Novel PHKG2 mutation causing GSD IX with prominent liver disease: report of three cases and review of literature

Albash, Buthainah; Imtiaz, Faiqa; Alzaidan, Hamad; Almanea, Hadeel; Banemai, Mohammed; Allam, Rabab; Alsuheel, Ali M.; Al‐Owain, Mohammed

doi:10.1007/s00431-013-2223-0

Cited by 28 publications

(19 citation statements)

References 16 publications

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“…Phosphorylase b kinase (PhK) is an important regulator of glycogen metabolism that activates glycogen phosphorylase activity to enhance glycogen breakdown (28). The Phka1 gene encodes one of four PhK subunits, the muscle-type PhK␣ subunit (PhK␣), and loss of PhK has been linked to type IX GSD (29,30). Our present analysis demonstrates that Nrf2 significantly activates SkM and liver glycogen metabolism.…”

mentioning

confidence: 62%

Nrf2-Mediated Regulation of Skeletal Muscle Glycogen Metabolism

Uruno

Yagishita

Katsuoka

et al. 2016

Molecular and Cellular Biology

108

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f Nrf2 (NF-E2-related factor 2) contributes to the maintenance of glucose homeostasis in vivo. Nrf2 suppresses blood glucose levels by protecting pancreatic ␤ cells from oxidative stress and improving peripheral tissue glucose utilization. To elucidate the molecular mechanisms by which Nrf2 contributes to the maintenance of glucose homeostasis, we generated skeletal muscle (SkM)-specific Keap1 knockout (Keap1MuKO) mice that express abundant Nrf2 in their SkM and then examined Nrf2 target gene expression in that tissue. In Keap1MuKO mice, blood glucose levels were significantly downregulated and the levels of the glycogen branching enzyme (Gbe1) and muscle-type PhK␣ subunit (Phka1) mRNAs, along with those of the glycogen branching enzyme (GBE) and the phosphorylase b kinase ␣ subunit (PhK␣) protein, were significantly upregulated in mouse SkM. Consistent with this result, chemical Nrf2 inducers promoted Gbe1 and Phka1 mRNA expression in both mouse SkM and C2C12 myotubes. Chromatin immunoprecipitation analysis demonstrated that Nrf2 binds the Gbe1 and Phka1 upstream promoter regions. In Keap1MuKO mice, muscle glycogen content was strongly reduced and forced GBE expression in C2C12 myotubes promoted glucose uptake. Therefore, our results demonstrate that Nrf2 induction in SkM increases GBE and PhK␣ expression and reduces muscle glycogen content, resulting in improved glucose tolerance. Our results also indicate that Nrf2 differentially regulates glycogen metabolism in SkM and the liver.T he tight regulation of glucose homeostasis is essential for the maintenance of biological functions. As glucose metabolites are major energy sources for skeletal muscle (SkM) contraction (1-3), SkM requires an efficient supply of glucose metabolites during exercise. Perturbations in SkM glucose metabolism often provoke metabolic disorders; e.g., impaired glucose tolerance and diabetes mellitus. SkM and liver store glucose as glycogen (4), which is used to generate glucose metabolites when energy is required; consequently, efficient SkM glycogen utilization is an important factor in exercise and the maintenance of glucose homeostasis (4).Our bodies are continuously exposed to toxic chemicals (often electrophiles) and oxidative stress from the environment; these stresses are termed environmental stresses (5). While these environmental stresses are known to provoke tissue damage, they also affect cellular metabolism and energy production (5). The Keap1-Nrf2 system protects our bodies against these environmental stresses (6, 7). Nrf2 (NF-E2-related factor 2) belongs to the cap 'n' collar subfamily of basic region-leucine zipper-type transcription factors (8). Under unstressed conditions, Keap1 (Kelch-like ECHassociated protein 1) constitutively represses Nrf2 activity (9) by acting as an adaptor subunit for cullin-3-based ubiquitin E3 ligase (7). This E3 ligase complex efficiently ubiquitinates Nrf2, leading to its rapid proteasomal degradation (10). When cells are exposed to either electrophilic toxic chemicals or reactive oxygen spec...

