Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

Abstract

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.

Impact of estrogens in males and androgens in females

“…In contrast to male ERα KO mice, male mice with KO of ERβ retain relatively normal fertility in two different models (18,19). Surprisingly, however, a small number of male humans with mutations in ERβ are associated with 46, XY disorders of sex development, showing markedly abnormal or absent gonads (27). These differences between mice and men with mutated or no ERβ highlight the importance of studying estrogen signaling in both mouse models and human patients.…”

Long‐term outcomes and molecular analysis of a large cohort of patients with 46,XY disorder of sex development due to partial gonadal dysgenesis

“…Twenty-seven patients were analysed during the 2010s by targeted massively parallel sequencing. An amplicon-based capture panel was designed against exonic regions of 63 genes, including 43 genes already associated with human DSDs and 20 candidate genes involved in gonadal determination pathways or with a DSD phenotype in rats 1,[11][12][13][14][15][16][17][18] (see Appendix 2). Capture of the target sequences was performed using a custom Sure Select Target Enrichment System Kit (Agilent).…”

Novas perspectivas no diagnóstico etiológico dos distúrbios do desenvolvimento sexual 46, XY

“…(114) . Primeiramente, as variantes segregam com o fenótipo com padrão de herança autossômico dominante na maior parte das famílias e duas variantes de novo (caso 21 deste estudo e o caso chinês-americano previamente reportado pelo grupo (70) (109) . Além disso, variantes alélicas polimórficas foram associadas à ocorrência de hipospádia (125)(126)(127)(128) .…”

“…As variantes em questão estão presentes em baixa frequência ou ausentes em bancos de dados populacionais, estão localizadas em domínios importantes da proteína (domínio altamente conservado do ER-β de ligação ao DNA, domínio N terminal e domínio de ligação ao ligante, respectivamente) e são preditas como deletérias pelos algoritmos de predição in silico. A análise estrutural das variantes p.Asn181del e p.Leu426Arg demonstra haver impacto na conformação da proteína (129) . O gene CBX2 já está sabidamente associado à disgenesia gonadal e possui seus alvos e suas funções dentro da cascata da determinação testicular já estão estabelecidos (12,80,130) .…”

“…Foi realizado estudo funcional da variante em colaboração com o grupo da Universidade de Ghent, na Bélgica, coordenado pela Profa. Elfride De Baere que mostrou, por ensaio de luciferase, que houve aumento significativo da ativação do receptor, independente do ligante específico da unidade β do receptor estrogênico (109) .…”