Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome

Paul Martin Holterhus*, Hennie T. Brüggenwirth, Olaf Hiort, Annette Kleinkauf-Houcken, Klaus Kruse, Gernot H.G. Sinnecker, Albert O. Brinkmann

*Corresponding author for this work
75 Citations (Scopus)


Premature step 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 step 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 step 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.

Original languageEnglish
JournalJournal of Clinical Endocrinology and Metabolism
Issue number11
Pages (from-to)3584-3589
Number of pages6
Publication statusPublished - 1997

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)


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