Diagnostic criteria for acute pancreatitis should be reconsidered in patients with diabetes mellitus (original) (raw)
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Gastroenterology, 2000
Mutations of the cationic trypsinogen have been described in hereditary pancreatitis. We report a new trypsinogen mutation in the activation peptide of the proenzyme in a family with chronic pancreatitis. Methods: The coding region of the cationic trypsinogen gene was sequenced after polymerase chain reaction amplification. The following peptides homologous to the N-terminal end of cationic trypsinogen were synthesized (one-letter code, mutated amino acid underlined): wild-type peptide, APFDDDDKIVGG; pD22G, APFDDDGKIVGG; pK23R, APFDDDDRIVGG. The sequences of pD22G and pK23R correspond to the recently identified mutation K23R and to the mutation described here (D22G). To mimic trypsinogen activation, these peptides were digested with trypsin for 30 minutes at pH 5.0 -8.0, and the fragments were analyzed by high-performance liquid chromatography. Results: In a family with clinical evidence of hereditary chronic pancreatitis, a missense mutation of codon 22 (GAC3 GGC) of the cationic trypsinogen was found. This mutation results in a substitution of aspartic acid by glycine; therefore, the mutation was called D22G. Chromatographic analysis of tryptic digests of the peptides pD22G and pK23R showed hydrolysis rates of 22% and 75%, respectively, whereas the wild-type peptide was hydrolyzed at only 6%. The cleavage rates were reduced at lower pH, and no hydrolysis occurred without trypsin. Conclusions: The activation peptides of the trypsinogen variants D22G and K23R could be released at a higher rate than in wild-type trypsinogen, resulting in increased amounts of trypsin in the pancreas, which could initiate pancreatitis.
Human Mutation, 2004
Communicated by Richard G.H. Cotton Mutations in the serine protease inhibitor Kazal type 1 gene (SPINK1) encoding pancreatic secretory trypsin inhibitor (PSTI) have recently been found to be associated with chronic pancreatitis. Nevertheless, knowledge of severe mutations is particularly scarce, both in terms of number and in the extent of clinical information. The aim of this study was to expand the known spectrum of such mutations. 46 unrelated families, each including at least two pancreatitis patients and carrying neither cationic trypsinogen (PRSS1) mutations nor the frequent SPINK1 N34S mutation, participated in this study. The four exons and their flanking sequences of the SPINK1 gene were screened by denaturing high performance liquid chromatography analysis (DHPLC); and mutations were identified by direct sequencing. A heterozygous microdeletion mutation (c.27delC), which occurs within a symmetric element, was identified in two families. In one family, c.27delC showed segregation with the disease across two generations, with a penetrance of up to 75%. But in the other family, however, the same mutation manifested as a low-penetrance susceptibility factor. In addition, a novel heterozygous splicing mutation, c.87+1G>A (G>A substitution at nucleotide +1 of intron 2) was found in one family with familial pancreatitis. Our results also helped to resolve the sharply differing views about PSTI's role in pancreatitis.
Trypsinogen copy number mutations in patients with idiopathic chronic pancreatitis
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 2008
Abbreviations used in this paper: CNM, copy number mutation; CNV, copy number variation; FCP, familial chronic pancreatitis; FISH, fluorescence in situ hybridization; ICP, idiopathic chronic pancreatitis; kb, kilobase; QFM-PCR, quantitative fluorescent multiplex polymerase chain reaction; TCP, tropical calcific pancreatitis.
Journal of Human Genetics, 2001
Chronic pancreatitis (CP) is a continuing or relapsing inflammatory disease of the pancreas. Several studies have demonstrated that mutations in the cationic trypsinogen (PRSS1) gene and the cystic fibrosis transmembrane conductance regulator (CFTR) gene are causative of the pathogenesis in a subset of hereditary and/or idiopathic CP cases. Recently, the N34S alteration of the pancreatic secretory trypsin inhibitor (PSTI) gene has been suggested to be closely associated with the pathogenesis of hereditary and/or idiopathic CP. Herein we analyzed genetic alterations of the PSTI gene in 32 unrelated Japanese CP patients who developed juvenile-onset CP or had a family history of CP; 5 patients were found to harbor alterations in this gene. In 3 of these 5 patients, heterozygous N34S alterations were found; this frequency is significantly lower than that in Caucasian patients reported previously. Moreover, a novel homozygous G-to-A transition in the promoter region of PSTI at 215 bp upstream from the translation initiation site (Ϫ215GϾA) was observed in 2 patients. We further surveyed the Ϫ215GϾA alteration in 117 normal individuals; none of these individuals harbored this alteration. Our results suggested that the Ϫ215GϾA alteration, as well as the N34S alteration, is a predisposing factor for CP.
The course of genetically determined chronic pancreatitis
JOP : Journal of the pancreas, 2003
The clinical course of chronic pancreatitis in patients with mutations of cationic trypsinogen and the trypsin inhibitor SPINK1 has not yet been characterized. Cationic trypsinogen (PRSS1) and the serine protease inhibitor, Kazal type 1 (SPINK1), were analyzed in patients with pancreatitis of unclear origin. Eighty subjects with trypsinogen mutations (21x N29I, 59x R122H) and 59 patients with the SPINK1 N34S variant (11 homozygous, 48 heterozygous) were included in the study. In patients with mutations of PRSS1 (N29I, R122H) and SPINK1 (N34S) the parameters such as calcification, dilatation of the main pancreatic duct, diabetes mellitus, hospital treatments, and surgery were recorded. Case control studies were performed to compare both mutational groups, and the follow-up time served as a matching criterion. The Kaplan-Meier analysis was used to estimate the time course of the symptoms. Ten years after the onset of the disease, the probability (+/-SE) of symptoms in patients with PR...