Genetic mutations in exons 3 and 4 of the pancreatic secretory trypsin inhibitor in patients with pancreatitis

Kuwata, Kinuko; Hirota, Masahiko; Sugita, Haruo; Kai, Makoto; Hayashi, Naoki; Nakamura, Masaaki; Matsuura, Toshinobu; Adachi, Naoto; Nishimori, Isao; Ogawa, Michio

doi:10.1007/s005350170045

Cited by 46 publications

(23 citation statements)

References 19 publications

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“…25,26 By contrast, all four remaining missense mutations (ie p.D50E, 26 p.Y54H, 27 p.R65Q, 28 and p.R67C 29,30 ) were found in isolated patients or families. Of the six variations, only p.N34S and p.R67C were subjected to functional characterization, whereas the former one was shown to be fully active, 20 the latter was suggested to significantly affect PSTI's conformation.…”

Section: Resultsmentioning

confidence: 91%

Functional analysis of pancreatitis-associated missense mutations in the pancreatic secretory trypsin inhibitor (SPINK1) gene

et al. 2007

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Section: Resultsmentioning

confidence: 91%

Functional analysis of pancreatitis-associated missense mutations in the pancreatic secretory trypsin inhibitor (SPINK1) gene

et al. 2007

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“…Thus, loss of SPINK1 activity may result in activation of trypsin, eventually leading to pancreatitis. Actually, the association of several mutations in the SPINK1 gene with familial and juvenile pancreatitis are reported, 18,19 although the clinical significance of these mutations remains controversial. We previously generated the Spink3 (a mouse homologous gene)-deficient mice.…”

Section: Autophagy and Human Hereditary Pancreatitismentioning

confidence: 99%

Autophagy and acute pancreatitis: A novel autophagy theory for trypsinogen activation

Ohmuraya¹,

Yamamura

2008

Autophagy

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“…There have been many reports on the association between mutations in the SPINK1 genes and patients with pancreatitis [7,24,28,30,55,75]. Although these mutations may affect the conformation of nearby active sites, there has been no evidence that this mutation affects the binding affinity and inhibitory activity of SPINK1 to trypsin [27,29].…”

Section: Spink1/spink3 As a Trypsin Inhibitormentioning

confidence: 99%

The Roles of Serine Protease Inhibitor Kazal Type 1 (SPINK1) in Pancreatic Diseases

Ohmuraya

Yamamura

2011

Exp. Anim.

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Serine protease inhibitor Kazal type 1 (SPINK1) was originally identified as a trypsin inhibitor by Kazal et al. in 1948. SPINK1 is strongly elevated in pancreatitis and the elevation correlates with the severity of disease. In 2000, mutations in the SPINK1 gene were shown to be associated with chronic pancreatitis. Since then, there have been many reports on association between mutations in the SPINK1 genes and patients with pancreatitis. In 1982, SPINK1 was shown to be identical to tumor associated trypsin inhibitor (TATI). In addition, sequence similarities were detected between human epidermal growth factor (EGF) and human SPINK1 in 1983. Actually, SPINK1 was shown to stimulate growth of several cell lines including cancer cells in 1985. Recent clinical studies showed that high levels of SPINK1 protein in serum or urine were associated with adverse outcome in various cancer types. However, there was little evidence that showed in vivo function of SPINK1. Surprisingly, mice deficient in Spink3 (a mouse homologue gene of human SPINK1) showed excessive autophagy, but not pancreatitis in the exocrine pancreas, leading to autophagic cell death. We also demonstrated that SPINK1 acts as a growth factor through EGFR signaling. These data indicate that the role of the SPINK1 is not just as a trypsin inhibitor, but also as a growth factor as well as a negative regulator of autophagy. In this review, we summarize the roles of SPINK1/Spink3 in pancreatic diseases based on the data obtained from analyses using mouse models.

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Genetic mutations in exons 3 and 4 of the pancreatic secretory trypsin inhibitor in patients with pancreatitis

Abstract: The N34S mutation may cause a predisposition to pancreatitis, with incomplete penetrance. However, with the limited information available, it is not known whether the R67C mutation promotes pancreatitis.

Cited by 46 publications

References 19 publications

Functional analysis of pancreatitis-associated missense mutations in the pancreatic secretory trypsin inhibitor (SPINK1) gene

Functional analysis of pancreatitis-associated missense mutations in the pancreatic secretory trypsin inhibitor (SPINK1) gene

Autophagy and acute pancreatitis: A novel autophagy theory for trypsinogen activation

The Roles of Serine Protease Inhibitor Kazal Type 1 (SPINK1) in Pancreatic Diseases

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