Biochemistry - Lipid Metabolism

Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9.

Cohen, J et al. 2005. Nat Genet 37(2):161-165.

Abstract:

The low-density lipoprotein receptor (LDLR) prevents hypercholesterolemia and atherosclerosis by removing low-density lipoprotein (LDL) from circulation. Mutations in the genes encoding either LDLR or its ligand (APOB) cause severe hypercholesterolemia. Missense mutations in PCSK9, encoding a serine protease in the secretory pathway, also cause hypercholesterolemia. These mutations are probably gain-of-function mutations, as overexpression of PCSK9 in the liver of mice produces hypercholesterolemia by reducing LDLR number. To test whether loss-of-function mutations in PCSK9 have the opposite effect, we sequenced the coding region of PCSK9 in 128 subjects (50% African American) with low plasma levels of LDL and found two nonsense mutations (Y142X and C679X). These mutations were common in African Americans (combined frequency, 2%) but rare in European Americans (<0.1%) and were associated with a 40% reduction in plasma levels of LDL cholesterol. These data indicate that common sequence variations have large effects on plasma cholesterol levels in selected populations.

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Mitochondrial respiratory-chain diseases.

DiMauro, S & Schon, EA, 2003. N. Engl. J. Med. 348(26):2656-2668.

Intro Comments

...More than a billion years ago, aerobic bacteria colonized primordial eukaryotic cells that lacked the ability to use oxygen metabolically. A symbiotic relationship developed and became permanent. The bacteria evolved into mitochondria, thus endowing the host cells with aerobic metabolism, a much more efficient way to produce energy than anaerobic glycolysis. Structurally, mitochondria have four compartments: the outer membrane, the inner membrane, the intermembrane space, and the matrix (the region inside the inner membrane). They perform numerous tasks, such as pyruvate oxidation, the Krebs cycle, and metabolism of amino acids, fatty acids, and steroids, but the most crucial is probably the generation of energy as adenosine triphosphate (ATP), by means of the electron-transport chain and the oxidative-phosphorylation system (the "respiratory chain") (Figure 1). The respiratory chain, located in the inner mitochondrial membrane, consists of five multimeric protein complexes (Figure 2B): reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase-ubiquinone oxidoreductase (complex I, approximately 46 subunits), succinate dehydrogenase-ubiquinone oxidoreductase (complex II, 4 subunits), ubiquinone-cytochrome c oxidoreductase (complex III, 11 subunits), cytochrome c oxidase (complex IV, 13 subunits), and ATP synthase (complex V, approximately 16 subunits). The respiratory chain also requires two small electron carriers, ubiquinone (coenzyme Q10) and cytochrome c.

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Comment

A very well illustrated review and discussion of the genetics and functional gene products of human mitochondrial DNA.  The biochemistry and physiology of these mitochondrial processes are nicely presented with excellent figures and tables.  Numerous examples of complex disease states are correlated with well characterized genetic deficiencies of this organelle's DNA.

Mitochondrial defects may play role in the Metabolic Syndrome

Hampton, T, 2004. JAMA 292(23):2823-2824.

Intro. comments

...While the metabolic syndrome has been thrust into the spotlight because of the obesity epidemic, it is clear that the condition is not simply caused by lifestyle habits such as overeating and inactivity. Genetic components likely play a role, and scientists have now identified a potential genetic culprit for some individuals with the condition. ... An estimated 47 million people in the United States have the metabolic syndrome, which is associated with the development of diabetes and heart disease. Factors characteristic of the syndrome include central obesity (excessive fat tissue in and around the abdomen), atherogenic dyslipidemia (high triglycerides and low HDL cholesterol), raised blood pressure (130/85 mm Hg or higher), insulin resistance (with or without glucose intolerance), prothrombotic state (eg, high fibrinogen or plasminogen activator inhibitor in the blood), proinflammatory state, and hypomagnesemia is another possible associated finding.

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Comment

This is a short overview of the research paper by Wilson et al. (see below) and presents a very good summary of its findings in a broader clinical context.

Genetic variation at the scavenger receptor class B type I gene locus determines plasma lipoprotein concentrations and particle size and interacts with type 2 diabetes: the framingham study.

Osgood, D et al., 2003. J. Clin. Endocrinol. Metab. 88(6):2869-2879.

The scavenger receptor class B type I (SR-BI) is a key component in the reverse cholesterol transport pathway. We have previously reported three common polymorphisms associated with plasma lipids and body mass index. We hypothesized that diabetic status may interact with these polymorphisms in determining plasma lipid concentrations and particle size. We evaluated this hypothesis in 2463 nondiabetic (49% men) and 187 diabetic (64% men) participants in the Framingham Study. SR-BI and APOE genotypes, anthropometric, clinical, biochemical, and lifestyle variables were determined. After multivariate adjustment, we found a consistent association between the exon 8 polymorphism and high-density lipoprotein cholesterol concentration and particle size. Interaction effects were not significant for exon 8 and intron 5 polymorphisms. However, we found statistically significant interactions between SR-BI exon 1 genotypes and type 2 diabetes, indicating that diabetic subjects with the less common allele (allele A) have lower lipid concentrations. For low-density lipoprotein cholesterol, the adjusted means (+/-SE) were 3.31 +/- 0.03 and 3.29 +/- 0.04 mmol/liter for G/G and G/A or A/A in nondiabetics, respectively, compared with 3.19 +/- 0.10 and 2.75 +/- 0.01 mmol/liter for G/G and G/A or A/A in diabetics (P = 0.03 for interaction). Similar results were obtained for HDL(2)-C. In conclusion, SR-BI gene variation modulates the lipid profile, particularly in type 2 diabetes, contributing to the metabolic abnormalities in these subjects

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A cluster of metabolic defects caused by mutation in a mitochondrial tRNA

Wilson et al., 2004.  Science 306(5699):1190-1194.

Abstract

Hypertension and dyslipidemia are risk factors for atherosclerosis and occur together more often than expected by chance. Although this clustering suggests shared causation, unifying factors remain unknown. We describe a large kindred with a syndrome including hypertension, hypercholesterolemia, and hypomagnesemia. Each phenotype is transmitted on the maternal lineage with a pattern indicating mitochondrial inheritance. Analysis of the mitochondrial genome of the maternal lineage identified a homoplasmic mutation substituting cytidine for uridine immediately 5' to the mitochondrial transfer RNA(Ile) anticodon. Uridine at this position is nearly invariate among transfer RNAs because of its role in stabilizing the anticodon loop. Given the known loss of mitochondrial function with aging, these findings may have implications for the common clustering of these metabolic disorders.

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Comment

A good illustration of how classical pedigree analysis can be combined with genomics approaches to characterize the genetic basis of complex diseases.  Surprisingly, the findings reveal a causal relationship between a mitochondrial mutation and hypertension, hypercholesterolemia, and hypomagnesemia (Metabolic Syndrome).  These approaches are incorporated with a very good discussion of the physiological aspects of the affected patients, including such variables as age, sex and BMI.