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<p>The molecular underpinnings contributing to the onset of Barrett’s esophagus (BE) remain elusive. By studying familial clusters of the disease, here we identify a significant association between genetic variants in the V-set and Immunoglobulin Domain Containing 10 Like (<i>VSIG10L</i>) gene and BE predisposition. Using mammalian tissues and patient-derived organoids, we show <i>VSIG10L</i> is selectively expressed in the suprabasal squamous cells of the esophageal mucosa and is essential for epithelial maturation and homeostasis. Mice carrying human-orthologous germline mutations in <i>Vsig10l</i> exhibit loss of desmosomes, concomitant with disrupted epithelial differentiation programs, in the squamous mucosa. Upon long-term exposure to a bile acid (deoxycholate) supplemented diet, <i>Vsig10l</i>-mutant mice develop overt BE-like lesions in the forestomach. Furthermore, loss of esophageal <i>VSIG10L</i> expression is observed frequently in patients with chronic gastroesophageal reflux disease, a known risk factor for BE. Collectively, our study uncovers a fundamental link between VSIG10L, esophageal homeostasis, and BE predisposition.</p>

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VSIG10L is a major determinant of esophageal homeostasis and inherited predisposition to Barrett’s esophagus

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月29日

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  • Durgadevi Ravillah,
  • Salendra Singh,
  • Ramachandra M. Katabathula,
  • Adam M. Kresak,
  • Bhavatharini Udhayakumar,
  • Rajesh Gupta,
  • Wendy Brock,
  • Yosuke Mitani,
  • Vaibhav Jain,
  • Emily Hocke,
  • Simon G. Gregory,
  • Katherine S. Garman,
  • Joel T. Gabre,
  • Hisashi Fujioka,
  • Joseph E. Willis,
  • Amitabh Chak,
  • Kishore Guda

摘要

The molecular underpinnings contributing to the onset of Barrett’s esophagus (BE) remain elusive. By studying familial clusters of the disease, here we identify a significant association between genetic variants in the V-set and Immunoglobulin Domain Containing 10 Like (VSIG10L) gene and BE predisposition. Using mammalian tissues and patient-derived organoids, we show VSIG10L is selectively expressed in the suprabasal squamous cells of the esophageal mucosa and is essential for epithelial maturation and homeostasis. Mice carrying human-orthologous germline mutations in Vsig10l exhibit loss of desmosomes, concomitant with disrupted epithelial differentiation programs, in the squamous mucosa. Upon long-term exposure to a bile acid (deoxycholate) supplemented diet, Vsig10l-mutant mice develop overt BE-like lesions in the forestomach. Furthermore, loss of esophageal VSIG10L expression is observed frequently in patients with chronic gastroesophageal reflux disease, a known risk factor for BE. Collectively, our study uncovers a fundamental link between VSIG10L, esophageal homeostasis, and BE predisposition.