A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis

Witt, Heiko; Luck, W. A. P.; Becker, Michael

doi:10.1016/s0016-5085(99)70543-3

Cited by 236 publications

(158 citation statements)

References 12 publications

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“…7,[16][17][18][19][20][21][22][23][24][25][26] Whilst no one doubts its disease-causing role in HP, some 27 do argue that 'self-destruct' mechanism proposed for R122H 7 has not yet been proven. In our opinion, however, this may be due to inadequate evaluation rather than a lack of good supporting data and, accordingly, we wish to highlight several issues.…”

Section: R122h (R117h)mentioning

confidence: 99%

“…Transgenic models are attractive but certainly will be confounded by the existence of multiple functional trypsinogen genes and different protective mechanisms against trypsinogen activation in mice. The R122H mutation, in most cases, 7,[16][17][18][19][20][21][22][23][24][25][26] resulted from a single G > A (CGC > CAC) transition, which most probably occurred as a spontaneous deamination of 5-methylcytosine to give thymine in the CpG dinucleotides on the opposite strand. Interestingly, we identified a GC > AT (CGC > CAT) 2 bp nucleotide substitution, which also resulted in a R122H mutation but clearly arose via a different genetic mechanism -gene conversion.…”

Section: R122h (R117h)mentioning

confidence: 99%

“…Witt et al 26 first described a strong association between a novel DNA variant named A16V with chronic pancreatitis. In their study, four out of 44 children and adolescents with chronic pancreatitis were found to carry the A16V variant.…”

Section: A16vmentioning

confidence: 99%

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Molecular basis of hereditary pancreatitis

Chen¹,

Férec²

2000

Eur J Hum Genet

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Hereditary pancreatitis (HP) is an autosomal dominant disease. Two heterozygous missense mutations, R122H (R117H) and N29I (N21I), in the cationic trypsinogen gene have been clearly associated with HP. The 'self-destruct' model proposed for the R122H mutation is discussed in connection with the existing theory of pancreatitis, and the basic biochemistry and physiology of trypsinogen, with particular reference to R122 as the primary autolysis site of the cationic trypsinogen. Two different genetic mechanisms are identified which cause the R122H mutation, and gene conversion is the likely cause of the N29I mutation. A unifying model, which highlights an indirect impairment on the R122 autolysis site is hypothesised for the N29I mutation. Possible predisposition to pancreatitis by additional DNA variants in the gene, such as the A16V signal peptide cleavage site mutation and the K23R activation peptide cleavage site mutation is suspected, but not proven. Evidence of genetic heterogeneity of HP is reviewed and cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations detected in HP families are re-evaluated. Finally, large scale association studies are expected to clarify the additional variants' role in pancreatitis and to identify new HP genes.

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Section: R122h (R117h)mentioning

confidence: 99%

Section: R122h (R117h)mentioning

confidence: 99%

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Molecular basis of hereditary pancreatitis

Chen¹,

Férec²

2000

Eur J Hum Genet

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“…13,14 PRSS1 gene mutations R122H and A16V were analysed by enzymatic restriction with the appropriate endonuclease as described. 4,6 PRSS1 gene exons 1 -4 were analysed by DGGE as described, 7 and exon 5 was analysed by direct DNA sequencing with Big Dye terminator kit (Perkin Elmer).…”

Section: Methodsmentioning

confidence: 99%

“…2,4 Also, mutation A16V in the PRSS1 gene, which interferes with the signal peptide cleavage, has been identified in chronic pancreatitis and in HP families with low penetrance. 6 Other PRSS1 gene mutations have been reported to be associated with HP. 7 -9 Ockenga et al, 10 have recently shown that mutations of the CFTR gene but not PRSS1 are associated with recurrent or chronic idiopathic pancreatitis.…”

Section: Introductionmentioning

confidence: 99%

Cationic trypsinogen and pancreatic secretory trypsin inhibitor gene mutations in neonatal hypertrypsinaemia

et al. 2003

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Neonatal hypertrypsinaemia with normal sweat chloride detected during CF screening may be related to trypsin activation. We have looked for mutations of the cationic trypsinogen (PRSS1) and pancreatic secretory trypsin inhibitor (PSTI) genes in 50 hypertrypsinaemic neonates with known CFTR genotypes and negative sweat test. No mutations were found in either gene. Two silent polymorphisms were detected in the PRSS1 gene. A polymorphism in the promoter region and an intronic polymorphism of the PSTI gene were found. No difference was observed in the frequency of PRSS1 or PSTI polymorphisms in neonates carrying or not carrying CF mutations. These results do not provide an indication for an increased frequency of mutations in the PRSS1 and PSTI genes in this group of neonates with transient hypertrypsinaemia.

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Negative-Pressure Ventilation

Keim¹,

Teich²

2003

JAMA

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A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis

Cited by 236 publications

References 12 publications

Molecular basis of hereditary pancreatitis

Molecular basis of hereditary pancreatitis

Cationic trypsinogen and pancreatic secretory trypsin inhibitor gene mutations in neonatal hypertrypsinaemia

Negative-Pressure Ventilation

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