title: A naturally occurring deletion in the SRY promoter region affecting the Sp1 binding site is associated with sex reversal.
abstract: Male to female sex reversal results from failure of testis development. Mutations in the SRY gene or in other genes involved in the sexual differentiation pathway are considered to cause XY gonadal dysgenesis. The majority of the mutations in the SRY described so far are located within the SRY coding region, mainly in the HMG-box conserved domain. Comparison of 5' flanking SRY gene sequences among different species indicated the presence of several putative conserved consensus sequences for different transcription regulators. In this study, we investigated a 360 bp sequence encompassing the SRY putative core promoter, in 17 patients with variable degrees of 46,XY sex reversal, which have been previously shown not to bear mutations in the SRYcoding region. Sequencing analysis of the SRYpromoter in one patient with complete XY gonadal dysgenesis revealed a three base pair deletion in one of the Sp1 binding sites. The deletion abolished Sp1 binding in vitro. This is the first report on a naturally occurring mutation affecting the Sp1 regulatory element in the SRY promoter region, which is associated with sex reversal. Additionally, upon familial investigation the father, who had 18 genital surgeries due to severe hypospadia without cryptorchidism, was found to bear the same deletion and several relatives were referred to have sexual ambiguity.
authors.affiliation: Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas, São Paulo, Brasil.
authors.forename: J G
authors.initials: JG
authors.lastname: Assumpção
authors.forename: L F Caldas
authors.initials: LF
authors.lastname: Ferraz
authors.forename: C E
authors.initials: CE
authors.lastname: Benedetti
authors.forename: A T
authors.initials: AT
authors.lastname: Maciel-Guerra
authors.forename: G
authors.initials: G
authors.lastname: Guerra
authors.forename: A P
authors.initials: AP
authors.lastname: Marques-de-Faria
authors.forename: M T Matias
authors.initials: MT
authors.lastname: Baptista
authors.forename: M P
authors.initials: MP
authors.lastname: de Mello
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D001665:Binding Sites; D012734:Disorders of Sex Development; D005260:Female; D017353:Gene Deletion; D024282:Genes, sry; D006066:Gonads / Q000033:anatomy & histology / Q000502:physiology; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016415:Sequence Alignment; D016329:Sp1 Transcription Factor / Q000378:metabolism*
chemical_list: D016329:Sp1 Transcription Factor