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Biomedical subjects

A Munnich

Publications and source records attributed to A Munnich.

At least 487 records · Page 27Linked to original sources
PubMed1988

In vivo regulation of glycolytic and gluconeogenic enzyme gene expression in newborn rat liver.

Glucagon and its second messenger, cAMP, are known to rapidly block expression of the L-type pyruvate kinase gene and to stimulate expression of phosphoenolpyruvate (PEP) carboxykinase gene in the liver in vivo. The respective roles, however, of hyperglucagonemia, insulinopenia, and carbohydrate deprivation in the inhibition of L-type pyruvate kinase gene expression during fasting are poorly understood. In addition, the long-term effects of physiological hyperglucagonemia on expression of the two genes are not known. In this study, we investigate the effects of long-term physiological hyperglucagonemia and insulinopenia induced by suckling (which provides a high-fat, low-carbohydrate diet) on expression of the two genes in the liver of normal newborn rats. We show that transcription of the L-type pyruvate kinase gene is inhibited at birth and remains low during the whole suckling period, whereas transcription of the PEP carboxykinase gene is maximal in the neonate, and then decreases despite very high levels of plasma glucagon during suckling. In contrast to the adult, however, in which L-type pyruvate kinase gene expression in the liver is blocked by cAMP and stimulated by carbohydrates, the regulation of L-type pyruvate kinase gene expression in the newborn undergoes a developmental maturation: the inhibitory effect of glucagon is never complete in developing rat liver and the stimulatory effect of glucose could not be detected during suckling, due to either hyperglucagonemia, immaturity of the gene regulatory system, or both.

Animals↗
PubMed1988

[Genetic counseling in ornithine carbamoyltransferase deficiency].

Ornithine transcarbamylase (OTC) deficiency is an inborn error of urea cycle metabolism, responsible for lethal hyperammonemia in males and for severe symptoms in at least 20% of heterozygous females. The authors provide here additional data on the informativity of the protein loading test (PLT) for the detection of heterozygotes. They show that the risk of being a carrier for the mother of an affected boy falls from 2/3 a priori to only 1/8 if her PLT is negative. The risk for the mother of heterozygote girl falls from 1/2 a priori to 1/16 if her PLT is negative.

Amino Acid Metabolism, Inborn Errors↗
PubMed1988

Clinical and molecular heterogeneity of phenylalanine hydroxylase deficiencies in France.

RFLPs of 68 normal and 74 mutant alleles at the phenylalanine hydroxylase (PAH) locus were determined in 37 French kindreds. A total of 23 haplotypes, including 18 normal and 16 mutant alleles, were observed. Two-thirds of all mutant alleles were confined within only four haplotypes, while the last third was accounted for by 12 haplotypes, including eight haplotypes absent from Caucasian pedigrees reported thus far. Several mutant haplotypes were present in typical phenylketonuria only, others were present in variants only, and some were present in both. In addition, a particular mutant haplotype (haplotype 2) was found to harbor different mutations in our series, resulting in either typical phenylketonuria or in mild hyperphenylalaninemias. The diploid combination of so many mutant haplotypes in PAH-deficient patients and of compound heterozygosity at the PAH locus in southern Europe might account for the broad spectrum of individual phenotypes observed in France.

France↗
PubMed1988

[Cis- and trans- mutations in genetic diseases].

Whereas a great number of mutations located in the coding regions of genes have been described, genetic defects involving regulatory elements (cis-) or diffusible effectors controlling gene expression (trans-) are poorly known. Moreover, it appears that the structural defects of transcribed regions of genes have already delivered their "conceptual" message, whereas few studies of the consequences of one single gene defect on the expression of other genes and on in vivo functions are available. In the present communication, we wish to address the following issue: can we take advantage of Nature's experiments, ie. diseases, to extend our knowledge of the coordinate regulation of gene expression, via an original pathway, ie. the pathophysiological pathway? Can we select a few inborn or acquired metabolic diseases as models which could provide insight into as yet unknown factors involved in trans- regulation of gene expression?

Diabetes Mellitus, Type 1↗
PubMed1987

Differential effects of glucose and fructose on liver L-type pyruvate kinase gene expression in vivo.

