Phenotypic Variability of the Homozygous IVS3+2T&gt;C Mutation in the Serine Protease Inhibitor Kazal Type 1 (SPINK1) Gene in Patients with Chronic Pancreatitis

Ota, Yuji; Masamune, Atsushi; Inui, Kentaro; Kaneda, Kiyoshi; Shimosegawa, Tooru; Kikuyama, Masataka

doi:10.1620/tjem.221.197

Cited by 15 publications

(11 citation statements)

References 23 publications

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“…The IVS3+2T>C (c.194+2T>C) mutation is a loss of functional splicing mutation; it affects the consensus splicing donor site in intron 3 and may cause skipping of the entire exon 3, where the trypsin-binding site is located [26]. The phenotypic variability of the homozygous IVS3+2T>C mutation in SPINK1 gene in CP patients has been established by this group.…”

Section: Discussionmentioning

confidence: 99%

Frequency of CFTR, SPINK1, and Cathepsin B Gene Mutation in North Indian Population: Connections between Genetics and Clinical Data

Singh

Choudhuri

Agarwal

2014

The Scientific World Journal

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Objectives. Genetic mutations and polymorphisms have been correlated with chronic pancreatitis (CP). This study aims to investigate the association of genetic variants of cystic fibrosis transmembrane conductance regulator (CFTR) and serine protease inhibitor Kazal type 1 (SPINK-1) genes and Cathepsin B gene polymorphisms with CP and to associate genetic backgrounds with clinical phenotypes. Methods. 150 CP patients and 150 normal controls were enrolled consecutively. We analyzed SPINK-1 N34S and IVS3+2T>C gene mutations by PCR-restriction-fragment length polymorphism (RFLP). The identification of DF508, G551D, G542X, R117H, and W1282X mutations was carried out by ARMS-PCR. S549N mutation, IVS8 polyTn polymorphism, and Cathepsin B Lec26Val were analysed by PCR-RFLP, nested PCR, and PCR-RFLP plus sequencing, respectively. Results. We found a significant association of SPINK1 (N34S) gene polymorphism. IVS1−37T>C polymorphism shows linkage with 101A>G. 300 chromosomes belonging to the CFTR subgroup exhibited minor allele frequency of 0.04, 0.03, 0.03, 0.013, 0.006, and 0.02 for DF508, G452X, G551D, S549N, R117H, and IVS8 T5, respectively. Except for R117H and IVS8 T5 polymorphisms, all other mutations showed significant variation. Conclusion. Analysis of potential susceptibility variants is needed to support nature of the genes and environment in pancreatitis. This data may help establish genetic screening and prenatal setup for Indian population.

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Section: Discussionmentioning

confidence: 99%

Frequency of CFTR, SPINK1, and Cathepsin B Gene Mutation in North Indian Population: Connections between Genetics and Clinical Data

Singh

Choudhuri

Agarwal

2014

The Scientific World Journal

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“…In addition to CP, we and others have reported that the p.N34S mutation is strongly associated with recurrent acute pancreatitis, but does not increase the risk of the first or sentinel acute pancreatitis event (Aoun et al 2010;Masamune et al 2011). The second most common mutation c.194+2T>C (IVS3+2T>C) has been reported in patients with idiopathic, familial, and alcoholic CP (Witt et al 2000;Pfützer et al 2000;Bhatia et al 2002;Kume et al 2005;Oh et al 2009;Ota et al 2010;Sun et al 2013). Table 3 shows the frequency of the SPINK1 mutations in Japanese patients with CP.…”

Section: Spink1 Mutationsmentioning

confidence: 99%

Genetics of Pancreatitis: The 2014 Update

Masamune

2014

Tohoku J. Exp. Med.

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Chronic pancreatitis is a progressive inflammatory disease in which pancreatic secretory parenchyma is destroyed and replaced by fibrous tissue, eventually leading to malnutrition and diabetes. Alcohol is the leading cause in Western countries, but genetic factors are also implicated. Since the identification of mutations in the cationic trypsinogen (PRSS1) gene as a cause of hereditary pancreatitis in 1996, we have seen great progress in our understanding of the genetics of pancreatitis. It has been established that mutations in the genes related to the activation and inactivation of trypsin(ogen) such as PRSS1, serine protease inhibitor Kazal type 1 (SPINK1) and chymotrypsin C (CTRC) genes are associated with pancreatitis. In 2013, carboxypeptidase A1 (CPA1) was identified as a novel pancreatitis susceptibility gene. Endoplasmic reticulum stress in pancreatic acinar cells resulting from the mis-folding of mutated pancreatic enzymes has been shown to act as a novel mechanism underlying the susceptibility to pancreatitis. In Japan, the nationwide survey revealed 171 patients (96 males and 75 females) with hereditary pancreatitis in 59 families based on the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer criteria. Because about 30% of families with hereditary pancreatitis do not carry mutations in any of the known pancreatitis susceptibility genes, other yet unidentified genes might be involved. Next generation sequencers can perform billions of sequencing reactions with a read length of 150-250 nucleotides. Comprehensive analysis using next generation sequencers will be a promising strategy to identify novel pancreatitis-associated genes and further clarify the pathogenesis of pancreatitis.

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“…Thus, IVS3+2T-C mutation results in functional loss of SPINK1 and disturbs the protease/antiprotease balance within the pancreas leading to the development of the pancreatitis. [8]…”

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confidence: 99%