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<p>Premature ovarian insufficiency (POI), characterized by ovarian dysfunction before age 40, remains idiopathic in over 50% of cases, underscoring the urgent need to elucidate its genetic underpinnings. Here, we report a consanguineous Iranian family with five females diagnosed with POI, exhibiting elevated gonadotropins, undetectable anti-Müllerian hormone, and bilateral ovarian atrophy. Whole Exome Sequencing identified a novel homozygous missense variant in&#xa0;<i>BIRC6</i>&#xa0;(NM_016252.4: c.11266C &gt; T; p.Arg3756Cys), a gene encoding an apoptosis regulator. Segregation analysis confirmed an autosomal recessive inheritance pattern, with homozygosity exclusively in affected individuals. Functional studies in a CRISPR/Cas9-generated&#xa0;<i>birc6</i><sup><i>del12</i></sup>&#xa0;zebrafish model recapitulated POI phenotypes: homozygous females exhibited reduced fecundity, aberrant oocyte morphology, and elevated embryonic death. Transcriptional analysis revealed dysregulation of apoptotic (<i>badb</i>,&#xa0;<i>sortilin</i>,&#xa0;<i>apc</i>) and fertility-related (<i>nanos1</i>,&#xa0;<i>vtg1</i>) genes, alongside unaltered estradiol levels, implicating apoptosis-driven follicular atresia rather than endocrine dysfunction. Compensatory increase in egg production in mutants mirrored human POI progression, where initial irregular cycles culminate in follicular depletion. This study establishes&#xa0;<i>BIRC6</i>&#xa0;as a novel POI candidate, links its anti-apoptotic function to ovarian homeostasis, and highlights zebrafish as a tractable model for dissecting POI mechanisms. Our findings expand the genetic landscape of infertility and suggest therapeutic potential for apoptosis modulation in fertility preservation.</p>

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A Novel BIRC6 Variant Impairs Apoptotic Regulation in Familial Premature Ovarian Insufficiency: Functional Validation in a CRISPR/Cas9 Zebrafish Model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月4日

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  • Mahsa Kazerani,
  • Umut Cagiral,
  • Seyedeh Zoha Tabatabaei,
  • Remziye Nur Akalper,
  • Ugur Bora,
  • Sadegh Babashah,
  • Gunes Ozhan,
  • Mehdi Totonchi

摘要

Premature ovarian insufficiency (POI), characterized by ovarian dysfunction before age 40, remains idiopathic in over 50% of cases, underscoring the urgent need to elucidate its genetic underpinnings. Here, we report a consanguineous Iranian family with five females diagnosed with POI, exhibiting elevated gonadotropins, undetectable anti-Müllerian hormone, and bilateral ovarian atrophy. Whole Exome Sequencing identified a novel homozygous missense variant in BIRC6 (NM_016252.4: c.11266C > T; p.Arg3756Cys), a gene encoding an apoptosis regulator. Segregation analysis confirmed an autosomal recessive inheritance pattern, with homozygosity exclusively in affected individuals. Functional studies in a CRISPR/Cas9-generated birc6del12 zebrafish model recapitulated POI phenotypes: homozygous females exhibited reduced fecundity, aberrant oocyte morphology, and elevated embryonic death. Transcriptional analysis revealed dysregulation of apoptotic (badb, sortilin, apc) and fertility-related (nanos1, vtg1) genes, alongside unaltered estradiol levels, implicating apoptosis-driven follicular atresia rather than endocrine dysfunction. Compensatory increase in egg production in mutants mirrored human POI progression, where initial irregular cycles culminate in follicular depletion. This study establishes BIRC6 as a novel POI candidate, links its anti-apoptotic function to ovarian homeostasis, and highlights zebrafish as a tractable model for dissecting POI mechanisms. Our findings expand the genetic landscape of infertility and suggest therapeutic potential for apoptosis modulation in fertility preservation.