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Eur J Hum Genet. 2007 Sep;15(9):936-42. Epub 2007 Jun 13.

Functional analysis of pancreatitis-associated missense mutations in the pancreatic secretory trypsin inhibitor (SPINK1) gene.

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INSERM, U613, Etablissement Français du Sang - Bretagne, Brest 29220, France.


Variations in the SPINK1 gene (encoding pancreatic secretory trypsin inhibitor (PSTI)) are associated with chronic pancreatitis. We have recently determined the functional consequences of three missense mutations that occurred within the signal peptide sequence of PSTI by Western blotting analysis of wild-type and mutant PSTI expressed in Chinese hamster ovary cells. Here, this approach was extended to analyze seven missense mutations (p.N34S, p.G48E, p.D50E, p.Y54H, p.P55S, p.R65Q and p.R67C) occurring within the mature peptide of PSTI. This analysis enabled us to classify these missense mutations into three categories. The first category comprises the p.N34S and p.P55S polymorphisms, both of which occur in evolutionarily non-conserved residues, involve amino-acid substitutions with similar physicochemical properties, and do not cause any significant reduction in terms of PSTI mature peptide expression. The second category contains only the p.R65Q missense mutation, which occurs in a well-conserved residue, involves the substitution of a positively charged amino acid by a non-charged one, and causes a approximately 60% reduction of protein expression. The third category comprises p.G48E, p.D50E, p.Y54H, and p.R67C, all of which occur in strictly conserved residues, involve charged amino acids, and cause complete or nearly complete loss of PSTI expression. Having excluded the possibility that the reduced protein expression may have resulted from reduced transcription or unstable mRNA, we surmise that these missense mutations probably cause intracellular retention of their respective mutant proteins. This is suggestive of a potential unifying pathological mechanism underlying both the signal peptide and mature peptide mutations.

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