Sex Chromosomes and Sex-Linked Genes

Resume Au cours des quinze dernieres annees l'attention s'est beaucoup plus portee sur les enzymopathies hereditaires du globule rouge entrainant une anemie hemolytique que sur les deficits enzymatiques erythrocytaires non responsables d'une maladie hematologique. Dans cette derniere categorie, l'anomalie erythrocytaire constitue un indicateur precieux soit d'un deficit enzymatique generalise, soit de l'impact des modifications d'environnement sur le metabolisme intra-erythrocytaire. Le diagnostic de plusieurs enzymopathies sans retentissement hematologique peut etre aisement etabli par l'etude des globules rouges : c'est le cas de la galactosemie (deficit en galactose-1-phosphate uridyl transferase), du deficit en galactokinase, du deficit en hypoxanthine-guanine phosphoribosyltransferase et de l'acatalasemie. L'identification des heterozygotes est egalement possible. Pour la galactosemie, un depistage systematique a la naissance est realisable par l'etude d'un echantillon de sang seche sur papier filtre. Les anomalies nutritionnelles peuvent retentir sur l'equipement enzymatique erythrocytaire et conduire a un diagnostic errone d'enzymopathie hereditaire. L'exemple le plus frappant est celui du deficit en glutathion-reductase. Cette anomalie a longtemps ete consideree comme hereditaire. En fait, bien qu'une certaine variabilite genetique essentiellement decelable par electrophorese existe, la plupart des cas decrits correspondent a un deficit acquis, que l'on peut corriger in vitro par l'addition de FAD ou in vivo par l'administration de riboflavine. De meme l'activite de la transaminase glutamo-oxalo-acetique erythrocytaire depend de l'apport quotidien en pyridoxine. L'administration d'acide nicotinique multiplie par 10 le taux du NAD dans les globules rouges. Le bleu de methylene ou la diaminodiphenyl sulfone augmentent le glutathion erythrocytaire. La teneur en 2,3 diphosphoglycerate des globules rouges depend du taux d'hemoglobine et du pH sanguin. La connaissance et la comprehension de l'effet des variations de l'environnement sur les enzymes et le metabolisme erythrocytaires permettent d'envisager le traitement de certaines maladies metaboliques hereditaires. Nous avons essaye de traiter par l'acide nicotinique deux subets atteints d'anemie hemolytique congenitale ou spherocytaire due a un deficit en G6PD. Malgre l'absence de resultats positifs, il est permis d'esperer que sous une autre forme, une telle approche therapeutique puisse s'averer plus efficace.

Red cell metabolism

In 1908, Sir Archibald Garrod in his Croonian lectures coined the name 'inborn errors of metabolism' to describe a group of rare metabolic disorders which appeared to be genetically determined. In 1923, he described six such conditions in a monograph-alcaptonuria, pentosuria, cystinuria, albinism, pancreatic steatorrhoea and porphyria. He predicted that a biochemical reason would be found for these disorders and that they probably resulted from a block at some point in metabolism due to the congenital deficiency of a specific enzyme. The development of chromatographic and enzymatic techniques over the past 15 years has led to the elucidation of many metabolic pathways and provided the scientific proof of his brilliant induction. Garrod thought that in alcaptonuria, the accumulation of homogentisic acid was evidence that this substance was a normal metabolite in the breakdown of tyrosine and that its increase was due to a failure of oxidation of homogentisic acid. Now, a half century later, Garrod's hypothesis has been proved by demonstration of the absence of homogentisic acid oxidase activity in the liver of a patient with alcaptonuria (La Du, Zannoni, Laster and Seegmiller, 1958). In the past decade many abnormalities in the excretion of aminQ acids have been noted in association with hereditary biochemical disorders and mental retardation. Among these may be noted maple syrup urine disease (Dancis, Levitz, Miller and Westall, 1959), in which there is a metabolic block in the degradative pathway of the branched chain amino acids isoleucine, leucine and valine; this is associated with mental retardation, muscular hypertonicity and a maple syrup odour to the urine. Hartnup disease was first described by Baron, Dent, Harris, Hart and Jepson in 1956; this is characterized by a pellagra-like, light-sensitive skin rash, cerebellar ataxia and emotional instability. A constant feature of the disease is a generalized aminoaciduria related to an intermittent upset in tryptophane metabolism (Milne, Crawford, Girao and Loughridge, 1960). Harris, Penrose and Thomas (1959) described cystathionuria in an elderly mentally-retarded patient. Glycinuria has recently been described by Childs, Nyhan, Borden, Bard and Cooke (1961) where mental retardation and microcephaly were accompanied by excess glycine in urine and blood. Metabolic errors in carbohydrate metabolism have been known for many years; pentosuria as cited by Garrod in 1908 was first described in 1892 by Salkowski and Jastrowitz. Galactosaemia was also first noted in 1908 by Reuss-although the mechanism of its occurrence was only described in 1956 by Schwarz, Golberg, Komrower and Holzel in England and Isselbacher, Anderson, Kurahashi and Kalckar in America. Gargoylism was recognized in 1917 by Hunter, but it is only within recent years that it has been discovered to be due to deviations in the metabolism of mucopolysaccharides (Dorfman and Lorincz, 1957; Meyer, Hoffman and Linker, 1957). All these conditions are rare and there are, as yet, few specific instances in which a chemical disturbance results in mental retardation; less than 5% of the mentally defective population are of this type. With the exception of Hartnup disease, these metabolic disturbances are responsible for the more severe degrees of mental retardation. Some are amenable to treatment especially when diagnosed and treated from an early age, e.g. phenylketonuria, galactosaemia, maple syrup urine, but in them the actual cause of the brain damage is still unknown. With the increased interest in these metabolic errors in recent years it was considered desirable to determine their incidence in Northern Ireland. With special reference to phenylketonuria it was felt that the registration of all phenylketonuric families would allow the condition to be anticipated in any new siblings so that treatment could be started at an early age when success would be more sure.