Dietary carbohydrates are known to stimulate L-type pyruvate kinase gene expression at the transcriptional level in the liver. However, the short-term effects, the time course, and the mechanism of the gene activation by elemental hexoses in normal fasted rats remain unknown. In the present study, both glucose and fructose were found to stimulate the gene expression at the transcriptional level in liver. However, the kinetics and the extent of the mRNA induction differed according to the carbohydrate given. Fructose stimulated early (2-4 h) and transiently the gene transcription, the RNA precursor, and the mRNA accumulation in 48-h-fasted rats while maximum stimulation of the RNA synthesis by glucose was delayed until the 12th h of refeeding, despite an early rise of plasma insulin. In contrast, insulin release was not required for fructose to trigger the gene transcription, nor did the high cyclic AMP levels in fasted rat liver prevent RNA synthesis by fructose. The agent(s) operating early in fructose-fed animals might be powerful enough to not require insulin for gene activation and to balance the inhibitory action of glucagon in the liver.

Animals↗
PubMed1987

Dietary and hormonal regulation of L-type pyruvate kinase gene expression in rat small intestine.

L-type pyruvate kinase is an enzyme of the glycolytic pathway whose activity and mRNA levels fluctuate in the small intestine according to dietary status. Both the enzyme activity and mRNA concentration decline during fasting and increase upon refeeding either a glucose-rich or a fructose-rich diet. Using a single-strand M 13 phage complementary to L-type pyruvate kinase mRNA as probe, we determined the level of the mRNA in the small intestine of normal, adrenalectomized, thyroidectomized, diabetic and glucagon-treated or cAMP-treated animals refed either a glucose-rich or a fructose-rich diet. The specific mRNA is present in the small intestine of normal fasted rats and increases twofold and threefold on refeeding glucose and fructose respectively. However, the hormonal control of the gene expression differs according to the dietary carbohydrate. The L-type pyruvate kinase mRNA increase, induced by glucose feeding, is hormone-dependent and requires the presence of thyroid hormones and insulin. In fructose-fed rats a certain level of mRNA increase occurs regardless of the hormonal status of the animals, but the full induction of the mRNA by fructose requires the presence of glucocorticoids, thyroid hormones and insulin. Thus, the hormonal regulation of L-type pyruvate kinase gene expression in the small intestine is largely similar to that described in normal rat liver but the basal mRNA level and the stimulation of the mRNA increase by fructose are higher in the small intestine.

Adrenalectomy↗
PubMed1987

[Prenatal screening for phenylketonuria in 2 families by trophoblast biopsy].

Prenatal diagnosis of phenylketonuria (PKU) is now available owing to restriction fragment length polymorphism (RFLP) of the phenylalanine hydroxylase gene. Biopsies of chorionic villi were carried ou at 11 weeks gestation in 2 families who had previously a child with the classical form of PKU and who were considered informative after DNA studies. Fetal DNA was extracted and studied with restriction enzymes selected according to the study of each family. Hybridization studies suggested that one fetus was affected by the disease and that the second was normal. Termination of pregnancy was carried out in the first case; however, study of the fetus could not be performed. In the second family, the pregnancy resulted in the delivery of a normal child, as shown by normal phenylalanine level at birth.

Adult↗
PubMed1986

Transcriptional and post-transcriptional regulation of L-type pyruvate kinase gene expression in rat liver.

The effects of starvation, refeeding a diet high in carbohydrate, administration of glucagon and cyclic AMP, thyroidectomy, and adrenalectomy on transcription of the gene for liver L-type pyruvate kinase and on the accumulation of cytoplasmic mRNA for L-type pyruvate kinase were investigated in rat. Transcription of the gene was undetectable in either fasted or protein-fed rats. Refeeding fasted rats a carbohydrate-rich diet stimulated an increase in L-type pyruvate kinase mRNA, preceded by an increase in the gene transcription. Transcription was maximal at 12 h of refeeding, decreasing to 10% of maximum at 72 h. The level of L-type pyruvate kinase mRNA remained constant at 50% of maximum for at least 120 h. Neither thyroidectomy nor adrenalectomy affected gene transcription in fasted rats refed the carbohydrate-rich diet, despite a decrease in mRNA abundance to 40 and 20%, respectively, of controls fed a normal diet. Glucagon or cyclic AMP totally blocked the increase in transcription of the L-type pyruvate kinase gene caused by feeding a carbohydrate-rich diet to previously fasted rats. Nevertheless, the level of L-type pyruvate kinase mRNA remained high for 3 h after glucagon administration. After 3 h, the mRNA decreased rapidly with a half-life less than 1 h. Thus, expression of the gene for L-type pyruvate kinase is regulated at both transcriptional and post-transcriptional levels. The transcription is regulated by two major effectors, one positive, namely carbohydrates, and one negative, namely glucagon (via cyclic AMP). Both agents probably act at the level of the mRNA stability as well. Glucocorticoids and thyroid hormones do not regulate transcription of the gene for L-type pyruvate kinase but do appear to be required for a normal accumulation of the transcripts in the cytoplasm.

