Mutated Gene Causes Hyperlipidemia

The mutation leads to a frameshift (L413fsX414) that results in loss of the active site and enzyme function.

Researchers from the University of California, San Francisco (USA) searched a genetic database of some 12,000 patients and identified a number of people who had mutations in the CYP7A1 gene. Mutations in the suspected gene samples were detected using a technique known as differential DNA melting, which pinpoints the mutated genes based on their abnormal mobility when the DNA is placed in an electrical field. CYP7A1 produces the enzyme cholesterol 7-alpha hydroxylase (CYP7A1), which is essential for the normal elimination of cholesterol. The enzyme initiates the primary conversion of cholesterol into bile acids in the liver.

As reported in the July 2002 issue of The Journal of Clinical Investigation, high levels of low-density lipoprotein (LDL) cholesterol were seen in three homozygous subjects. Analysis of a liver biopsy and stool from one of these subjects revealed double the normal hepatic cholesterol content, a markedly deficient rate of bile acid excretion, and evidence for up regulation of the alternative bile acid pathway. Two male subjects studied had hypertriglyceridemia and premature gallstone disease, and their LDL cholesterol levels were noticeably resistant to 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors.

"Our finding adds to the roster of genes that can cause a disorder of cholesterol in the blood and increase the risk of heart disease and stroke,” said Dr. John Kane, professor of medicine and senior author of the report. "By understanding the mechanism--how this gene affects cholesterol regulation--we can diagnose those at risk earlier and choose better treatments for them.”



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