Estrogen Receptor α Inactivation in 2 Sisters: Different Phenotypic Severities for the Same Pathogenic Variant

Area of Science:

• Endocrinology
• Genetics
• Reproductive Biology

Background:

• Estrogens are crucial for reproduction, acting via nuclear receptors like estrogen receptor alpha (ERα).
• Loss-of-function mutations in ESR1, the gene encoding ERα, are rare, with only a few cases reported globally.
• Understanding ERα function is key to diagnosing and managing reproductive endocrine disorders.

Observation:

• A consanguineous Jordanian family presented two sisters with varying degrees of endocrine and ovarian dysfunction.
• The elder sister exhibited primary amenorrhea and absent breast development, while the younger sister had delayed puberty.
• Both sisters presented with elevated estradiol levels and high gonadotropin levels, suggesting estrogen resistance.

Findings:

• Genetic analysis revealed a homozygous ESR1 variant (ERα-E385V) in both sisters.
• ERα-E385V demonstrated impaired E2-dependent transcriptional activity and altered nuclear translocation.
• The mutation also induced ligand-independent ERα activation, affecting KISS1 promoter activity.

Implications:

• This study identifies a novel ERα variant contributing to estrogen resistance and reproductive defects.
• The differing phenotypes between the sisters suggest potential compensatory mechanisms influencing ERα loss-of-function severity.
• Further research into these compensatory pathways could offer new therapeutic targets for endocrine disorders.