As part of a long-term cohort study, members of a large extended family undergo periodic analysis of multiple serum markers. Many male participants are found to have abnormal laboratory results despite no obvious signs of disease. Further analysis shows that these men have an X-linked mutation affecting the phosphoribosyl pyrophosphate (PRPP) synthetase gene, resulting in greatly increased substrate conversion.Which of the following organs is most likely to develop pathology secondary to this mutation?

Question

As part of a long-term cohort study, members of a large extended family undergo periodic analysis of multiple serum markers.  Many male participants are found to have abnormal laboratory results despite no obvious signs of disease.  Further analysis shows that these men have an X-linked mutation affecting the phosphoribosyl pyrophosphate (PRPP) synthetase gene, resulting in greatly increased substrate conversion.Which of the following organs is most likely to develop pathology secondary to this mutation?

Quizplus · Accepted Answer

11ec160b_36f8_a966_9249_1953642dbc3b_MD0001_00 Gout is a disease caused by tissue deposition of monosodium urate crystals. Elevated uric acid levels are a known risk factor for gout and increased purine metabolism is one possible cause of hyperuricemia. Phosphoribosyl pyrophosphate (PRPP) synthetase is the enzyme responsible for the production of the activated ribose necessary for de novo synthesis of purine and pyrimidine nucleotides. The mutation described in the question stem will cause increased production of purines due to feed-forward activation of the purine synthesis pathway. As a result, more purine molecules will undergo degradation, resulting in hyperuricemia and an increased risk of gout. (Choice A) The aorta can develop aneurysms in patients with Marfan syndrome, which results from defects in fibrillin-1. (Choices B and D) The heart and liver can be affected by glycogen storage diseases resulting from a variety of enzyme deficiencies such as glucose-6-phosphatase deficiency (von Gierke disease) and acid maltase deficiency (Pompe disease). (Choice E) The pancreas is affected in patients with cystic fibrosis, which results from a mutation in the cystic fibrosis transmembrane conductance regulator gene. Common sequelae include pancreatitis, pancreatic insufficiency, and destruction of islet cells. Educational objective: Gout occurs with increased frequency in patients with activating mutations involving phosphoribosyl pyrophosphate synthetase due to increased production and degradation of purines. __________ References: Inherited superactivity of phosphoribosylpyrophosphate synthetase: association of uric acid overproduction and sensorineural deafness. (http://www.ncbi.nlm.nih.gov/pubmed/2843048)

As Part of a Long-Term Cohort Study, Members of a Large