Metabolic Syndrome Affects ~47 million in United States Characterization High blood pressure Diabetes High cholesterol and triglycerides Metabolic syndrome is a common condition that affects roughly 47 million people in the United States. It is characterized by a constellation of symptoms that raise the risk of cardiovascular disease. These include high cholesterol, high blood pressure, and diabetes. The exact cause of metabolic syndrome is not known, but a number of possibilities have been suggested in recent years, including insulin resistance and obesity. In 2004, a group led by Richard Lifton of Yale University reported that, at least in the case of one family, metabolic syndrome was the result of a point mutation in the mitochondrial genome (mtDNA). © 2005 Prentice Hall Inc. / A Pearson Education Company / Upper Saddle River, New Jersey 07458

A mitochondrial mutation Analysis of metabolic syndrome in one family Multiple generations Maternal inheritance Culprit was mtDNA mutation Base substitution in a tRNA gene Does not necessarily mean mtDNA mutation is always the cause The Yale study began with a female patient who complained of symptoms associated with metabolic syndrome. Additionally, she showed unusually low levels of magnesium in her blood. She further claimed that numerous members of her family suffered from the same condition. Fortunately for Lifton and his co-workers, the woman’s family was large, spanned multiple generations, and all lived in the same geographical area. By examining the pedigree of the woman’s family (shown in the slide), researchers were able to quickly establish a maternal pattern of inheritance, suggesting that a gene in mtDNA was involved. By comparing the full mitochondrial genomes of affected and non-affected family members and non-family controls, the team was able to find a base substitution of cytidine for a highly conserved thymidine in a mitochondrial tRNA gene. The mutation segregated with family members suffering from metabolic syndrome. It is somewhat surprising that the mutation did not cause a more serious disease because tRNAs are essential to the normal functioning of mitochondria. Also interesting is the observation that members of the female patient’s family did not develop metabolic syndrome until later in life, typically after 30 years. This may indicate that additional factors are involved in the appearance of the disease. While the Yale study provides only a single example of metabolic syndrome caused by a mtDNA mutation, it shows that a mitochondrial defect can also be involved in a common disease. Most mitochondrial diseases are very rare. Also, while previous studies had implicated genes for symptoms like high blood pressure when they occur in isolation, this study was the first to find a gene involved in generating the co-occurring symptoms associated with metabolic syndrome. From Figure 1 in Wilson, F. H. et al. (2004) “A Cluster of Metabolic Defects Caused by Mutation in a Mitochondrial tRNA” Science 306: 1190-1194. © 2005 Prentice Hall Inc. / A Pearson Education Company / Upper Saddle River, New Jersey 07458