Mutations of the cationic trypsinogen gene in patients with hereditary pancreatitis

Creighton, J. E.; Lyall, R; Wilson, David I.; Curtis, Ann; Charnley, Richard

doi:10.1046/j.1365-2168.2000.01326.x

Cited by 33 publications

(15 citation statements)

References 15 publications

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“…Positive results were confirmed by direct sequencing (MWG Biotech, Milton Keynes, UK). Screening for the N29I mutation was performed as previously described, using an amplification refractory mutation specific (ARMS) technique [15]. The A16V mutation was sought by PCR amplification followed by digestion with Ita I (Roche, Lewes, UK), an isoschizomer to the restriction enzyme Fnu4 HI, as previously described [13].…”

Section: Methodsmentioning

confidence: 99%

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Mutations of the Cationic Trypsinogen Gene in Hereditary and Non-Hereditary Pancreatitis

et al. 2001

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Background/Aims: Mutations in the cationic trypsinogen gene have been detected in patients with hereditary pancreatitis (HP). This study investigates the prevalence of the R122H, N29I, A16V and –28delTCC mutations in the common, non-hereditary forms of chronic pancreatitis and in a HP family. Methods: DNA was prepared from blood samples of 53 patients with chronic pancreatitis (36 alcoholic, 14 idiopathic and 3 hereditary), 20 alcoholic controls and 20 healthy, ethnically matched controls. The R122H and A16V mutations were identified by the polymerase chain reaction (PCR) and restriction enzyme digestion. A nested-PCR was used to identify the N29I mutation. The –28delTCC deletion and the C133807T polymorphism were sought by direct sequencing. Results: The R122H mutation was detected in 1 patient with alcoholic chronic pancreatitis and all 3 affected members of a HP family. The N29I, A16V and –28delTCC mutations were not detected in any of the study subjects. At the C133807T polymorphism, the C allele and C/C genotype were significantly increased in alcoholic chronic pancreatitis (p = 0.001 and p = 0.0004, respectively) while the T allele and CT genotype were significantly reduced (p = 0.001 and p = 0.004, respectively) compared to healthy controls. Conclusions: Mutations of the cationic trypsinogen gene are rarely found in chronic pancreatitis patients of typical aetiology. Screening for these mutations should be considered in those with a family history consistent with hereditary pancreatitis but may also be appropriate in a well-defined subgroup of patients with non-hereditary chronic pancreatitis, i.e. those who have developed the disease before the age of 30.

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Section: Methodsmentioning

confidence: 99%

“…A single A–T transversion mutation (N29I) in exon 2 results in an asparagine to isoleucine substitution. These mutations have since been identified in HP families from France [11], Germany [12, 13], the UK [14, 15], the USA [16, 17]and Japan [18]. …”

Section: Introductionmentioning

confidence: 99%

Mutations of the Cationic Trypsinogen Gene in Hereditary and Non-Hereditary Pancreatitis

et al. 2001

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“…Since the first report of hereditary pancreatitis in 1952 [6], more than 150 kindreds have been identified worldwide, the majority of which are of Caucasian ancestry with a few families reported from Japan [7, 8, 9, 10, 11, 12, 13]. …”

Section: Introductionmentioning

confidence: 99%

R116C Mutation of Cationic Trypsinogen in a Turkish Family with Recurrent Pancreatitis Illustrates Genetic Microheterogeneity of Hereditary Pancreatitis

et al. 2001

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Hereditary pancreatitis is due to heterozygosity for gain-of-function mutations in the cationic trypsinogen gene which result in increased levels of active trypsin within pancreatic acinar cells and autodigestion of the pancreas. The number of disease-causing defects is generally considered to be low. To gain further insight into the molecular basis of this disorder, DNA sequence analysis of all five exons was performed in 109 unrelated patients with idiopathic chronic pancreatitis in order to determine the variability of the underlying mutations. Two German females and one German male were carriers of the most common N29I and R122H mutations (trypsinogen numbering system). In a Turkish proband, an arginine (CGT) to cysteine (TGT) substitution at amino acid position 116 was identified. Family screening demonstrated that the patient had inherited the mutation from his asymptomatic father and that he had transmitted it to both of his children, his daughter being symptomatic since the age of 3 years. In addition, a German male was found to be a heterozygote for a D100H (GAC→CAC) amino acid replacement. Our data provide evidence for genetic heterogeneity of hereditary pancreatitis. The growing number of cationic trypsinogen mutations is expected to change current mutation screening practices for this disease.

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“…In Newcastle upon Tyne, UK, the pancreatic clinic now has individuals belonging to thirteen families with hereditary pancreatitis. Data on nine of these families has been previously published [10] . The R122H (R117H) mutation was identified in three families and the N29I (N21I) mutation was demonstrated in a further five families.…”

Section: Clinical Presentation In Hereditary Pancreatitismentioning

confidence: 99%

“…A second mutation in the cationic trypsinogen gene was subsequently discovered, which was found to be a single A to thiamine (T) transversion mutation in exon 2 resulting in an asparagine (ACC) to isoleucine (ATC) substitution at amino acid 21 [3] . These two mutations (R117H and N21I) have now been identified in families with hereditary pancreatitis from many countries including France [4] , Germany [9] , United Kingdom [10] , Japan [11] and the USA [3,7] . A further mutation, which appears to be much less common, is the A16V mutation, which was originally identified in three patients with idiopathic pancreatitis and in one patient with HP [12] .…”

Section: The Genetics Of Hereditary Pancreatitismentioning

confidence: 99%

Hereditary pancreatitis

Charnley¹

2003

WJG

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Hereditary pancreatitis is an autosomal dominant condition, which results in recurrent attacks of acute pancreatitis, progressing to chronic pancreatitis often at a young age. The majority of patients with hereditary pancreatitis express one of two mutations (R122H or N29I) in the cationic trypsinogen gene (PRSS1 gene). It has been hypothesised that one of these mutations, the R122H mutation causes pancreatitis by altering a trypsin recognition site so preventing deactivation of trypsin within the pancreas and prolonging its action, resulting in autodigestion. Families with these two mutations have been identified in many countries and there are also other rarer mutations, which have also been linked to hereditary pancreatitis.Patients with hereditary pancreatitis present in the same way as those with sporadic pancreatitis but at an earlier age. It is common for patients to remain undiagnosed for many years, particularly if they present with non-specific symptoms. Hereditary pancreatitis should always be considered in patients who present with recurrent pancreatitis with a family history of pancreatic disease. If patients with the 2 common mutations are compared, those with the R122H mutation are more likely to present at a younger age and are more likely to require surgical intervention than those with N29I. Hereditary pancreatitis carries a 40 % lifetime risk of pancreatic cancer with those patients aged between 50 to 70 being most at risk in whom screening tests may become important.

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Mutations of the cationic trypsinogen gene in patients with hereditary pancreatitis

Abstract: Two mutations in the cationic trypsinogen gene cause hereditary pancreatitis in eight of nine families originating in this region. The R117H mutation is associated with a more severe form of the disease in terms of age at onset of symptoms and requirement for surgical intervention.

Cited by 33 publications

References 15 publications

Mutations of the Cationic Trypsinogen Gene in Hereditary and Non-Hereditary Pancreatitis

Mutations of the Cationic Trypsinogen Gene in Hereditary and Non-Hereditary Pancreatitis

R116C Mutation of Cationic Trypsinogen in a Turkish Family with Recurrent Pancreatitis Illustrates Genetic Microheterogeneity of Hereditary Pancreatitis

Hereditary pancreatitis

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