Mutational analysis of the pancreatic secretory trypsin inhibitor gene in familial and juvenile pancreatitis in Japan

Abstract

The same set of N34S mutations (N34S + IVS1-37T>C + IVS3-69insTTTT) that exists in other countries was found in the PSTI gene in Japanese familial and juvenile pancreatitis patients. Another unique mutation (R67C) was also observed in two patients; 272C>T was suggested to be a normal polymorphism.

Mutations in the serine protease inhibitor kazal type 1 (SPINK1) gene in Japanese patients with pancreatitis

“…As previously reported [7,9,12] , N34S mutation cosegregated with IVS1-37T 1 C. In addition, the -215G 1 A mutation was in a complete linkage with IVS3 + 2T 1 C (D´ = 1). The [N34S; IVS1-37T 1 C] mutation was found in 8 of 80 patients with CP and in 1 patient with SLE-related AP.…”

“…SPINK1 is thought to be the fi rst line of defense against prematurely activated trypsinogen [16] , and the loss of SPINK1 function results in the increased intrapancreatic trypsin activity [7,8] . Although it is still controversial, it has been suggested that mutations in the SPINK1 gene are associated with a predisposition to pancreatitis [7][8][9][10][11][12] . We here showed that two SPINK1 mutations (i.e.…”

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

“…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.…”

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

“…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]. Interestingly, N34S, the most commonly observed mutation, was shown to cosegregate with two intronic mutations: IVS1-37T>C and IVS3-69insTTTT [6,28,57,75]. This suggests that these intronic mutations, rather than N34S itself, are associated with the predisposition to pancreatitis.…”

“…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].…”