resistance to androgen action. Individuals bearing the complete form of the disease (CAIS) present a female phenotype and a lack of pubic and axillary hair. In the present study, four 46,XY patients born in two generations from a kindred with a history of AIS were examined for genetic abnormalities in the androgen receptor gene (AR). All eight exons encoding the AR protein were individually amplified from genomic DNA followed by a mutation screening with single-strand conformation polymorphism analysis. Sequencing of the mutant AR revealed a novel insertion/deletion mutation in exon 5. A deletion of 7 bp is replaced by an insertion of 11 nucleotides, which represents a duplication of the adjacent downstream sequence. The mutation g.2640_2646delAGGATGC/2652_2662insTTCGCCCCTGA, results in a frameshift that introduces a premature termination signal TGA, nine codons downstream. Such a rearrangement predicts a truncation of the AR, thereby deleting a large portion of the ligand-binding domain (amino acid position 768-919). Furthermore, although this mutation breaks the translational reading frame starting from codon 760, examination of the complementary DNA suggested that it does not disturb mRNA splicing. These changes have been found in all the patients and appear to account for the observed absence of detectable androgen binding to the AR in cultured fibroblasts and for the CAIS phenotype in the kindred. This disorder represents the first insertion/deletion mutation of the AR that probably arose by a slipped-strand mispairing mechanism.
authors.affiliation: Department of Reproductive Biology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Tlalpan C.P. 14000, México D.F., México. vilchisuf@prodigy.net.mx
authors.forename: Felipe
authors.initials: F
authors.lastname: Vilchis
authors.forename: Luis
authors.initials: L
authors.lastname: Ramos
authors.forename: Susana
authors.initials: S
authors.lastname: Kofman-Alfaro
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Zenteno
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Méndez
authors.forename: Bertha
authors.initials: B
authors.lastname: Chávez
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D013734:Androgen-Insensitivity Syndrome / Q000235:genetics; D000728:Androgens / Q000378:metabolism*; D001483:Base Sequence; D015153:Blotting, Western; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000378:metabolism; D005091:Exons; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009690:Nucleic Acid Conformation; D010375:Pedigree; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000728:Androgens; D018076:DNA, Complementary; D012333:RNA, Messenger; D011944:Receptors, Androgen