title: Absence of inactivating mutations and deletions in the DMRT1 and FGF9 genes in a large cohort of 46,XY patients with gonadal dysgenesis.
abstract: Despite advances in our understanding of the mechanisms involved in sex determination and differentiation, the specific roles of many genes in these processes are not completely understood in humans. Both DMRT1 and FGF9 are among this group of genes. Dmrt1 controls germ cell differentiation, proliferation, migration and pluripotency and Sertoli cell proliferation and differentiation. Fgf9 has been considered a critical factor in early testicular development and germ cell survival in mice. We screened for the presence of DMRT1 and FGF9 mutations in 33 patients with 46,XY gonadal dysgenesis. No deletions in either DMRT1 or FGF9 were identified using the MLPA technique. Eight allelic variants of DMRT1 were identified, and in silico analysis suggested that the novel c.968-15insTTCTCTCT variant and the c.774G>C (rs146975077) variant could have potentially deleterious effects on the DMRT1 protein. Nine previously described FGF9 allelic variants and six different alleles of the 3' UTR microsatellite were identified. However, none of these DMRT1 or FGF9 variants was associated with increased 46,XY gonadal dysgenesis. In conclusion, our study suggests that neither DMRT1 nor FGF9 abnormalities are frequently involved in dysgenetic male gonad development in patients with non-syndromic 46,XY disorder of sex development.
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular (LIM42) da Disciplina de Endocrinologia e Metabologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil.
authors.forename: Aline Zamboni
authors.initials: AZ
authors.lastname: Machado
authors.forename: Thatiana Evilen
authors.initials: TE
authors.lastname: da Silva
authors.forename: Elaine Maria
authors.initials: EM
authors.lastname: Frade Costa
authors.forename: Mariza Gerdulo
authors.initials: MG
authors.lastname: Dos Santos
authors.forename: Mirian Yumie
authors.initials: MY
authors.lastname: Nishi
authors.forename: Vinicius Nahime
authors.initials: VN
authors.lastname: Brito
authors.forename: Berenice Bilharinho
authors.initials: BB
authors.lastname: Mendonca
authors.forename: Sorahia
authors.initials: S
authors.lastname: Domenice
mesh_terms: D020413:3' Untranslated Regions; D000483:Alleles; D001483:Base Sequence; D051525:Fibroblast Growth Factor 9 / Q000235:genetics*; D018628:Gene Dosage; D006061:Gonadal Dysgenesis, 46,XY / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; C110547:DMRT1 protein; D051525:Fibroblast Growth Factor 9; D014157:Transcription Factors