Liver Phosphorylase Kinase Deficiency Research Articles

Variability of disease spectrum in children with liver phosphorylase kinase deficiency caused by mutations in the PHKG2 gene

Liver phosphorylase b kinase (PhK) deficiency (glycogen storage disease type IX), one of the most common causes of glycogen storage disease, is caused by mutations in the PHKA2, PHKB, and PHKG2 genes. Presenting symptoms include hepatomegaly, ketotic hypoglycemia, and growth delay. Clinical severity varies widely. Autosomal recessive mutations in the PHKG2 gene, which cause about 10–15% of cases, have been associated with severe symptoms including increased risk of liver cirrhosis in childhood. We have summarized the molecular, biochemical, and clinical findings in five patients, age 5–16years, diagnosed with liver PhK deficiency caused by PHKG2 gene mutations. We have identified five novel and two previously reported mutations in the PHKG2 gene in these five patients. Clinical severity was variable among these patients. Histopathological studies were performed for four of the patients on liver biopsy samples, all of which showed signs of fibrosis but not cirrhosis. One of the patients (aged 9years) developed a liver adenoma which later resolved. All patients are currently doing well. Their clinical symptoms have improved with age and treatment. These cases add to the current knowledge of clinical variability in patients with PHKG2 mutations. Long term studies, involving follow-up of these patients into adulthood, are needed.

Autosomal Recessive Phosphorylase Kinase Deficiency in Liver, Caused by Mutations in the Gene Encoding the β Subunit ( PHKB)

The association of autosomal recessive phosphorylase kinase deficiency in liver of a 3 1/2-year-old female child with mutations in the gene encoding the common part of the beta subunit of phosphorylase kinase is reported. The proband had a severe deficiency of phosphorylase kinase in liver, while the phosphorylase kinase activity in erythrocytes was only slightly diminished. She had no symptoms of muscle involvement. The complete coding sequences of the liver gamma subunit and of the beta subunit of phosphorylase kinase of the proband were analyzed for the presence of mutations, by either reverse-transcribed PCR or SSCP analysis. Three deviations from the normal sequence were found in the region encoding the common part of the beta subunit of phosphorylase kinase-namely, a 1827G-->A (W609X) transition, a 2309A-->G (Y770C) transition, and a deletion of nucleotides 2896-2911-whereas no mutations were detected in the sequence encoding the liver gamma subunit of phosphorylase kinase. The 1827G-->A mutation and the deletion both result in the formation of early stop codons. Investigation of DNA showed that the deletion is caused by a splice-acceptor site mutation (IVS30(-1),g-->t). Family analysis revealed that the 1827G-->A and IVS30(-1),g-->t substitutions are located on different parental chromosomes and that compound heterozygosity for these mutations segregates with the disease. The 2309A-->G mutation was detected in 2%-3% of the normal population. Thus, it is concluded that the deficiency of phosphorylase kinase in this proband is caused by compound heterozygosity for the 1827G-->A and the IVS30(-1),g-->t mutations and that the 2309A-->G mutation is a polymorphism. This implies that a defect in the sequence encoding the common part of the beta subunit of phosphorylase kinase may present as liver phosphorylase kinase deficiency.

Autosomal Recessive Liver Phosphorylase Kinase Deficiency Caused by a Novel Splice-Site Mutation in the Gene Encoding the Liver Gamma Subunit (PHKG2)

To facilitate mutation analysis of patients with an autosomal recessive form of liver phosphorylase kinase deficiency, the genomic structure of the gene encoding the testis/liver gamma subunit (PHKG2) was established. The gene consist of 10 exons. The translation start site is located in exon 2. Analysis of DNA from two female siblings, affected with liver phosphorylase kinase deficiency, by exon specific amplification followed by direct sequencing, revealed a single donor splice site mutation in thePHKG2gene, IVS4+1(g → a). The mutation leads to the skipping of exon 4, which results in a frameshift, starting at nucleotide 272, a premature stop codon after 32 additional amino acids, and subsequent loss of the catalytic site. It is concluded that deficiency of phosphorylase kinase in liver of the patients is caused by the IVS4 + 1(g → a) mutation. In the patients described here, this genotype is associated with development of liver fibrosis.

