Mosaicism due to a Somatic Mutation of the Androgen Receptor Gene Determines Phenotype in Androgen Insensitivity Syndrome1
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 virilizatio...
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Veröffentlicht in: | The journal of clinical endocrinology and metabolism 1997-11, Vol.82 (11), p.3584-3589 |
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Sprache: | eng |
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Zusammenfassung: | 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. |
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ISSN: | 0021-972X 1945-7197 |
DOI: | 10.1210/jcem.82.11.4375 |