Abstract
The androgen insensitivity syndrome (AIS) is a congenital disease characterized by androgen resistance due to androgen receptor (AR) gene mutations, resulting in disorders of sex differentiation in 46,XY individuals. However, the underlying mechanisms in the majority of AR variants and the phenotype–genotype correlations are unclear. Here, we identified a p.Y764H variant of the AR gene that results in different phenotypes in a family. Structural analyses revealed that amino acid substitution affected protein properties and spatial conformation, and in vitro, functional studies showed impaired nuclear translocation ability of the mutated protein. Moreover, the extent to which this variant reduced nuclear translocation depends on the dihydrotestosterone (DHT) concentrations. Our results, for the first time, demonstrated a pathogenesis of the p.Y764H mutations in AR resulting in AIS phenotype, and indicated that AIS patients with p.Y764H mutation and preserved gonad might have residual AR activity at high androgen levels, putting patients at risk for pubertal virilization in the future. We provide an in-depth insight into the pathogenesis in AIS based on the amino acid substitution, which may help aid its precise diagnosis, personalized treatment, and organized follow-up to avoid gender dysphoria.
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Acknowledgements
The project was financially supported by the Key Subject Program from Shanghai Municipal Commission of Health and Family Planning (2016ZB0102), Yangtze River Delta Project of Shanghai Science and Technology Commission (13495810300), Shanghai Collaborative Innovation Center for Translational Medicine (TM201611), Medical Professionals Cross Research Fund of Shanghai Jiao Tong University (YG2015MS39) and Jin Lei Pediatric Endocrinology Growth Research Fund for Young Physicians (PEGRF201506002). The funding organizations had no role in study design, data collection, and analysis, preparation of the manuscript, or in the decision to submit the article for publication.
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Liu, C., Lyu, Y. & Li, P. A hemizygous mutation in the androgen receptor gene causes different phenotypes of androgen insensitivity syndrome in two siblings by disrupting the nuclear translocation. Mol Genet Genomics 295, 1103–1111 (2020). https://doi.org/10.1007/s00438-020-01686-6
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DOI: https://doi.org/10.1007/s00438-020-01686-6