Chronic Pancreatitis Associated with the p.G208A Variant of PRSS1 Gene in a European Patient

Eszter Hegyi; Iveta Cierna; Ludmila Vavrova; Denisa Ilencikova; Michal Konecny; Laszlo Kovacs

doi:10.6092/1590-8577/1896

Eszter Hegyi Second Department of Pediatrics, Comenius University Medical School, University Children’s Hospital. Bratislava, Slovakia
Iveta Cierna Second Department of Pediatrics, Comenius University Medical School, University Children’s Hospital. Bratislava, Slovakia
Ludmila Vavrova Department of Clinical Genetics, St. Elizabeth Cancer Institute. Bratislava, Slovakia
Denisa Ilencikova Second Department of Pediatrics, Comenius University Medical School, University Children’s Hospital. Bratislava, Slovakia
Michal Konecny Department of Clinical Genetics, St. Elizabeth Cancer Institute. Bratislava, Slovakia
Laszlo Kovacs Second Department of Pediatrics, Comenius University Medical School, University Children’s Hospital. Bratislava, Slovakia

DOI: https://doi.org/10.6092/1590-8577/1896

Keywords: chymotrypsin C, Pancreatitis, Chronic, PRSS1 protein, human

Abstract

Context The major etiologic factor of chronic pancreatitis in adults is excessive alcohol consumption, whereas among children structural anomalies, systemic and metabolic disorders, and genetic factors are prevalent. Mutations in the cationic trypsinogen gene (PRSS1) cause hereditary pancreatitis, while mutations in serine protease inhibitor Kazal type 1 (SPINK1), cystic fibrosis transmembrane conductance regulator (CFTR) and chymotrypsin C (CTRC) genes have been shown to associate with chronic pancreatitis as independent risk factors. Case report We present a case of 13-year-old boy with idiopathic chronic pancreatitis. Given the unexplained attacks of pancreatitis since early childhood and despite the negative family history, molecular-genetic analysis of four pancreatitis susceptibility genes (PRSS1, SPINK1, CTRC and CFTR) was performed. The boy was found to carry the c.623G>C (p.G208A) mutation of the PRSS1 gene and the c.180C>T (p.G60G) mutation of the CTRC gene, both in heterozygous state. These mutations are considered as contributing risk factors for chronic pancreatitis. Conclusions In children with idiopathic chronic pancreatitis genetic causes should be considered, even in absence of positive family history. To the best of our knowledge, this is the first description of a European patient with chronic pancreatitis associated with the p.G208A mutation of PRSS1 gene. This mutation was previously reported only in Asian subjects and is thought to be a unique genetic cause of pancreatitis in Asia.

Image: Sequence chromatograms.

Downloads

Download data is not yet available.

References

Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996; 14(2):141–5. [PMID: 8841182].

Szmola R, Sahin-Tóth M. Uncertainties in the classification of human cationic trypsinogen (PRSS1) variants as hereditary pancreatitis-associated mutations. J Med Genet 2010; 47(5):348–50. [PMID: 20452997].

Witt H, Luck W, Hennies HC, Classen M, Kage A, Lass U, et al. Mutation in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 2000; 25(2):213-6. [PMID: 10835640].

Sharer N, Schwarz M, Malone G, Howarth A, Painter J, Super M, Braganza J. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med 1998; 339(10):645-52. [PMID: 9725921].

Masson E, Chen JM, Scotet V, Le Maréchal C, Férec C. Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum Genet 2008; 123(1):83-91. [PMID: 18172691].

Masamune A, Nakano E, Kume K, Takikawa T, Kakuta Y, Shimosegawa T. PRSS1 c.623G>C (p.G208A) variant is associated with pancreatitis in Japan. Gut Published Online First: [17 May 2013] doi:10.1136/gutjnl-2013-304925. [PMID: 23686146].

Schnúr A, Beer S, Witt H, Hegyi P, Sahin-Tóth M. Functional effects of 13 rare PRSS1 variants presumed to cause chronic pancreatitis. Gut Published Online First: [1 March 2013] doi:10.1136/gutjnl-2012-304331. [PMID: 23455445].

Szabó A, Sahin-Tóth M. Determinants of chymotrypsin C cleavage specificity in the calcium-binding loop of human cationic trypsinogen. FEBS J 2012; 279(23):4283-92. [PMID: 23035638].

Kereszturi E, Szmola R, Kukor Z, Simon P, Weiss FU, Lerch MM, Sahin-Tóth M. Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism. Hum Mutat. 2009; 30(4):575-82. [PMID: 19191323].

Lee YJ, Kim KM, Choi JH, Lee BH, Kim GH, Yoo HW. High incidence of PRSS1 and SPINK1 mutations in Korean children with acute recurrent and chronic pancreatitis. J Pediatr Gastroenterol Nutr 2011; 52(4):478-81. [PMID: 21415673].

Keiles S, Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas 2006; 33(3):221-7. [PMID: 17003641].

Derikx MH, Szmola R, te Morsche RH, Sunderasan S, Chacko A, Drenth JP. Tropical calcific pancreatitis and its association with CTRC and SPINK1 (p.N34S) variants. Eur J Gastroenterol Hepatol 2009; 21(8):889–94. [PMID: 19404200].