Biochemistry- Intermediary Metabolism

Targeted Therapy for Inherited GPI Deficiency

Almeida, AM et al., 2007. N. Engl. J. Med. 356(16):1641-1647.

Abstract

Disrupted binding of the transcription factor Sp1 to the mutated promoter region of the mannosyl transferase-encoding gene PIGM causes inherited glycosylphosphatidylinositol (GPI) deficiency characterized by splanchnic vein thrombosis and epilepsy. We show that this results in histone hypoacetylation at the promoter of PIGM. The histone deacetylase inhibitor butyrate increases PIGM transcription and surface GPI expression in vitro as well as in vivo through enhanced histone acetylation in an Sp1-dependent manner. More important, the drug caused complete cessation of intractable seizures in a child with inherited GPI deficiency.

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Comment

An interest paper illustrating how genomics and epigenomics can be applied pediatric medicine not only to understand the basic genetic defect of a disease but also to devise a treatment which can alleviate some of the symptoms.

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.

Gene-transfer technology: a preventive neurotherapy to curb obesity, ameliorate metabolic syndrome and extend life expectancy

Kalra, SP & Kalra, PS, 2005. Trends Pharmacol.Sci. 26(10):488-495.

Abstract

Leptin insufficiency at crucial target sites in the hypothalamic circuitries that integrate energy intake and expenditure underlies abnormal rates of fat accumulation. The payload of this 'fat burden' is metabolic syndrome, a cluster of life-threatening metabolic afflictions, and a shorter lifespan. Currently available therapies employed to combat obesity have disadvantages such as poor compliance for lifestyle modification or transient effectiveness and undesirable side-effects of pharmacological interventions. Recent studies suggest that neurotherapy comprising a single central administration of recombinant adeno-associated virus vector encoding the leptin gene severely depletes fat and ameliorates the major symptoms of metabolic syndrome for extended periods in rodents. These persistent benefits avert the deleterious impact of the 'fat burden' and extend life expectancy. Thus, the novel approach of central gene-transfer technology has distinct advantages over current therapies and has the potential to correct or slow the progression of inherited or acquired hypothalamic diseases.

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Comment

A thorough and well illustrated review of metabolic syndrome biochemistry, physiology and pharmacology together with various standard intervention approaches.  The concept of leptin insufficiency is nicely defined for the subsequent use of gene-transfer as a neurotherapy to ameliorate this insufficiency.  The general use of such gene therapies for their anti-aging and anti-obesity effects is discussed.

Bench meets bedside: A 10-year-old girl and amino acid residue glycine 75 of the facilitative glucose transporter GLUT1.

Klepper, J et al., 2005. Biochemistry 44(38):12621-12626.

Abstract

In 2000, amino acid residue G75 of the facilitative glucose transporter GLUT1 was identified by mutagenesis as being essential for transport function [Olsowski, A., et al. (2000) Biochemistry 39, 2469-74]. In 2002, we identified a heterozygous missense mutation substituting glycine at residue 75 for tryptophan in a 10-year-old girl with intractable seizures and low glucose concentrations in the cerebrospinal fluid indicative of GLUT1 deficiency. Glucose uptake into erythrocytes of the patient was 36% of controls, and GLUT1-specific immunoreactivity was normal, indicating a functional GLUT1 defect. In silico three-dimensional modeling of the G75W mutant provided a smaller gyration radius for transmembrane segment 2 as the potential pathogenic mechanism in this patient. This case illustrates a GLUT1 mutation characterized in vitro and later confirmed by disease itself and highlights the potential of basic science and clinical medicine to collaborate for the benefit of patients.

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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.

Journal Link  | PMID

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.