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

(2018) GENETICS IN MEDICINE. 20(7). p.717-727
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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.
Keywords
46_XY DSD, disorders of sex development, ESR2 variants, novel candidate gene, whole-exome sequencing, ESTROGEN-RECEPTOR BETA, CRYSTAL-STRUCTURE, BINDING DOMAIN, HYPOSPADIAS, MUTATIONS, GENES, POLYMORPHISMS, COMPLEXES, PATHWAYS, RISK

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Chicago
Baetens, Dorien, Tülay Güran, Berenice B Mendonca, Nathalia L Gomes, Lode De Cauwer, Frank Peelman, Hannah Verdin, et al. 2018. “Biallelic and Monoallelic ESR2 Variants Associated with 46,XY Disorders of Sex Development.” Genetics in Medicine 20 (7): 717–727.
APA
Baetens, D., Güran, T., Mendonca, B. B., Gomes, N. L., De Cauwer, L., Peelman, F., Verdin, H., et al. (2018). Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development. GENETICS IN MEDICINE, 20(7), 717–727.
Vancouver
1.
Baetens D, Güran T, Mendonca BB, Gomes NL, De Cauwer L, Peelman F, et al. Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development. GENETICS IN MEDICINE. 2018;20(7):717–27.
MLA
Baetens, Dorien et al. “Biallelic and Monoallelic ESR2 Variants Associated with 46,XY Disorders of Sex Development.” GENETICS IN MEDICINE 20.7 (2018): 717–727. Print.
@article{8583344,
  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{\textrangle}T p.(Gly84Val) and c.1277T{\textrangle}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.},
  author       = {Baetens, Dorien and G{\"u}ran, T{\"u}lay and Mendonca, Berenice B and Gomes, Nathalia L and De Cauwer, Lode and Peelman, Frank and Verdin, Hannah and Vuylsteke, Marnik and Van Der Linden, Mala{\"i}ka and Stoop, Hans and Looijenga, Leendert H and De Bosscher, Karolien and Cools, Martine and De Baere, Elfride and ESR2 study group, the and De Preter, Katleen},
  issn         = {1098-3600},
  journal      = {GENETICS IN MEDICINE},
  language     = {eng},
  number       = {7},
  pages        = {717--727},
  title        = {Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development},
  url          = {http://dx.doi.org/10.1038/gim.2017.163},
  volume       = {20},
  year         = {2018},
}

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