Mutations in SRY and WT1 genes required for gonadal development are not responsible for XY partial gonadal dysgenesis

Abstract

The WT1 transcription factor regulates SRY expression during the initial steps of the sex determination process in humans, activating a gene cascade leading to testis differentiation. In addition to causing Wilms' tumor, mutations in WT1 are often responsible for urogenital defects in men, while SRY mutations are mainly related to 46,XY pure gonadal dysgenesis. In order to evaluate their role in abnormal testicular organogenesis, we screened for SRY and WT1 gene mutations in 10 children with XY partial gonadal dysgenesis, 2 of whom with a history of Wilms' tumor. The open reading frame and 360 bp of the 5' flanking sequence of the SRY gene, and the ten exons and intron boundaries of the WT1 gene were amplified by PCR of genomic DNA. Single-strand conformation polymorphism was initially used for WT1 mutation screening. Since shifts in fragment migration were only observed for intron/exon 4, the ten WT1 exons from all patients were sequenced manually. No mutations were detected in the SRY 5' untranslated region or within SRY open-reading frame sequences. WT1 sequencing revealed one missense mutation (D396N) in the ninth exon of a patient who also had Wilms' tumor. In addition, two silent point mutations were found in the first exon including one described here for the first time. Some non-coding sequence variations were detected, representing one new (IVS4+85A>G) and two already described (-7ATG T>G, IVS9-49 T>C) single nucleotide polymorphisms. Therefore, mutations in two major genes required for gonadal development, SRY and WT1, are not responsible for XY partial gonadal dysgenesis.

<b><i>NR5A1</i></b> Loss-of-Function Mutations Lead to 46,XY Partial Gonadal Dysgenesis Phenotype: Report of Three Novel Mutations

“…In addition, the heterozygous polymorphic variation p.Gly146Ala (rs1110061) was also identified in this patient. SRY , WT1 [Scolfaro et al, 2001;Tagliarini et al, 2005], DMRT1, and SOX9 (not published) were previously analyzed and no mutations were found.…”

“…3 A). SRY , WT1 [Scolfaro et al, 2001;Tagliarini et al, 2005], DMRT1, and SOX9 (not published) were previously analyzed and no mutations were found in this patient. Three different in silico predictive tools were used to evaluate possible consequences of the c.1138+1G>T mutation.…”

Novel DMRT1 3'UTR+11insT mutation associated to XY partial gonadal dysgenesis

“…SRY and WT1 genes were studied before but the patient did not carry mutations in either gene (7). Therefore, deletions and mutations on 9p and DMRT1 gene, respectively, were investigated.…”

“…The Y-chromosome-located SRY gene encodes a small testis-specific protein containing a DNA-binding motif known as the HMG (high mobility group) box. However, mutations in SRY are not frequent especially in cases of 46,XY partial gonadal dysgenesis (6,7).…”

Uso da FISH em mucosa oral para investigação de mosaicismo com linhagem 45,X: estudo com homens saudáveis e pacientes com distúrbios da diferenciação do sexo

“…A DGM tem como diagnóstico diferencial a disge nesia gonadal parcial 46,XY (DGP XY), caracterizada por ambiguidade genital com cariótipo 46,XY sem mo saicismo em pacientes com diferenciação testicular par cial, presença de derivados dos dutos de Müller e sem sinais clínicos da ST. Na maioria dos casos a etiologia é desconhecida, mas já foram descritas mutações nos genes SRY e NR5A1 (11,12). A distinção entre DGP XY e DGM se dá por meio do exame de cariótipo, bus cando afastar com alto grau de probabilidade a presença de linhagem 45,X.…”