Characterization of a novel androgen receptor gene variant identified in an Iranian family with complete androgen insensitivity syndrome (CAIS): a molecular dynamics simulation study

Abstract

Androgen insensitivity syndrome (AIS) is a common form of 46, XY disorder in sex development disease (DSD). It is due to the androgen receptor (AR) gene mutations and includes clinical subgroups of complete AIS (CAIS) and partial AIS (PAIS), along with a vast area of clinical heterogeneity of completely normal female external genitalia to male infertility. In this study, the Whole Exome Sequencing (WES) was utilized to detect the cause of DSD in a consanguineous Iranian family with two female patients with normal external genitalia and 46, XY karyotype. Sanger sequencing was applied to validate the candidate variant. Next, we predicted the structural alteration induced by the variant on AR protein using bioinformatics analysis such as molecular dynamic (MD) and molecular docking simulations. WES results identified a novel hemizygous p.L763V variant in the AR gene in the proband that was compatible with the X-linked recessive pattern of inheritance. Bioinformatics studies confirmed the loss of AR function. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, it was categorized as pathogenic. This study broadens the AR mutation spectrum and introduces the novel p.L763V missense pathogenic variant leading to AR failure to bind to its ligand, and the resulting CAIS clinical subgroup. This study presents a prosperous application of WES and bioinformatics analysis to recognize the underlying cause of DSD in Iran, necessary for its clinical/psychological management.

Communicated by Ramaswamy H. Sarma

Keywords:

• Androgen insensitivity syndrome
• androgen receptor
• whole exome sequencing
• Sanger sequencing
• bioinformatics study

Acknowledgments

Authors would like to express their gratitude to all participants of this project, the personnel of Cellular and Molecular Research Center of Shahrekord University of Medical Sciences, Shahrekord, Iran and the personnel of Department of Genetics and Molecular Biology of Isfahan University of Medical Sciences, Isfahan, Iran for approval of the present study and collaborating with this project.

Consent to participate

Written informed consent was obtained from the parents.

Disclosure statement

The authors have no competing interests to declare that are relevant to the content of this article.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Institutional Review Boards (IRB) of the Shahrekord and Isfahan Universities of Medical Sciences (No. IR.SKUMS.REC.1397.84 and IR.MUI.RESEARCH.REC.1397.109).

Additional information

Funding

This work was supported by the Isfahan University of Medical Sciences under Grant number 197060 and the Shahrekord University of Medical Sciences under Grant [number 3571].