Characterization of liver GSD IX γ2 pathophysiology in a novel Phkg2/ mouse model

Gibson, Rebecca A.; Lim, Jeong‐A; Choi, Su Jin; Flores, Leticia; Clinton, Lani K.; Bali, Deeksha; Young, Sarah P.; Asokan, Aravind; Sun, Baodong; Kishnani, Priya S.

doi:10.1016/j.ymgme.2021.05.008

Cited by 6 publications

(7 citation statements)

References 51 publications

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“…We reviewed seven truncated mutations (p.R44X; p.H48QfsX5; p.L93SfsX17; p.R168X; p.R185X; p.I268FfsX12; p.Q287X) leading to liver dysfunction or cirrhosis [ 1 , 5 , 12 ] and four truncating mutations (p.H89PfsX13, p.E8X, p.Q83X, p.W300X) that do not result in liver cirrhosis [ 2 , 8 , 13 ], and related PhK enzyme activity is summarized in Table 2. As noted, residues R168, R185, I268, and Q287 belong to the phosphotransferase domain, which plays a key role in the catalytic function of the enzyme [ 14 ]. Residues R44 and H48 are located in the phosphorylase kinase domain adjacent to the P-loop motif Gly-Arg-Gly-Val-Ser-Ser-Val-Val (residues 31 to 38), which is a highly conserved component of the ATP-binding site.…”

Section: Discussionmentioning

confidence: 99%

A very rare case report of glycogen storage disease type IXc with novel PHKG2 variants

Shao

Jiang

et al. 2022

BMC Pediatr

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Background Pathogenic mutations in the PHKG2 are associated with a very rare disease—glycogen storage disease IXc (GSD-IXc)—and are characterized by severe liver disease. Case presentation Here, we report a patient with jaundice, hypoglycaemia, growth retardation, progressive increase in liver transaminase and prominent hepatomegaly from the neonatal period. Genetic testing revealed two novel, previously unreported PHKG2 mutations (F233S and R320DfsX5). Functional experiments indicated that both F223S and R320DfsX5 lead to a decrease in key phosphorylase b kinase enzyme activity. With raw cornstarch therapy, hypoglycaemia and lactic acidosis were ameliorated and serum aminotransferases decreased. Conclusion These findings expand the gene spectrum and contribute to the interpretation of clinical presentations of these two novel PHKG2 mutations.

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Section: Discussionmentioning

confidence: 99%

A very rare case report of glycogen storage disease type IXc with novel PHKG2 variants

Shao

Jiang

et al. 2022

BMC Pediatr

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“…Due to its critical role in glycogenolysis, we postulated that deletion of PHK may mimic the GSD-IX phenotype reported in clinical cases [ 1 , 14 ]. As Phkg2 −/− mice successfully recapitulated human GSD-IX-γ [ 21 ], here we characterized the metabolic abnormalities associated with GSD-IX-beta, utilizing a knockout mouse harboring a deficiency in the PHK beta subunit and studied its role in the underlying disease mechanism. Through phenotypical analysis, with hepatomegaly ( Figure 1 C,D), sub-normal level of fasting glucose profile ( Figure 2 A), and significantly elevated blood ketone levels ( Figure 2 B), we confirm that Phkb −/− mouse perfectly mimics GSD-IX-beta deficiency and it enabled further investigations to find disease mechanism underlying PHK-beta deficiency.…”

Section: Discussionmentioning

confidence: 99%

“…While GSD IX is likely the most common form of GSD, basic science research with disease models has focused on the comparably more severe types of GSD including GSD I [ 18 , 19 ] and GSD-III [ 20 ]. For GSD-IX, a mouse model for GSD IX gamma 2 has recently been characterized [ 21 ]. The Phkg2 knockout mouse model recapitulated the liver specific phenotype of GSD-IXγ patients, showing significantly reduced phosphorylase kinase activity with elevated glycogen accumulation and early signs of liver damage at 3 months of age.…”

Section: Introductionmentioning

confidence: 99%

“…The Phkg2 knockout mouse model recapitulated the liver specific phenotype of GSD-IXγ patients, showing significantly reduced phosphorylase kinase activity with elevated glycogen accumulation and early signs of liver damage at 3 months of age. As serious complications such as liver fibrosis and cirrhosis had been reported in GSD-IXc [ 22 ], longer-term monitoring on this model will be required for better understanding of this type of GSD-IX [ 21 ]. In contrast to the GSD-IXc, patients with PHKB deficiency typically show milder symptoms [ 1 , 13 , 23 , 24 ], and this has led to less attention being devoted to investigating the pathological processes in GSD-IXb.…”

