期刊
GENETICS IN MEDICINE
卷 20, 期 7, 页码 717-727出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/gim.2017.163
关键词
46,XY DSD; disorders of sex development; ESR2 variants; novel candidate gene; whole-exome sequencing
资金
- Research Foundation -Flanders (FWO) (Bilateral Scientific Cooperation Brazil) [NXT-DSDG0D6713N]
- Ghent University Special Research Fund [BOF15/GOA/011]
- Ghent University Special Research Fund (BOF Starting Grant)
- Belspo IAP project (Belgian Medical Genomics Initiative) [P7/43]
Purpose: Disorders or differences of sex development (DSDs) are rare congenital conditions characterized by atypical sex development. Despite advances in genomic technologies, the molecular cause remains unknown in 50% of cases. Methods: Homozygosity mapping and whole-exome sequencing revealed an ESR2 variant in an individual with syndromic 46, XY DSD. Additional cases with 46, XY DSD underwent whole-exome sequencing and targeted next-generation sequencing of ESR2. Functional characterization of the identified variants included luciferase assays and protein structure analysis. Gonadal ESR2 expression was assessed in human embryonic data sets and immunostaining of estrogen receptor-beta (ER-beta) was performed in an 8-week-old human male embryo. Results: We identified a homozygous ESR2 variant, c.541_543del p. (Asn181del), located in the highly conserved DNA-binding domain of ER-beta, in an individual with syndromic 46, XY DSD. Two additional heterozygous missense variants, c.251G>T p.(Gly84Val) and c.1277T>G p.(Leu426Arg), located in the N-terminus and the ligand-binding domain of ER-beta, were found in unrelated, nonsyndromic 46, XY DSD cases. Significantly increased transcriptional activation and an impact on protein conformation were shown for the p.(Asn181del) and p.(Leu426Arg) variants. Testicular ESR2 expression was previously documented and ER-beta immunostaining was positive in the developing intestine and eyes. Conclusion: Our study supports a role for ESR2 as a novel candidate gene for 46, XY DSD.
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