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Background <p>The transient receptor potential cation channel subfamily V member 6 (<i>TRPV6</i>) gene, encoding a calcium-selective ion channel, was recently identified as a susceptibility gene for pancreatitis. This study aimed to clarify the natural history of <i>TRPV6</i>-related pancreatitis and the impact of pancreas-specific deletion of <i>Trpv6</i> on pancreatitis in mice.</p> Methods <p>Clinical information of the patients carrying functionally impaired <i>TRPV6</i> variants, defined by Ca<sup>2+</sup> imaging and minigene assays, was collected from six international centers. Cumulative rates were assessed using Kaplan–Meier analysis. As controls, Japanese patients with alcohol-unrelated&#xa0;pancreatitis carrying pathogenic variants in <i>PRSS1</i> or <i>SPINK1</i>, as well as those without pathogenic variants in pancreatitis susceptibility genes, were enrolled. A pancreas-specific <i>Trpv6</i> conditional knockout mouse was established by crossing the <i>Trpv6</i> floxed mouse and the <i>Pdx-1-Cre</i> mouse. Pancreatitis was induced by repeated intraperitoneal injections of caerulein.</p> Results <p>Ninety-four patients with functionally impaired <i>TRPV6</i> variants, including six splice-site variants, were enrolled. The median age at symptom onset was 16&#xa0;years. The cumulative rates of pancreatic calcification, pancreatic exocrine insufficiency, diabetes mellitus, and interventions for pancreatitis were 55.5%, 20.1%, 10.8%, and 41.6% at 30&#xa0;years, and 81.5%, 49.6%, 45.4%, and 69.9% at 50&#xa0;years, respectively. Pancreas-specific <i>Trpv6</i> knockout mice developed more severe acute and chronic pancreatitis than the control mice. Caerulein treatment increased the TRPV6 expression in pancreatic acinar cells.</p> Conclusions <p>Functionally impaired <i>TRPV6</i> variants significantly influenced the clinical outcomes of chronic pancreatitis. TRPV6 in pancreatic acinar cells might play a protective role against pancreatitis in mice.</p>

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TRPV6-related pancreatitis: natural history and the impact of the pancreas-specific deletion on pancreatitis in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月17日

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  • Atsushi Masamune,
  • Emmanuelle Masson,
  • Wen-Bin Zou,
  • Agnieszka Magdalena Rygiel,
  • Sudipta Dhar Chowdhury,
  • Kazuhiro Kikuta,
  • Hidehiro Hayashi,
  • Akira Sasaki,
  • Hitomi Nakasuji,
  • Ryotaro Matsumoto,
  • Tetsuya Takikawa,
  • Yan Xu,
  • Ren Jie,
  • Yasumasa Sekino,
  • Toshiaki Abe,
  • Waku Hatta,
  • Tetsuya Niihori,
  • Yoko Aoki,
  • Reiko Sakaguchi,
  • Yasuo Mori,
  • Vinciane Rebours,
  • Louis Buscail,
  • Yuan-Chen Wang,
  • Reuben Thomas Kurien,
  • Sandhya S. Visweswariah,
  • Jonas Rosendahl,
  • Claude Ferec,
  • Grzegorz Oracz,
  • Heiko Witt,
  • Zhuan Liao,
  • Jian-Min Chen,
  • Shin Hamada

摘要

Background

The transient receptor potential cation channel subfamily V member 6 (TRPV6) gene, encoding a calcium-selective ion channel, was recently identified as a susceptibility gene for pancreatitis. This study aimed to clarify the natural history of TRPV6-related pancreatitis and the impact of pancreas-specific deletion of Trpv6 on pancreatitis in mice.

Methods

Clinical information of the patients carrying functionally impaired TRPV6 variants, defined by Ca2+ imaging and minigene assays, was collected from six international centers. Cumulative rates were assessed using Kaplan–Meier analysis. As controls, Japanese patients with alcohol-unrelated pancreatitis carrying pathogenic variants in PRSS1 or SPINK1, as well as those without pathogenic variants in pancreatitis susceptibility genes, were enrolled. A pancreas-specific Trpv6 conditional knockout mouse was established by crossing the Trpv6 floxed mouse and the Pdx-1-Cre mouse. Pancreatitis was induced by repeated intraperitoneal injections of caerulein.

Results

Ninety-four patients with functionally impaired TRPV6 variants, including six splice-site variants, were enrolled. The median age at symptom onset was 16 years. The cumulative rates of pancreatic calcification, pancreatic exocrine insufficiency, diabetes mellitus, and interventions for pancreatitis were 55.5%, 20.1%, 10.8%, and 41.6% at 30 years, and 81.5%, 49.6%, 45.4%, and 69.9% at 50 years, respectively. Pancreas-specific Trpv6 knockout mice developed more severe acute and chronic pancreatitis than the control mice. Caerulein treatment increased the TRPV6 expression in pancreatic acinar cells.

Conclusions

Functionally impaired TRPV6 variants significantly influenced the clinical outcomes of chronic pancreatitis. TRPV6 in pancreatic acinar cells might play a protective role against pancreatitis in mice.