A Thai family with hereditary pancreatitis and increased cancer risk due to a mutation inPRSS1gene

Abstract

AIM:To investigate mutation of serine protease 1-cationic trypsinogen (CT, PRSS1) gene in members of a Thai family with hereditary pancreatitis and pancreatic cancer. METHODS: Polymerase chain reaction and directsequencing were performed to analyze the PRSS1 gene in two members of the family affected by pancreatitis. Allele specific amplification (ASA) method was then developed to detect the mutation of the PRSS1 gene in all available members of the family and normal control subjects. RESULTS:A cytosine (C) to thymine (T) mutation at position 2441 (g.2441C>T) of the PRSS1 gene, which results in a substitution of arginine by cysteine at position 116 (R116C) of CT, was identified by direct sequencing in both clinically affected members of the family but was not found in the unaffected member. This mutation, which might be arising from deamination of methylated cytosine in CpG dinucleotide of codon 116 (CGT>TGT), was also detected by the ASA method in the two affected members and a proband's brother but was not observed in unaffected members and 54 normal control subjects. CONCLUSION:Autosomal dominant pancreatitis with increased cancer risk in the studied Thai family is most likely due to missense (R116C) mutation in the PRSS1 gene.

Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: A novel disease mechanism

“…This relatively rare mutation has been previously identified among patients of widely varying ethnicities such as Thais, Turks and Europeans (Le Maréchal et al, 2001; Tautermann et al, 2001; Teich et al, 2002; Pho-Iam et al, 2005) and here we confirm its association with autosomal dominant hereditary pancreatitis in a German kindred. Moreover, we demonstrate that mutation induced misfolding of cationic trypsinogen results in intracellular retention and decreased secretion.…”

“…Teich et al (2002) identified the p.R116C mutation in a pediatric patient with recurrent acute pancreatitis and in her unaffected mother. More recently, Pho-Iam et al (2005) described a Thai family with hereditary pancreatitis in which the p.R116C mutation was present in three affected (mother, son, mother’s sister) and one unaffected (mother’s brother) members.…”

Hereditary Pancreatitis in the United States: Survival and Rates of Pancreatic Cancer

“…Internationally, the majority of PRSS1 kindreds have been identified in the USA (13, 29, 30) and Europe (4, 31, 32), though few have also been reported from Japan (33), South America (34, 35), and Thailand (36). To date, HP has not been reported in patients of African ancestry.…”

Current status of molecular markers for early detection of sporadic pancreatic cancer

“…There is a proven association between carcinoma of the pancreas and both the sporadic (chiefly tropical calcifying pancreatitis [68]) and hereditary forms of CP (chiefly due to mutations in the PRSS1 [69] and cationic trypsinogen gene [70]), the standardized incidence ratio for development of PC in CP cases being 14–18, which is further increased by cigarette smoking [70]. Results from a prospective case-control study [71] seem to suggest that CP may be closely related to PC, although the answer to the question of a cause-and-effect relationship is not clear (the link between CP and PC was discussed in a recent article [72]).…”