Genetics in medicine : official journal of the American College of Medical Genetics · 2017
Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development.
Клинический случайСтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Baetens Dorien, Güran Tülay, Mendonca Berenice B, Gomes Nathalia L, De Cauwer Lode, Peelman Frank, Verdin Hannah, Vuylsteke Marnik, Van der Linden Malaïka, ESR2 STUDY GROUP, Atay Zeynep, Bereket Abdullah, de Krijger Ronald R, Preter Katleen de, Domenice Sorahia, Turan Serap, Stoop Hans, Looijenga Leendert H, De Bosscher Karolien, Cools Martine, De Baere Elfride
Аннотация
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-β (ER-β) 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-β, 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-β, 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-β 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.
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-β (ER-β) 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-β, 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-β, 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-β 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.