Blood glucose homeostasis in rats with a deficiency of liver phosphorylase kinase

The glycogen storage disorder (gsd/gsd) rat has little or no phosphorylase kinase activity in the liver and is unable to break down liver glycogen on fasting. Nevertheless, gsd/gsd rats do not become hypoglycaemic on fasting. Gsd/gsd rats showed a decreased rate of glucose turnover measured with [6-3H]glucose. Perfused livers from gsd/gsd rats showed decreased rates of gluconeogenesis from lactate and alanine when the results were expressed per gram of liver, but the total glucose produced per liver was normal. Measurement of gluconeogenesis in vivo using [14C]-bicarbonate showed that gsd/gsd rats had a decreased rate of glucose production from substrates that enter the gluconeogenic pathway before pyruvate. We conclude that gsd/gsd rats have adapted to unavailability of liver glycogen by decreasing peripheral uptake of glucose and not by increasing gluconeogenesis.

The action of anoxia and cyanide on glycogen breakdown in the liver of the gsd/gsd rat.

Perfusion of normal rat livers under anoxic conditions or the addition of KCN to aerobic perfusions activated phosphorylase and stimulated glycogen breakdown and glucose output. Livers from rats with a deficiency of liver phosphorylase kinase (gsd/gsd) showed a much smaller activation of phosphorylase with anoxia or KCN and produced glucose at about half the rate of normal livers. The increase in phosphorylase a in gsd/gsd livers was insufficient to account for the increase in glucose output. The addition of KCN to normal hepatocytes, activated phosphorylase and stimulated glucose output almost as effectively as glucagon. Hepatocytes from gsd/gsd rats showed only a very small increase in phosphorylase a on the addition of KCN, and glucose output did not increase. We conclude that in the perfused liver, anoxia and KCN stimulate glycogen breakdown and glucose output, at least in part, by a mechanism that does not involve conversion of phosphorylase b to phosphorylase a. In isolated hepatocytes KCN stimulates glucose output only by increasing the content of phosphorylase a.

Glycerolphosphate acyltransferase, dihydroxyacetonephosphate acyltransferase and carnitine palmitoyltransferase in a glycogen storage disease (gsd/gsd) rat

FEBS LettersVolume 132, Issue 1 p. 124-126 Full-length articleFree Access Glycerolphosphate acyltransferase, dihydroxyacetonephosphate acyltransferase and carnitine palmitoyltransferase in a glycogen storage disease (gsd/gsd) rat E.David Saggerson, E.David Saggerson CSIRO, Division of Human Nutrition, Glenthorne Laboratory, O'Halloran Hill, SA 5158, Australia Permanent address: Department of Biochemistry, University College London, Gower Street, London, WC1E 6BT, England Search for more papers by this authorDavid L. Topping, David L. Topping CSIRO, Division of Human Nutrition, Glenthorne Laboratory, O'Halloran Hill, SA 5158, AustraliaSearch for more papers by this author E.David Saggerson, E.David Saggerson CSIRO, Division of Human Nutrition, Glenthorne Laboratory, O'Halloran Hill, SA 5158, Australia Permanent address: Department of Biochemistry, University College London, Gower Street, London, WC1E 6BT, England Search for more papers by this authorDavid L. Topping, David L. Topping CSIRO, Division of Human Nutrition, Glenthorne Laboratory, O'Halloran Hill, SA 5158, AustraliaSearch for more papers by this author First published: September 14, 1981 https://doi.org/10.1016/0014-5793(81)80443-7Citations: 5 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. References 1 R.S. Malthus, D.G. Clark, Proc. Univ. Otago. Med. Sch., 55, (1977), 31– 32. 2 R.S. Malthus, D.G. Clark, C. Watts, J.G.T. Sneyd, Biochem. J., 188, (1980), 99– 106. 3 D.G. Clark, D.L. Topping, R.J. Illman, R.P. Trimble, R.S. Malthus, Metabolism, 29, (1980), 415– 420. 4 E.J. Bates, E.D. Saggerson, FEBS Lett., 84, (1977), 229– 232. 5 E.J. Bates, D.L. Topping, S.R. Sooranna, E.D. Saggerson, P.A. Mayes, FEBS Lett., 84, (1977), 225– 228. 6 E.J. Bates, E.D. Saggerson, Biochem. J., 182, (1979), 751– 762. 7 E.J. Bates, E.D. Saggerson, FEBS Lett., 128, (1981), 230– 233. 8 J.D. McGarry, D.W. Forster, Annu. Rev. Biochem., 49, (1980), 395– 420. 9 E.D. Saggerson, C.A. Carpenter, FEBS Lett., 129, (1981), 225– 228. 10 R.D. Harper, E.D. Saggerson, Biochem. J., 152, (1975), 485– 494. 11 O.H. Lowry, N.J. Rosebrough, A.L. Farr, R.J. Randall, J. Biol. Chem., 193, (1951), 265– 275. 12 W.E.M. Lands, P. Hart, J. Biol. Chem., 240, (1965), 1905– 1911. 13 G. Monroy, R.H. Roal, M.E. Pullman, J. Biol. Chem., 247, (1972), 6884– 6894. 14 D. Haldar, M.E. Pullman, Fed. Proc. FASEB, 34, (1975), 632– 15 Saggerson, E. D. (1981) unpublished. 16 C.L. Jones, A.K. Hajra, J. Biol. Chem., 255, (1980), 8289– 8295. 17 D.M. Schlossman, R.M. Bell, Arch. Biochem. Biophys., 182, (1977), 732– 742. Citing Literature Volume132, Issue1September 14, 1981Pages 124-126 ReferencesRelatedInformation

