ESPEYB21 6. Differences of Sexual Development (DSD) and Gender Incongruence (GI) DSD - Novel Genes and Mechanisms involved in Gonadal Development (4 abstracts)
6.4. Microdeletion at ESR1 intron 6 (DEL_6_75504) is a susceptibility factor for cryptorchidism and hypospadias
Masunaga Y , Fujisawa Y , Massart F , Spinelli C , Kojima Y , Mizuno K , Hayashi Y , Sasagawa I , Yoshida R , Kato F , Fukami M , Kamatani N , Saitsu H & Ogata T
J Clin Endocrinol Metab. 2023 Sep 18;108(10):2550-2560. doi: 10.1210/clinem/dgad187. PMID: 37010083
Brief Summary: This translational study identifies a new susceptibility region within the estrogen receptor α ( ESR1 ) gene, linked to cryptorchidism (CO) and hypospadias (HS), the most common birth defects of the male genital tract. CO occurs in approximately 1:100 male births and is 3-times more common in premature infants, while HS affects about 1:300 male births. The prevalence of both conditions has increased over the years, with premature infants showing higher prevalence and severity.
CO and HS are influenced by various genetic and environmental factors, including specific single-gene mutations. Masunaga Y et al. previously identified a tight linkage disequilibrium (LD) block within ESR1, spanning 5 single nucleotide polymorphisms (SNPs) in Japanese boys with CO and HS. Four major haplotypes were identified, with the “AGATC” haplotype being strongly associated with both conditions in a recessive manner. The researchers suggested that the “AGATC” haplotype could enhance estrogenic effects through increased ESR1 expression, contributing to CO and HS development.
In this study, 230 Italian boys (80 with CO and 150 with typical male genitalia) and 415 Japanese boys (149 with CO, 141 with HS, and 125 with typical male genitalia) were enrolled to investigate the susceptibility factor linked to this haplotype. Using Sanger sequencing, SNP typing, and whole-genome sequencing (WGS) methods, a 2244-bp microdeletion within the ESR1 gene, termed ΔESR1 (Structural variant: DEL_6_75504), was identified as the true susceptibility factor for CO and HS. This conclusion is based on the positive association of ΔESR1 with CO and HS and its nearly absolute LD with the “AGATC” haplotype in both Japanese and Italian boys, along with the observed upregulation of ESR1 expression linked to ΔESR1.
Expression studies using MCF-7 cells demonstrated that ΔESR1 leads to increased ESR1 expression, particularly under estrogenic conditions, which may explain its role in enhancing susceptibility to CO and HS, especially when exposed to environmental endocrine disruptors. These findings shed new light on the genetic basis of CO and HS, emphasizing the importance of ΔESR1 in the pathogenesis of these conditions. However, further investigation is needed on the frequency of this susceptibility locus in different populations, its effects on HS and CO development, and the availability of tests to explore the causal relationship between ΔESR1 and other risk loci in individuals with CO and HS.
Volume 21
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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