The mechanisms that balance food intake and energy expenditure determine who will be obese and who will be lean. One of the molecules that regulates energy balance in the mouse is the obese (ob) gene. Mutation of ob results in profound obesity and type II diabetes as part of a syndrome that resembles morbid obesity in humans. The ob gene product may function as part of a signalling pathway from adipose tissue that acts to regulate the size of the body fat depot.

Positional cloning of the mouse obese gene and its human homologue

Overlapping complementary DNA clones were isolated from epithelial cell libraries with a genomic DNA segment containing a portion of the putative cystic fibrosis (CF) locus, which is on chromosome 7 Transcripts, approximately 6500 nucleotides in size, were detectable in the tissues affected in patients with CF The predicted protein consists of two similar motifs, each with (i) a domain having properties consistent with membrane association and (ii) a domain believed to be involved in ATP (adenosine triphosphate) binding A deletion of three base pairs that results in the omission of a phenylalanine residue at the center of the first predicted nucleotide-binding domain was detected in CF patients

https://science.sciencemag.org/content/sci/245/4922/1066.full.pdf

Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.

Hyperhomocysteinaemia has been identified as a risk factor for cerebrovascular, peripheral vascular and coronary heart disease. Elevated levels of plasma homocysteine can result from genetic or nutrient-related disturbances in the trans-sulphuration or re-methylation pathways for homocysteine metabolism. 5, 10-Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the predominant circulatory form of folate and carbon donor for the re-methylation of homocysteine to methionine. Reduced MTHFR activity with a thermolabile enzyme has been reported in patients with coronary and peripheral artery disease. We have identified a common mutation in MTHFR which alters a highly-conserved amino acid; the substitution occurs at a frequency of approximately 38% of unselected chromosomes. The mutation in the heterozygous or homozygous state correlates with reduced enzyme activity and increased thermolability in lymphocyte extracts; in vitro expression of a mutagenized cDNA containing the mutation confirms its effect on thermolability of MTHFR. Finally, individuals homozygous for the mutation have significantly elevated plasma homocysteine levels. This mutation in MTHFR may represent an important genetic risk factor in vascular disease.

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A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase

In 1901 a physician, Archibald Garrod, observed a patient with black urine. He used this simple observation to demonstrate that a single mutant gene can produce a discrete block in a biochemical pathway, which he called an “inborn error of metabolism”. Garrod’s brilliant insight anticipated by 40 years the one gene-one enzyme concept of Beadle and Tatum. In similar fashion the chemist Linus Pauling and the biochemist Vernon Ingram, through study of patients with sickle cell anemia, showed that mutant genes alter the amino acid sequences of proteins. Clearly, many fundamental advances in biology were spawned by perceptive studies of human genetic diseases (1). We began our work in 1972 in an attempt to understand a human genetic disease, familial hypercholesterolemia or FH. In these patients the concentration of cholesterol in blood is elevated many fold above normal and heart attacks occur early in life. We postulated that this dominantly inherited disease results from a failure of end-product repression of cholesterol synthesis. The possibility fascinated us because genetic defects in feedback regulation had not been observed previously in humans or animals, and we hoped that study of this disease might throw light on fundamental regulatory mechanisms. Our approach was to apply the techniques of cell culture to unravel the postulated regulatory defect in FH. These studies led to the discovery of a cell surface receptor for a plasma cholesterol transport protein called low density lipoprotein (LDL) and to the elucidation of the mechanism by which this receptor mediates feedback control of cholesterol synthesis (2,3). FH was shown to be caused by inherited defects in the gene encoding the LDL receptor, which disrupt the normal control of cholesterol metabolism. Study of the LDL receptor in turn led to the understanding of receptor-mediated endocytosis, a genera! process by which cells communicate with each other through internalization of regulatory and nutritional molecules (4). Receptor-mediated endocytosis differs from previously described biochemical pathways because it depends upon the continuous and highly controlled movement of membraneembedded proteins from one cell organelle to another in a process termed

https://science.sciencemag.org/content/sci/232/4746/34.full.pdf

A receptor-mediated pathway for cholesterol homeostasis.

Although DNA is the carrier of genetic information, it has limited chemical stability. Hydrolysis, oxidation and nonenzymatic methylation of DNA occur at significant rates in vivo, and are counteracted by specific DNA repair processes. The spontaneous decay of DNA is likely to be a major factor in mutagenesis, carcinogenesis and ageing, and also sets limits for the recovery of DNA fragments from fossils.

Instability and decay of the primary structure of DNA

The metabolic basis of inherited disease , The metabolic basis of inherited disease , مرکز فناوری اطلاعات و اطلاع رسانی کشاورزی

The metabolic basis of inherited disease

/pdf/the-physiological-disposition-and-metabolic-fate-of-3c7ospzqrl.pdf

The physiological disposition and metabolic fate of hydrocortisone in man.

THE goitrogenic action of thiocyanate has been known since 1936 when Barker reported the occurrence of goiter in patients receiving thiocyanate therapy for hypertension and the correction of such goiter by the administration of desiccated thyroid. Astwood later (1943) produced goiter in rats with thiocyanate, but found no goitrogenic effect when iodide was given simultaneously. The action of thiocyanate was poorly understood until Franklin, Chaikoff and Lerner (1944) demonstrated that it interfered with thyroidal accumulation of iodine, in contrast to thiouracil which blocked the organic incorporation of iodine but did not inhibit its collection by the thyroid. In this way the process of iodine accumulation was clearly distinguished from that of hormone synthesis. Vanderlaan and Vanderlaan (1947) and Taurog, Chaikoff and Feller (1947) showed that iodine accumulated by animals treated with propylthiouracil was held in the form of the iodide ion.

The effect of certain anions upon the accumulation and retention of iodide by the thyroid gland.

Precursors of adrenal epinephrine and norepinephrine in vivo.

In 1948, Mason and Sprague (1) reported the isolation of hydrocortisone from the urine of a patient with Cushing's syndrome, and thus provided evidence that hydrocortisone was produced by the human adrenal cortex. Subsequently, hydrocortisone was found to be one of the principal corticoids in human adrenal gland perfusates (2) and in human peripheral blood (3). These observations strongly suggest that hydrocortisone may be the principal corticosteroid secreted by the adrenal cortex of man. Recent studies (4, 5) utilizing hydrocortisone-4-Cli have elucidated much new information regarding the metabolism and physiological disposition in man of this naturally occurring adrenal steroid. The availability of labeled hydrocortisone has made possible the direct estimation of the magnitude of the reservoir of hydrocortisone in the body, and the rate at which new, non-isotopic hydrocortisone is synthesized in the body and enters the reservoir. This report is concerned with the experimental determination of the magnitude of the miscible pool of hydrocortisone and the rate of its turnover in man. These estimations depend upon serial measurements of the specific activity of circulating hydrocortisone after the infusion of trace quantities of hydrocortisone4-0C1 and analyses of these data utilizing conventional turnover calculations (6, 7). Observations have been made in normal subjects, and subjects receiving adrenocorticotropin and A1 cortisone (prednisone).

/pdf/the-miscible-pool-and-turnover-rate-of-hydrocortisone-in-man-2k2m9m7om7.pdf

James B. Wyngaarden

Papers

The metabolic basis of inherited disease

The physiological disposition and metabolic fate of hydrocortisone in man.

The effect of certain anions upon the accumulation and retention of iodide by the thyroid gland.

Precursors of adrenal epinephrine and norepinephrine in vivo.

The miscible pool and turnover rate of hydrocortisone in man