We have analyzed the androgen receptor (AR) of a young Japanese man with sporadic Reifenstein syndrome. Androgen binding assays in cultured genital skin fibroblasts showed a normal maximum binding capacity and a normal apparent dissociation constant. However, androgen binding in fibroblasts decreased to 37% when the assay temperature was raised from 30°C to 41°C, indicating thermolability of the AR. Sequence analysis of the AR gene revealed a single nucleotide substitution (G→A) at nucleotide position 2,598 in exon E (or 5), resulting in conversion of valine (GTG) to methionine (ATG) at amino acid position 746 within the hormone-binding domain of the AR. This missense mutation may explain thermolability of the AR, which is thought to be the pathogenesis of Reifenstein syndrome in this patient. Sequence analysis also revealed that his mother was not a heterozygous carrier of this AR mutation. Moreover, sequence analysis of the D loop in the mitochondrial deoxyribonuleic acid (DNA) confirmed the familial relationship between this patient and his mother. These findings strongly suggest that this AR mutation is a de novo mutation newly occurring in this patient's generation.
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