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mentioning

confidence: 62%

Nrf2-Mediated Regulation of Skeletal Muscle Glycogen Metabolism

Uruno

Yagishita

Katsuoka

et al. 2016

Molecular and Cellular Biology

108

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“…About 25 cases have been described in the literature. 28,43,44 Where information is available, most the cases reported show evidence of fibrosis on liver biopsy, and about 50% have evidence of cirrhosis. 43,44 Liver cirrhosis can develop as early as the first few years of life.…”

Section: Phkg2-related Gsd IXmentioning

confidence: 99%

“…28,43,44 Where information is available, most the cases reported show evidence of fibrosis on liver biopsy, and about 50% have evidence of cirrhosis. 43,44 Liver cirrhosis can develop as early as the first few years of life. 44,45 Occasional findings include bile duct proliferation, cholestasis, cirrhosis related esophageal varices, and splenomegaly.…”

Section: Phkg2-related Gsd IXmentioning

confidence: 99%

Diagnosis and management of glycogen storage diseases type VI and IX: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

Kishnani

Goldstein

Austin

et al. 2019

Genetics in Medicine

110

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Disclaimer This practice resource is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this practice resource is completely voluntary and does not necessarily assure a successful medical outcome. This practice resource should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this practice resource. Clinicians also are advised to take notice of the date this practice resource was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures. Purpose: Glycogen storage disease (GSD) types VI and IX are rare diseases of variable clinical severity affecting primarily the liver. GSD VI is caused by deficient activity of hepatic glycogen phosphorylase, an enzyme encoded by the PYGL gene. GSD IX is caused by deficient activity of phosphorylase kinase (PhK), the enzyme subunits of which are encoded by various genes: ɑ (PHKA1, PHKA2), β (PHKB), ɣ (PHKG1, PHKG2), and δ (CALM1, CALM2, CALM3). Glycogen storage disease types VI and IX have a wide spectrum of clinical manifestations and often cannot be distinguished from each other, or from other liver GSDs, on clinical presentation alone. Individuals with GSDs VI and IX can present with hepatomegaly with elevated serum transaminases, ketotic hypoglycemia, hyperlipidemia, and poor growth. This guideline for the management of GSDs VI and IX was developed as an educational resource for health-care providers to facilitate prompt and accurate diagnosis and appropriate management of patients. Methods: A national group of experts in various aspects of GSDs VI and IX met to review the limited evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management. Evidence bases for these rare disorders are largely based on expert opinion, particularly when targeted therapeutics that have to clear the US Food and Drug Administration (FDA) remain unavailable. Results: This management guideline specifically addresses evaluation and diagnosis across multiple organ systems involved in GSDs VI and IX. Conditions to consider in a differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, and prenatal dia...

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“…Although there is no clear gene/phenotype correlation seen in PhK deficiency, patients with mutations in PHKG2 have been reported to have more severe symptoms and increased risk of developing liver cirrhosis in childhood (Maichele et al 1996;Burwinkel et al 1998aBurwinkel et al , b, 2000Burwinkel et al , 2003Beauchamp et al 2007a, b;Davit-Spraul et al 2011;Fahiminiya et al 2013;Albash et al 2014;Bali et al 2014;Roscher et al 2014), while those with mutations in PHKB tend to have milder involvement (Burwinkel et al 1997a, b;Beauchamp et al 2007a, b;Davit-Spraul et al 2011;Roscher et al 2014). A wide variability in clinical presentation and severity has been recognized among patients with the most common subtype, X-linked PhK deficiency, ranging from mild involvement to severe, recurrent hypoglycemia and liver cirrhosis in some reported cases (Burwinkel et al 1998a, b;Morava et al 2005;Beauchamp et al 2007a, b;Davit-Spraul et al 2011;Tsilianidis et al 2013;Roscher et al 2014).…”

Section: Introductionmentioning

confidence: 99%