Abstract
Despite the fact that genitourinary defects are among the most common birth defects in newborns, little is known about their etiology. Here we analyzed children born with congenital genitourinary tract masculinization disorders by array-comparative genomic hybridization, which revealed in 1.35% of cases the presence of de novo copy number gains at Xq28 encompassing the VAMP7 gene, which encodes a vesicle-trafficking protein that is part of the SNARE complex. Transgenic mice carrying a bacterial artificial chromosome encoding human VAMP7 mimicked the defective urogenital traits observed in boys with masculinization disorders such as cryptorchidism, urethral defects and hypospadias. Transgenic mice also exhibited reduced penile length, focal spermatogenic anomalies, diminished sperm motility and subfertility. VAMP7 colocalized with estrogen receptor α (ESR1) in the presence of its cognate ligand, 17β-estradiol. Elevated levels of VAMP7 markedly intensified ESR1-potentiated transcriptional activity by increasing ESR1 protein cellular content upon ligand stimulation and upregulated the expression of estrogen-responsive genes including ATF3, CYR61 and CTGF, all of which have been implicated in human hypospadias. Hence, increased gene dosage of VAMP7, and thus higher expression levels of its protein product, enhances estrogen receptor action in male genitourinary tissues, affects the virilization of the reproductive tract and results in genitourinary birth defects in humans.
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Acknowledgements
We would like to thank all the referring physicians and especially E.T. Gonzales, L. Cisek, N. Janzen, D.R. Roth, and E. Jones, the affected individuals and their family members who participated in this study. We thank M. Marcelli (Baylor College of Medicine) for providing the foreskin fibroblasts for analysis. We thank L. White, C. Shaw and F. De Mayo for their assistance. This study was supported in part by US National Institutes of Health grant K12 DK0083014 (KURe to D.J.L.) and R01DK078121 from the National Institute of Diabetes and Digestive and Kidney Diseases (to D.J.L.).
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Both senior authors, M.T.-L. and D.J.L., conceived and supervised the study, conducted experiments, analyzed data and wrote and revised the manuscript. S.H. and J.-F.L. performed experiments and analyzed data. B.Z., K.R., J.A. and A.S. performed experiments. S.W.C. conducted the human CGH array studies.
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Tannour-Louet, M., Han, S., Louet, JF. et al. Increased gene copy number of VAMP7 disrupts human male urogenital development through altered estrogen action. Nat Med 20, 715–724 (2014). https://doi.org/10.1038/nm.3580
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DOI: https://doi.org/10.1038/nm.3580
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