Section: Introductionmentioning

confidence: 99%

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A Mouse Model of Glycogen Storage Disease Type IX-Beta: A Role for Phkb in Glycogenolysis

Arends

Wilson

Estrella

et al. 2022

IJMS

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Glycogen storage disease type IX (GSD-IX) constitutes nearly a quarter of all GSDs. This ketotic form of GSD is caused by mutations in phosphorylase kinase (PhK), which is composed of four subunits (α, β, γ, δ). PhK is required for the activation of the liver isoform of glycogen phosphorylase (PYGL), which generates free glucose-1-phosphate monomers to be used as energy via cleavage of the α -(1,4) glycosidic linkages in glycogen chains. Mutations in any of the PhK subunits can negatively affect the regulatory and catalytic activity of PhK during glycogenolysis. To understand the pathogenesis of GSD-IX-beta, we characterized a newly created PHKB knockout (Phkb−/−) mouse model. In this study, we assessed fasting blood glucose and ketone levels, serum metabolite concentrations, glycogen phosphorylase activity, and gene expression of gluconeogenic genes and fibrotic genes. Phkb−/− mice displayed hepatomegaly with lower fasting blood glucose concentrations. Phkb−/− mice showed partial liver glycogen phosphorylase activity and increased sensitivity to pyruvate, indicative of partial glycogenolytic activity and upregulation of gluconeogenesis. Additionally, gene expression analysis demonstrated increased lipid metabolism in Phkb−/− mice. Gene expression analysis and liver histology in the livers of old Phkb−/− mice (>40 weeks) showed minimal profibrogenic features when analyzed with age-matched wild-type (WT) mice. Collectively, the Phkb−/− mouse recapitulates mild clinical features in patients with GSD-IX-beta. Metabolic and molecular analysis confirmed that Phkb−/− mice were capable of sustaining energy homeostasis during prolonged fasting by using partial glycogenolysis, increased gluconeogenesis, and potentially fatty acid oxidation in the liver.

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“…The tissue was slit into 0.5 × 2.0 cm pieces and embedded in paraffin (Leica Paraplast, USA). Subsequently, the samples were cut using a microtome (Leica RM2125 RTS, Leica Biosystems, USA) with a thickness of 5-7 µm, placed on 2 slides per sample and stained with hematoxylin and eosin (H&E) for cellular analysis, or Masson trichrome (MT) for the evaluation of the distribution and structure of collagen (21,22).…”

Section: Histologymentioning

confidence: 99%

Synergistic action between a synthetic cannabinoid compound and tramadol in neuropathic pain rats

et al. 2022

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In the present study the interaction of cannabinoid, PhAR-DBH-Me [(R, Z)-18-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-18-oxooctadec-9-en-7-ylphenyl-acetate] and tramadol in two neuropathy models, as well as their possible toxic effects, was analyzed. The anti-allodynic effect of PhAR-DBH-Me, tramadol, or their combination, were evaluated in neuropathic rats. Furthermore, the effective dose 35 (as the 35 % of the anti allodynic effect) was calculated from the maximum effect of each drug. Moreover, the isobolographic analysis was performed to determine the type of interaction between the drugs. A plasma acute toxicity study was carried out to assess the hepatic, renal, and heart functions after an individual or combined administration of the drugs, as well as histology using the hematoxylin-eosin or Masson-trichome method. PhAR-DBH-Me, tramadol, and their combination produced an antiallodynic effect on spinal nerve ligation (SNL) and cisplatin-induced neuropathic pain in rats. Moreover, PhAR-DBH-Me and tramadol combination showed a synergistic interaction in neuropathic pain rats induced by SNL but not for cisplatin-induced neuropathy. On the other hand, changes in renal and hepatic functions were not observed. Likewise, analysis of liver, kidney and heart histology showed no alterations compared with controls. Results show that the combination of PhAR-DBH-Me and tramadol attenuates the allodynia in SNL rats; the acute toxicology analysis suggests that this combination could be considered safe in administered doses.

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Characterization of liver GSD IX γ2 pathophysiology in a novel Phkg2/ mouse model

Cited by 6 publications

References 51 publications

A very rare case report of glycogen storage disease type IXc with novel PHKG2 variants

A very rare case report of glycogen storage disease type IXc with novel PHKG2 variants

A Mouse Model of Glycogen Storage Disease Type IX-Beta: A Role for Phkb in Glycogenolysis

Synergistic action between a synthetic cannabinoid compound and tramadol in neuropathic pain rats

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