Novel Mutations Segregating with Complete Androgen Insensitivity Syndrome and Their Molecular Characteristics

• Main Authors: Agnieszka Malcher, Piotr Jedrzejczak, Tomasz Stokowy, Soroosh Monem, Karolina Nowicka-Bauer, Agnieszka Zimna, Adam Czyzyk, Marzena Maciejewska-Jeske, Blazej Meczekalski, Katarzyna Bednarek-Rajewska, Aldona Wozniak, Natalia Rozwadowska, Maciej Kurpisz
• Format: Article
• Language: English
• Published: MDPI AG 2019-10-01
• Series: International Journal of Molecular Sciences
• Subjects: morris syndrome; androgen insensitivity syndrome; infertility; spermatogenesis; biomarkers; rare disease; rna-seq
• Online Access: https://www.mdpi.com/1422-0067/20/21/5418

We analyzed three cases of Complete Androgen Insensitivity Syndrome (CAIS) and report three hitherto undisclosed causes of the disease. RNA-Seq, Real-timePCR, Western immunoblotting, and immunohistochemistry were performed with the aim of characterizing the disease-causing variants. In case No.1, we have identified a novel androgen receptor (AR) mutation (c.840delT) within the first exon in the N-terminal transactivation domain. This thymine deletion resulted in a frameshift and thus introduced a premature stop codon at amino acid 282. In case No.2, we observed a nonsynonymous mutation in the ligand-binding domain (c.2491C&gt;T). Case No.3 did not reveal AR mutation; however, we have found a heterozygous mutation in <i>CYP11A1</i> gene, which has a role in steroid hormone biosynthesis. Comparative RNA-Seq analysis of CAIS and control revealed 4293 significantly deregulated genes. In patients with CAIS, we observed a significant increase in the expression levels of <i>PLCXD3</i>, <i>TM4SF18</i>, <i>CFI</i>, <i>GPX8</i>, and <i>SFRP4,</i> and a significant decrease in the expression of <i>SPATA16, TSACC, TCP10L,</i> and <i>DPY19L2</i> genes (more than 10-fold, <i>p</i> &lt; 0.05). Our findings will be helpful in molecular diagnostics of patients with CAIS, as well as the identified genes could be also potential biomarkers for the germ cells differentiation process.