Uncertainties in the classification of human cationic trypsinogen (PRSS1) variants as hereditary pancreatitis-associated mutations.
BACKGROUND
Autosomal dominant hereditary pancreatitis has been conclusively linked with cationic trypsinogen (PRSS1) mutations p.R122H and p.N29I, which can be found in approximately 90% of mutation-positive cases. To date, 35 additional rare or private PRSS1 variants have been identified in subjects with hereditary or sporadic, idiopathic chronic pancreatitis. Despite the lack of sufficient genetic and functional evidence, many of these rare variants have been labelled as pancreatitis associated. This problematic trend is notably illustrated by two recent studies that classified the p.A121T PRSS1 variant as pancreatitis associated, in large part owing to its intimate proximity to arginine-122, the residue affected by the disease causing p.R122H mutation.


RESULTS
Here we demonstrate that the p.A121T variant is functionally innocuous and shows no verifiable association with hereditary pancreatitis, on the basis of the available inconclusive data.


CONCLUSIONS
This case cautions that assignment of clinical relevance to rare PRSS1 variants should not be based on a perceived analogy with genuine disease causing PRSS1 mutations, and further studies are required to prove or rule out possible low penetrance causality of rare PRSS1 variants.
Szmola
Richárd
R
Sahin-Tóth
Miklós
M
D019943:Amino Acid Substitution; D005260:Female; D005799:Genes, Dominant; D014644:Genetic Variation; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009154:Mutation; D050500:Pancreatitis, Chronic / Q000201:enzymology* / Q000235:genetics*; D010375:Pedigree; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014357:Trypsin / Q000235:genetics* / Q000378:metabolism
D011994:Recombinant Proteins; C489303:PRSS1 protein, human; D014357:Trypsin
J Biol Chem. 2002 Feb 15;277(7):5404-10
11719509
Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11227-32
17592142
Clin Gastroenterol Hepatol. 2004 Mar;2(3):252-61
15017610
Pancreatology. 2001;1(5):439-43
12120221
Mol Biol Evol. 2003 Nov;20(11):1767-77
12832630
JOP. 2003 Jul;4(4):146-54
12853682
Hum Mutat. 2006 Aug;27(8):721-30
16791840
Hum Mutat. 2009 Apr;30(4):575-82
19191323
Nat Genet. 1996 Oct;14(2):141-5
8841182
Hum Mutat. 2005 Apr;25(4):343-7
15776435
J Med Genet. 2000 Nov;37(11):E36
11073545
Chin Med J (Engl). 2008 Jan 20;121(2):108-11
18272034
J Biol Chem. 2006 Apr 28;281(17):11879-86
16505482
Hum Mutat. 2004 Jan;23(1):22-31
14695529
Gut. 2001 Feb;48(2):247-50
11156648
Endocrinol Metab Clin North Am. 2006 Jun;35(2):303-12, ix
16632094
J Biol Chem. 2000 Jul 28;275(30):22750-5
10801865
J Med Genet. 2008 Aug;45(8):507-12
18511571
Gut. 2009 Jan;58(1):97-103
18755888
Hum Genet. 2008 Jun;123(5):521-9
18461367