Biochemists identify a mutation affecting the trypsinogen molecule that disrupts a critical site on the protein involved in inhibiting the active trypsin moiety. This mutation prevents trypsin from being permanently inactivated by enzymatic cleavage. Patients with this mutation would most likely suffer from which of the following conditions?

Question

Biochemists identify a mutation affecting the trypsinogen molecule that disrupts a critical site on the protein involved in inhibiting the active trypsin moiety.  This mutation prevents trypsin from being permanently inactivated by enzymatic cleavage.  Patients with this mutation would most likely suffer from which of the following conditions?

Quizplus · Accepted Answer

Pancreatic enzymes (except amylase and lipase) are synthesized and secreted in inactive form to protect the pancreas from autodigestion. These proenzymes (zymogens) are then activated by trypsin in the duodenal lumen after trypsinogen is converted into its active form, trypsin, by the action of duodenal enterokinase. Trypsin can also activate other trypsinogen molecules; therefore, even small amounts of it can result in an activation cascade. Because of trypsin's central role in the activation of pancreatic digestive proenzymes, multiple protective mechanisms exist to limit the amount of trypsinogen that becomes prematurely activated: Hereditary pancreatitis is a rare disorder that results from mutations involving the trypsinogen or SPINK1 gene. The most common mutation leads to the production of abnormal trypsin that is not susceptible to inactivating cleavage by trypsin. Because a small amount of trypsinogen normally activates prematurely within the pancreatic acini and ducts, these protective mechanisms are critical for preventing recurrent attacks of acute pancreatitis. (Choices A and E) Peptic ulcer disease and gastric adenocarcinoma are strongly associated with Helicobacter pylori infection. (Choice B) Patients with mutations affecting the serum protease inhibitor, alpha-1-antitrypsin, can have emphysema and liver cirrhosis. However, there is no association between cirrhosis and trypsinogen gene mutations. (Choice C) Megaloblastic anemia is due to deficiencies of vitamin B₁₂ and folate. It is also associated with a number of drugs (eg, methotrexate, phenytoin) and certain inborn metabolic errors. Educational objective: Multiple inhibitory mechanisms exist to prevent premature activation of trypsinogen before it reaches the duodenal lumen, including cleavage inactivation of trypsin by trypsin itself and production of trypsin inhibitors (eg, SPINK1). Gene mutations that render trypsin insensitive to cleavage inactivation cause hereditary pancreatitis.

Biochemists Identify a Mutation Affecting the Trypsinogen Molecule That Disrupts