Adrenalectomy↗
PubMed1986

Neurological deterioration and lactic acidemia in biotinidase deficiency. A treatable condition mimicking Leigh's disease.

A six-month-old girl with chronic lactic acidosis and neurological deterioration is described, who underwent a sudden severe decompensation during her initial neurological investigations. She responded dramatically to biotin therapy. The diagnosis of late onset multiple carboxylase deficiency due to biotinidase deficiency was confirmed. This entity should be considered in the differential diagnosis of hyperlactacidemic encephalopathies.

Acidosis, Lactic↗
PubMed1986

An extracorporeal hollow-fiber reactor for phenylketonuria using immobilized phenylalanine ammonia lyase.

A hollow-fiber hemodialyzer with immobilized phenylalanine ammonia lyase was tested in vitro for depletion of blood phenylalanine in a recirculating system. A sustained reduction of phenylalanine was obtained in less than 1 h. The product of phenylalanine deamination, trans-cinnamic acid, is a nontoxic compound metabolized to benzoic acid by the liver and eliminated in the urine as hippuric acid. As a model, this reactor may be relevant not only for the short-term management of hyperphenylalaninemia (particularly in pregnant phenylketonuric mothers), but for other metabolic diseases as well, provided that a biocatalyst effective on the accumulating substance is available.

Ammonia-Lyases↗
PubMed1985

Transient transcriptional inhibition of the transferrin gene by cyclic AMP.

Transferrin mRNA content and gene transcription rate were measured in the liver of rats submitted to iron overload or depletion, castration, treatment with sexual steroid hormones, glucagon and cyclic AMP. The influence of puberty in males and females and of pregnancy was also analysed. Glucagon and cyclic AMP reduced mRNA level by about 50% at the 12th hour of treatment and transferrin gene transcription by as much as 95% at the 30th minute of drug infusion, with a secondary increase of the transcription rate for a protracted treatment. None of the other hormones tested had any detectable effect on transferrin gene expression, the same being true for iron overload or depletion.

Animals↗
PubMed1985

Characterization and metabolic regulation of a liver-specific 5.4-kilobase mRNA whose synthesis is transcriptionally induced by carbohydrates and repressed by glucagon and cyclic AMP.

Four clones derived from a carbohydrate-induced rat liver cDNA library were found to hybridize with a 5.4-kilobase mRNA species encoding a 36 kDa protein. This mRNA was abundant in the liver, barely detectable in adipocytes and kidney, and absent from the other tissues tested. In the liver, the mRNA was fully induced by a carbohydrate-rich diet, but was undetectable during both starvation and feeding with a protein-rich or lipid-rich diet. Adrenalectomized, thyroidectomized and diabetic animals did not express the mRNA in their liver when re-fed with the carbohydrate-rich diet. When these animals were given the missing hormone, the amount of hybridizable RNA returned to normal values, but administration of the hormone alone failed to induce mRNA synthesis in starved animals. Both glucagon and its second messenger, cyclic AMP, abolished the induction of the mRNA in re-fed animals. Exogenous insulin, whatever the dose, did not reverse the inhibitory action of glucagon. In an isolated nuclei transcription system, no detectable RNA transcripts were found in starved animals, whereas feeding the animals with the carbohydrate-rich diet led to a maximum rate of gene transcription. Although unidentified, this mRNA proves to be a remarkable marker of dietary and hormonal control of gene expression in vivo. It will provide a useful model for further analysis of the role of cyclic AMP in regulating the transcription of eukaryotic genes.

Animals↗