Androgen insensitivity syndrome (AIS) is the most common cause of 46,XY disorders of sex development (46,XY DSD). This syndrome is an X-linked recessive genetic disease characterized by resistance to the actions of androgens in an individual with a male karyotype and it is caused by mutations in the androgen receptor (AR) gene. We evaluated two siblings with primary amenorrhea, normal secondary sex characteristics, absence of uterus and ovaries, intra-abdominal testis, and elevated testosterone levels. Sequence analysis of the AR gene revealed a splice acceptor site mutation in intron 2 (c.1769-1G > C). The analysis of mRNA showed that this mutation resulted in the activation of a cryptic splice acceptor site located in intron 2 and in the synthesis of an aberrant mRNA transcript with 69 nucleotides insertion between exon 2 and exon 3, leading to an insertion of 23 amino acids in the AR protein instead of generating a premature termination codon. The additional 23 amino acids insertion affects AR intracellular trafficking by impairing its translocation from the cytoplasm to the nucleus after hormone stimulation. The c.1769-1G > C mutation provides new insights into the molecular mechanism involved in splicing defects and expands the spectrum of mutations associated with the androgen insensitivity syndrome.
[1]Jilin Univ, Hosp 1, Dept Urol, Changchun 130021, Jilin, Peoples R China.
[2]Jilin Univ, Hosp 2, Orthoped Hosp, Dept Spinal Surg, Changchun 130041, Jilin, Peoples R China.
[3]Univ Calif Los Angeles, Sch Med, Dept Radiat Oncol, Los Angeles, CA 90095 USA.
[4]Jilin Univ, China Japan Union Hosp, Dept Radiol, Changchun 130033, Jilin, Peoples R China.
[5]Jilin Univ, Hosp 1, Ctr Prenatal Diag, 71 Xinmin St, Changchun 130021, Jilin, Peoples R China.
(8.0+极速模式)