Journal of gastroenterology · 2025
TRPV6-related pancreatitis: natural history and the impact of the pancreas-specific deletion on pancreatitis in mice.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Masamune Atsushi, Masson Emmanuelle, Zou Wen-Bin, Rygiel Agnieszka Magdalena, Chowdhury Sudipta Dhar, Kikuta Kazuhiro, Hayashi Hidehiro, Sasaki Akira, Nakasuji Hitomi, Matsumoto Ryotaro, Takikawa Tetsuya, Xu Yan, Jie Ren, Sekino Yasumasa, Abe Toshiaki, Hatta Waku, Niihori Tetsuya, Aoki Yoko, Sakaguchi Reiko, Mori Yasuo, Rebours Vinciane, Buscail Louis, Wang Yuan-Chen, Kurien Reuben Thomas, Visweswariah Sandhya S, Rosendahl Jonas, Ferec Claude, Oracz Grzegorz, Witt Heiko, Liao Zhuan, Chen Jian-Min, Hamada Shin
Аннотация
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.
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.