1. Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development
- Author
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Hannah Verdin, Tulay Guran, Berenice B. Mendonca, Zeynep Atay, Dorien Baetens, Lode De Cauwer, Nathalia Lisboa Gomes, Karolien De Bosscher, Sorahia Domenice, Serap Turan, Marnik Vuylsteke, Frank Peelman, Elfride De Baere, Ronald R. de Krijger, Hans Stoop, Leendert H. J. Looijenga, Katleen De Preter, Martine Cools, Malaïka Van der Linden, Abdullah Bereket, and Pathology
- Subjects
0301 basic medicine ,Male ,Candidate gene ,disorders of sex development ,Protein Conformation ,XY DSD ,0302 clinical medicine ,Gene Frequency ,Medicine and Health Sciences ,Missense mutation ,CRYSTAL-STRUCTURE ,Genetics(clinical) ,Disorders of sex development ,whole-exome sequencing ,Child ,Genetics (clinical) ,Exome sequencing ,Genetics ,RISK ,ESR2 variants ,Chromosome Mapping ,High-Throughput Nucleotide Sequencing ,Disease gene identification ,ESTROGEN-RECEPTOR BETA ,COMPLEXES ,Female ,GENES ,46_XY DSD ,Adolescent ,030209 endocrinology & metabolism ,Biology ,HYPOSPADIAS ,03 medical and health sciences ,Structure-Activity Relationship ,Young Adult ,Exome Sequencing ,medicine ,Estrogen Receptor beta ,Humans ,Allele ,Gene ,POLYMORPHISMS ,Alleles ,novel candidate gene ,BINDING DOMAIN ,Disorder of Sex Development, 46,XY ,MUTATIONS ,Biology and Life Sciences ,PATHWAYS ,medicine.disease ,030104 developmental biology ,Amino Acid Substitution ,Mutation ,SEQUENCIAMENTO GENÉTICO ,46,XY DSD ,Immunostaining - 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-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.
- Published
- 2018