International Journal of Molecular Sciences (Oct 2019)

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

  • 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

DOI
https://doi.org/10.3390/ijms20215418
Journal volume & issue
Vol. 20, no. 21
p. 5418

Abstract

Read online

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>T). Case No.3 did not reveal AR mutation; however, we have found a heterozygous mutation in CYP11A1 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 PLCXD3, TM4SF18, CFI, GPX8, and SFRP4, and a significant decrease in the expression of SPATA16, TSACC, TCP10L, and DPY19L2 genes (more than 10-fold, p < 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.

Keywords