Identification of the Underlying Androgen Receptor Defect in the Dallas Reifenstein Family

Area of Science:

• Genetics
• Molecular Biology
• Endocrinology

Background:

• The Dallas Reifenstein family, known since 1965, comprises 14 individuals with partial androgen insensitivity syndrome (PAIS).
• The specific genetic cause of PAIS in this family remained unidentified until this study.

Purpose of the Study:

• To pinpoint the underlying genetic defect responsible for PAIS in the Dallas Reifenstein family.
• To elucidate the molecular mechanism of the identified mutation.

Main Methods:

• Whole exome sequencing was performed on DNA from affected male family members.
• Segregation analysis in additional family members confirmed the mutation's link to the PAIS phenotype.
• Reverse transcription PCR was used to detect alternatively spliced AR transcripts.

Main Results:

• An intronic variant (NC_000023.10:g.66788676A>C) in the androgen receptor (AR) gene was identified in all affected individuals.
• This variant leads to an alternatively spliced AR transcript with an 185-nucleotide insertion and a premature stop codon.
• The mutation is predicted to cause reduced AR protein expression via nonsense-mediated decay and segregated with the PAIS phenotype.

Conclusions:

• An intronic AR mutation is the cause of PAIS in the Dallas Reifenstein family.
• This finding highlights the importance of investigating intronic AR mutations in PAIS cases where coding region mutations are not found.