Mutational analysis of the androgen receptor (NR3C4) gene in patients with 46,XY DSD

• Published in: Gene Vol. 641; pp. 86 - 93
• Main Authors: Ramos, L., Chávez, B., Mares, L., Valdés, E., Vilchis, F.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 30.01.2018
• Subjects: Adolescent; Adult; Androgen insensitivity syndrome (AIS); Androgen-Insensitivity Syndrome - genetics; CAIS; Child; Child, Preschool; Disorder of sex development (DSD); Disorders of Sex Development - genetics; DNA Mutational Analysis; Female; Genital ambiguity; Humans; Infant; Male; Mexico; Mutation - genetics; PAIS; Receptors, Androgen - genetics; Sex Differentiation - genetics; Sexual differentiation; Steroid receptors; Young Adult; Androgen insensitivity syndrome (AIS); DAPI; AIS; SSCP; AR; DHT; DMEM; Genital ambiguity; SBD; SNP; FBS; CAIS; Steroid receptors; 46,XY DSD; GSFs; FSH; Disorder of sex development (DSD); LH; MAIS; WT; Sexual differentiation; PAIS; NTD
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2017.10.038

Androgen insensitivity syndrome (AIS) is an X-linked disorder caused by mutations in the NR3C4 gene, which encodes the androgen receptor (AR). In this study, we performed mutational analyses to identify AR molecular defects, in individuals with 46,XY disorders of sex development (46,XY DSD) and a presumptive diagnosis of AIS. Eighteen different gene mutations, including seven previously unreported new variants, were detected in 26 unrelated cases. These included two deletion mutations (P49fs*185 and E308f*320) in exon 1 and five substitution mutations (p.S792P, p.D829G, p.R832P, p.L839F, and p.K906E) located in the steroid-binding domain. Expression analyses of mutants generated by site-directed mutagenesis indicated that these new gene variants impaired AR function by affecting its binding activity. Seventeen of 18 mutations likely lead to reduced or absent responses to androgens, which may in turn account for the different degrees of undermasculinization observed. Our study provides insight into the functional consequences of these mutations. Mutation screening of the NR3C4 gene in patients with 46,XY DSD. [Display omitted] •Eighteen different NR3C4 variants were identified in 26 cases of 46,XY DSD.•Seven novel NR3C4 mutations are characterized in patients with AIS.•NR3C4 small deletion mutations abolish the AR functional activity.•Mutations in NR3C4 result in a spectrum of masculinization defects.•Nonsense mutations and small deletions in NR3C4 lead to complete AIS.