Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis

Masamune, Atsushi; Kotani, Hiroshi; Sörgel, Franziska Lena; Chen, Jian‐Min; Hamada, Shin; Sakaguchi, Reiko; Masson, Emmanuelle; Nakano, Eriko; Kakuta, Yoichi; Niihori, Tetsuya; Funayama, Ryo; Shirota, Matsuyuki; Hirano, Takeshi; Kawamoto, Tetsuya; Atsuki, Hosokoshi; Kaneda, Kiyoshi; Unger, Lara Sophie; Ewers, Maren; Laumen, Helmut; Bugert, Peter; Mori, Masayuki; Tsvilovskyy, Volodymyr; Weißgerber, Petra; Kriebs, Ulrich; Fecher‐Trost, Claudia; Freichel, Marc; Diakopoulos, Kalliope N.; Berninger, Alexandra; Lesina, Marina; Ishii, Kentaro; Itoi, Takao; Ikeura, Tsukasa; Okazaki, Kazuichi; Kaune, Tom; Rosendahl, Jonas; Nagasaki, Masao; Uezono, Yasuhito; Algül, Hana; Nakayama, Keiko; Matsubara, Yoichi; Aoki, Yoko; Férec, Claude; Mori, Yasuo; Witt, Heiko; Shimosegawa, Tooru

doi:10.1053/j.gastro.2020.01.005

Cited by 89 publications

(88 citation statements)

References 58 publications

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“…We sequenced additional Chinese patients and performed functional analysis of all identified TRPV6 variants, demonstrating a significant association between rare functionally deficient variants and CP. This result is consistent with the just‐published study by Masamune et al (2020), which was initiated by findings from whole‐exome sequencing of a patient with idiopathic CP and his healthy parents.…”

Section: Discussionsupporting

confidence: 92%

“…Intracellular Ca 2+ concentration measurement was used for functional screening of all identified TRPV6 nonsynonymous variants in both Masamune et al (2020) study and ours. In this regard, the functional classifications of the nine variants that were identified in both studies were entirely consistent: seven variants (p.Ala18Ser, p.Cys197Arg, p.Ile223Thr, p.Met418Val, p.Arg661Trp, p.Gly695Ser, and p.Met721Thr) were classified by both studies as functionally normal, while the other two variants (p.Glu575Lys and p.Arg345His) were classified by both studies as functionally deficient.…”

Section: Discussionmentioning

confidence: 91%

“…Of particular relevance, EGFP‐tagged TRPV (1–6) constructs in HT1080 cells have been successfully used to study the response of TRPV channels to mechanical stress (Nagasawa, & Kojima, 2015). The use of EGFP‐fused constructs here appeared to somehow reduce the sensitivity of the functional studies, as compared to the use of untagged constructs (Masamune et al, 2020). Specifically, almost all functionally deficient variants in the Masamune study had <25% activity of normal, but only 2 of the 10 functionally deficient variants in our study had <25% activity of normal.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, during the review of this study, an international collaborative study involving Japanese, French, and German groups was published. This study reported that functionally defective TRPV6 variants are strongly associated with early‐onset CP (Masamune et al, 2020); and an accompanying editorial gave a detailed background on the TRPV6 channel (Sahin‐Tóth, 2020).…”

Section: Introductionmentioning

confidence: 99%

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TRPV6 variants confer susceptibility to chronic pancreatitis in the Chinese population

et al. 2020

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Chronic pancreatitis (CP) is a progressive fibroinflammatory syndrome of the pancreatic tissue caused by genetic and environmental factors. Previously reported susceptibility genes in CP explain less than half of the apparent heritability. To uncover novel pathogenic mechanisms, we initially performed low‐coverage whole‐genome sequencing on 464 Chinese CP patients and 504 controls. The transient receptor potential cation channel, Subfamily V, Member 6 (TRPV6) gene was found to be significantly associated with CP after a burden test of aggregated rare nonsynonymous variants with a combined annotation dependent depletion score > 20 (p = .020). In the replication stage, we analyzed the entire coding sequence and exon/intron boundaries of the TPRV6 gene by Sanger sequencing in another 205 patients with CP and 105 controls. Integration of the findings from the two stages resulted in the identification of 25 TRPV6 variants: 1 rare nonsense variant, 20 rare missense variants, and 4 common missense variants. Loss‐of‐function variants, as determined by intracellular Ca2+ concentration in transfected HEK293T cells, were significantly overrepresented in patients as compared to controls (9/669 [1.35%] vs. 1/609 [0.16%]; odds ratio = 8.29; p = .022). This study provides evidence suggesting that TRPV6 is a novel susceptibility gene for CP.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TRPV6 variants confer susceptibility to chronic pancreatitis in the Chinese population

et al. 2020

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“…In this regard, Sofia and colleagues have recently analyzed the STIM1 in 80 patients with idiopathic chronic pancreatitis (ICP) and found three missense mutations in different patients (Sofia et al, 2016). Indeed, a recently genetic study of the Ca 2+ channel TRPV6 in pancreatitis cohorts described variants of the protein linked to Ca 2+ deregulation leading to the appearance of pancreatitis features (Masamune et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

p.E152K-STIM1 mutation deregulates Ca²⁺signaling contributing to chronic pancreatitis

Burgos

Philippe

Antigny

et al. 2020

Preprint

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statement: p.E152K-STIM1 variant found in pancreatitis patients leads to intracellular changes in calcium homeostasis through SERCA interaction, enabling intracellular trypsin activation and pancreatic acinar cell death. ABSTRACTSince deregulation of intracellular Ca 2+ can lead to intracellular trypsin activation and STIM1 (stromal interaction molecule-1) protein is the main regulator of Ca 2+ homeostasis in pancreatic acinar cells, we explored the Ca 2+ signaling in 37 STIM1 variants found in three pancreatitis patient cohorts. Extensive functional analysis of one particular variant, p.E152K, identified in three patients, provided a plausible link between dysregulated Ca 2+ signaling within pancreatic acinar cells and chronic pancreatitis susceptibility. Specifically, p.E152K, located within the STIM1 EF-hand and sterile α-motif domain, increased the release of Ca 2+ from the endoplasmic reticulum in patient-derived fibroblasts and transfected HEK293T cells. This event was mediated by altered STIM1-sarco/endoplasmic reticulum calcium transport ATPase (SERCA) interactions and enhanced SERCA pump activity leading to increased Store Operated Calcium Entry (SOCE).In the pancreatic AR42J cells expressing the p.E152K variant, Ca 2+ -signaling perturbations correlated with defects in trypsin activation and secretion, and increased cytotoxicity after cholecystokinin stimulation.

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Hereditary Pancreatitis and Complex Genetic Causes

Ohlsen¹,

Whitcomb

2023

The Pancreas

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Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis

Cited by 89 publications

References 58 publications

TRPV6 variants confer susceptibility to chronic pancreatitis in the Chinese population

TRPV6 variants confer susceptibility to chronic pancreatitis in the Chinese population

p.E152K-STIM1 mutation deregulates Ca²⁺signaling contributing to chronic pancreatitis

Hereditary Pancreatitis and Complex Genetic Causes

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Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis

Cited by 89 publications

References 58 publications

TRPV6 variants confer susceptibility to chronic pancreatitis in the Chinese population

TRPV6 variants confer susceptibility to chronic pancreatitis in the Chinese population

p.E152K-STIM1 mutation deregulates Ca2+signaling contributing to chronic pancreatitis

Hereditary Pancreatitis and Complex Genetic Causes

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Product

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p.E152K-STIM1 mutation deregulates Ca²⁺signaling contributing to chronic pancreatitis