https://adc.bmj.com/content/archdischild/37/195/505.full.pdf

Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland.

The biological interconversion of galactose and glucose takes place only by way of the Leloir pathway and requires the three enzymes galactokinase, galactose-1-P uridylyltransferase, and UDP-galactose 4-epimerase. The only biological importance of these enzymes appears to be to provide for the interconversion of galactosyl and glucosyl groups. Galactose mutarotase also participates by producing the galactokinase substrate alpha-D-galactose from its beta-anomer. The galacto/gluco configurational change takes place at the level of the nucleotide sugar by an oxidation/reduction mechanism in the active site of the epimerase NAD+ complex. The nucleotide portion of UDP-galactose and UDP-glucose participates in the epimerization process in two ways: 1) by serving as a binding anchor that allows epimerization to take place at glycosyl-C-4 through weak binding of the sugar, and 2) by inducing a conformational change in the epimerase that destabilizes NAD+ and increases its reactivity toward substrates. Reversible hydride transfer is thereby facilitated between NAD+ and carbon-4 of the weakly bound sugars. The structure of the enzyme reveals many details of the binding of NAD+ and inhibitors at the active site. The essential roles of the kinase and transferase are to attach the UDP group to galactose, allowing for its participation in catalysis by the epimerase. The transferase is a Zn/Fe metalloprotein, in which the metal ions stabilize the structure rather than participating in catalysis. The structure is interesting in that it consists of single beta-sheet with 13 antiparallel strands and 1 parallel strand connected by 6 helices. The mechanism of UMP attachment at the active site of the transferase is a double displacement, with the participation of a covalent UMP-His 166-enzyme intermediate in the Escherichia coli enzyme. The evolution of this mechanism appears to have been guided by the principle of economy in the evolution of binding sites.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fasebj.10.4.8647345

The Leloir pathway: a mechanistic imperative for three enzymes to change the stereochemical configuration of a single carbon in galactose

Das Thema „moderne Probleme der Humangenetik“ ist weit gespannt. Es erfordert vom Referenten, das er eine Auswahl dessen trifft, was er fur besonders wesentlich halt. Fur diese Auswahl gibt es zwar objektive Kriterien; trotzdem ist es nicht zu vermeiden, das sich in ihr die subjektive Meinung des Referenten widerspiegelt, die durch seine personliche Eigenart, seine eigene Arbeitsrichtung, aber auch durch Zufalligkeiten seiner Entwicklung und Literaturkenntnis bestimmt ist.

Moderne Probleme der Humangenetik

https://science.sciencemag.org/content/sci/123/3198/635.full.pdf

Congenital Galactosemia, a Single Enzymatic Block in Galactose Metabolism

A specific enzymatic assay for the diagnosis of congenital galactosemia. I. The consumption test.

https://science.sciencemag.org/content/sci/125/3238/114.full.pdf

Kiyoshi Kurahashi

Papers

Congenital Galactosemia, a Single Enzymatic Block in Galactose Metabolism

A specific enzymatic assay for the diagnosis of congenital galactosemia. I. The consumption test.

Enzyme formation in galactose-negative mutants of Escherichia coli.

Interference with growth of certain Escherichia coli mutants by galactose.

Galactose-1-phosphate uridyl transferase: its purification and application.