title: Increased gene copy number of VAMP7 disrupts human male urogenital development through altered estrogen action.
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.
authors.affiliation: 1] Scott Department of Urology, Baylor College of Medicine, Houston, Texas, USA. [2] Institut de Pharmacologie Moléculaire et Cellulaire, CNRS, Sophia Antipolis, France.
authors.forename: Mounia
authors.initials: M
authors.lastname: Tannour-Louet
authors.affiliation: 1] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA. [2].
authors.forename: Shuo
authors.initials: S
authors.lastname: Han
authors.affiliation: 1] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA. [2] Centre Méditerranéen de Médecine Moléculaire, INSERM U1065, Nice, France. [3].
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Louet
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Karina
authors.initials: K
authors.lastname: Romero
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Josephine
authors.initials: J
authors.lastname: Addai
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Aysegul
authors.initials: A
authors.lastname: Sahin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.affiliation: 1] Scott Department of Urology, Baylor College of Medicine, Houston, Texas, USA. [2] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA. [3] Center for Reproductive Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Dolores J
authors.initials: DJ
authors.lastname: Lamb
mesh_terms: D000818:Animals; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000502:physiology*; D005298:Fertility; D018628:Gene Dosage; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D050683:R-SNARE Proteins / Q000235:genetics*; D011944:Receptors, Androgen / Q000378:metabolism; D014566:Urogenital System / Q000196:embryology*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D050683:R-SNARE Proteins; D011944:Receptors, Androgen; C121241:VAMP7 protein, human