Intragenic duplication: a novel mutational mechanism in XXXX .

@entity1 @entity1522 @entity788 @entity3208 @entity2036 @entity535 @entity73012 @entity467 @entity4306 @entity2975 @entity20618 @entity73011
OBJECTIVES: In a @entity4306 family from Denmark, we identified a novel intragenic duplication of 9 @entity2036 in exon-2 of the @entity1 @entity20618 ( @entity20618 ) gene ( @entity73011 ) which at the @entity535 level resulted in the insertion of 3 @entity1522 within the activation peptide of @entity20618 ( @entity73012 ). The aim of the present study was to characterize the effect of this unique genetic alteration on the function of @entity1 @entity20618 . METHODS: Wild-type and mutant cationic trypsinogens were produced recombinantly and purified to homogeneity. Trypsinogen activation was followed by enzymatic assays and @entity3208 - @entity2975 gel electrophoresis. Trypsinogen secretion was measured from transfected HEK 293T cells. RESULTS: Recombinant @entity20618 carrying the @entity73012 mutation exhibited greater than 10-fold increased autoactivation. Activation by @entity1 @entity467 also was accelerated by 10-fold. Secretion of the @entity73012 mutant from transfected cells was diminished, consistent with intracellular autoactivation. CONCLUSIONS: This is the first report of an intragenic duplication within the @entity20618 gene causing @entity4306 . The accelerated activation of @entity73012 by @entity467 is a unique biochemical property not found in any other @entity788 -associated trypsinogen mutant. In contrast, the robust autoactivation of the novel mutant confirms the notion that increased autoactivation is a disease-relevant mechanism in @entity4306 .