Glycogen-storage disease in rats, a genetically determined deficiency of liver phosphorylase kinase

Glycogen-storage disease in rats, a genetically determined deficiency of liver phosphorylase kinase

Liver glycogen synthase in rats with a glycogen-storage disorder. The role of glycogen in the regulation of glycogen synthase.

1. A strain of rats with a genetically‐determined liver glycogen‐storage disorder (gsd/gsd) caused by a deficiency of liver phosphorylase kinase has a very high concentration of glycogen in the liver with a total glycogen synthase activity higher than in liver of fed normal animals, but only a small amount of the enzyme in the active form. In the livers of both starved and fed normal rats and gsd/gsd rats, there is a positive correlation between glycogen content and total glycogen synthase (r= 0.79) and an inverse correlation between glycogen content and active glycogen synthase (r= 0.86).2. Homogenates of livers from the gsd/gsd rats have lower glycogen‐synthase phosphatase activities than homogenates from fed normal rats which in turn have lower activities than those from starved rats. The addition of glycogen to homogenates of liver from starved rats reduced the glycogen‐synthase phosphatase activity.3. Dilution of homogenates of gsd/gsd rat liver produced an increase in glycogen‐synthase phosphatase activity which could be reversed by adding glycogen.4. The gsd/gsd rats were shown to have liver glycogen‐synthase phosphatase activity comparable to normal rats when the enzyme was measured in dilute homogenates from both groups with the same glycogen concentration.5. It is suggested that inhibition of glycogen‐synthase phosphatase by high glycogen concentrations is responsible for the low levels of activation of glycogen synthase in the gsd/gsd rats and that glycogen itself is probably the major factor controlling glycogen synthesis in gsd/gsd and fed normal rats.

A glycogen storage disease ( [formula omitted]) rat: Studies on lipid metabolism, lipogenesis, plasma metabolites, and bile acid secretion

An inbred strain of rat with a nonlethal form of liver glycogen storage disease has recently been described. The defect appears to result from a specific deficiency of liver phosphorylase kinase. The present in vivo studies have demonstrated that, in addition to high levels of liver glycogen and hypoglycemia, rates of hepatic fatty acid and cholesterol biosynthesis were depressed. Triacylglycerol levels in the plasma and liver of the affected rats were also diminished but the concentration of cholesterol in both plasma and liver were unchanged. No differences in either the concentration or molar composition of plasma fatty acids were detected. Although the concentration of cholesterol in bile was reduced in the affected rats, total bile acids, mainly hyodeoxycholate, chenodeoxycholate, and cholate were increased. There were also differences in the concentrations of plasma amino acids, with alanine, valine, leucine and isoleucine being reduced in the mutant, whereas proline, ornithine, tyrosine, and glutamate + glutamine were raised. These differences presumably reflect the inaccessibility of liver glycogen glucose. Further studies are required to fully understand some of these changes, but it is apparent that this rat offers a valuable model for studies on equivalent forms of human glycogen storage diseases.

Glycogen-storage disease in rats, a genetically determined deficiency of liver phosphorylase kinase.

Rats from an inbred strain (NZR/Mh) were found to have high concentrations of glycogen in their livers, even after 24 h of starvation. Despite this, blood glucose concentrations were well maintained on starvation for up to 72 h. The primary defect is a deficiency of liver phosphorylase kinase, causing a lack of active glycogen phosphorylase, although total phosphorylase is normal. The intravenous injection of glucagon caused a rapid activation of cyclic AMP-dependent protein kinase in the liver, but no increase in either phosphorylase kinase or phosphorylase a activity. Although total glycogen synthase activity in the livers of affected rats was higher than normal, glycogen synthase in the active form was very low, presumably as a result of the high liver glycogen content. The condition is transmitted as autosomal recessive and, apart from hepatomegaly, the affected rats appear healthy.