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

• Published in: International journal of molecular sciences Vol. 20; no. 21; p. 5418
• Main Authors: Malcher, Agnieszka, Jedrzejczak, Piotr, Stokowy, Tomasz, Monem, Soroosh, Nowicka-Bauer, Karolina, Zimna, Agnieszka, Czyzyk, Adam, Maciejewska-Jeske, Marzena, Meczekalski, Blazej, Bednarek-Rajewska, Katarzyna, Wozniak, Aldona, Rozwadowska, Natalia, Kurpisz, Maciej
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 30.10.2019; MDPI
• Subjects: Adolescent; Adult; Amino acids; androgen insensitivity syndrome; Androgen receptors; Androgen-Insensitivity Syndrome - genetics; Androgen-Insensitivity Syndrome - metabolism; Androgens; biomarkers; Biosynthesis; Case-Control Studies; Cell differentiation; Cholesterol Side-Chain Cleavage Enzyme - genetics; Cholesterol Side-Chain Cleavage Enzyme - metabolism; Deregulation; Domains; Exons; Female; Fertility; Frameshift Mutation; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Genes; Genotype & phenotype; Germ cells; Humans; Immunoblotting; Immunohistochemistry; Infertility; Ligands; Male; Males; Middle Aged; morris syndrome; Mutation; Nonsense mutation; Polymorphism, Single Nucleotide; Protein Domains; Proteins; rare disease; Receptors, Androgen - chemistry; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; rna-seq; Sequence Analysis, DNA - methods; Signal transduction; Spermatogenesis; Stop codon; Thymine; Young Adult; rare disease; RNA-seq; biomarkers; spermatogenesis; infertility; Morris syndrome; androgen insensitivity syndrome
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20215418

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 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 , , , , and and a significant decrease in the expression of and genes (more than 10-fold, < 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.