Complete Androgen Insensitivity Syndrome due to Mutations in the DNA-Binding Domain of the Human Androgen Receptor Gene

Abstract

Androgen insensitivity syndrome (AIS) is an X-linked recessive disorder with a 46,XY karyotype caused by alterations in the androgen receptor<i> (AR)</i> gene. We have identified 2 mutations in the <i>AR</i> gene that resulted in complete androgen insensitivity syndrome (CAIS) in 2 unrelated cases. This study includes cytogenetics, hormonal, molecular, and bioinformatics analysis including sequencing of the <i>SRY</i> (sex-determining region Y) and <i>AR</i> genes. Mutational analysis in the first case of primary amenorrhea revealed a novel nucleotide substitution (IVS2-2A>G) in the second intron of the <i>AR</i> gene. The mutation is located in the acceptor splice site (2 nucleotides before exon 3) and caused skipping of exon 3 and formation of an abnormal protein. The second mutation (g. 98762_98764delTCT) was identified in a case of oligoamenorrhea and caused the deletion of 1 amino acid (p.∆Phe583). Both identified mutations were located in the conserved P-box region of the DNA-binding domain which is responsible for base-specific contacts with the DNA major groove. Furthermore, a hormonal imbalance was also noticed in both cases with high levels of gonadotropins like FSH and LH in both cases. The present study concluded that both identified <i>AR</i> mutations are predicted to either abolish or decrease the binding ability of the AR to androgen response elements of its downstream genes.

Magnetic Resonance Imagery Findings in Androgen Insensitivity

“…7 In complete AIS, there is mutation of the AR gene located on the long arm of the X chromosome and it follows X-linked recessive inheritance. 8 Approximately 40% of the patients with AIS may have no family history of mutations of the AR gene. 9 The AR in AIS is unresponsive to androgen action and androgens are converted into oestrogens with action of aromatase.…”

“… 7 In complete AIS, there is mutation of the AR gene located on the long arm of the X chromosome and it follows X-linked recessive inheritance. 8 Approximately 40% of the patients with AIS may have no family history of mutations of the AR gene. 9 …”

Newly Developed Targeted Therapies Against the Androgen Receptor in Triple-Negative Breast Cancer: A Review

“…Evidence indicated that central roles in the AR-NTD are involved in modulating AR-DBD functions; this revealed an intradomain functional dependency in the AR (Brodie and McEwan, 2005). Like AR-NTD, mutations in the AR-DBD were also accompanied by several diseases and abnormalities, such as complete androgen insensitivity syndrome (Chauhan et al, 2018).…”

Streamlined identification of clinically and functionally relevant genetic regulators of lower-tract urogenital development

“…Among the most undeniably powerful known active regulators of LGU development is the androgen signaling pathway, which is required to generate the phenotypic presentation of the genetic male relative to the female. It is required for penile outgrowth, testicular formation and descent, scrotal formation, spermatogenesis, and positive feedback for testosterone levels ( 15 – 21 ). Androgen signaling has additional roles across variant tissues in order to generate secondary sex characteristics, both strictly anatomical as well as neurological/behavioral ( 22 ).…”