Muscle glycogenosis with low phosphorylase kinase activity: mutations in PHKA1, PHKG1 or six other candidate genes explain only a minority of cases

Burwinkel, Barbara; Hu, Bin; Schroers, Anja; Clemens, Paula R.; Moses, Shimon; Shin, Yoon S.; Pongratz, D.; Vorgerd, Matthias; Kilimann, Manfred W.

doi:10.1038/sj.ejhg.5200996

Cited by 47 publications

(36 citation statements)

References 56 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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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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“…Mutations in the PHKB gene encoding the b subunit have been reported, but are normally associated with a liver specific clinical phenotype leaving the muscle functions unaffected. No mutations have been detected in the genes encoding the muscle g (PHKG1) and d (CALM) subunits in myopathic patients with Phk deficiency, despite extended mutation studies [Burwinkel et al, 2003]. Patients suffering from liver glycogenosis caused by mutations in the PHKG2 gene encoding the liver/testis isoform show a clear liver disease with hepatomegaly and early cirrhosis, but sometimes also have reduced PhK activity in the muscle with muscle hypotonia [Maichele et al, 1996].…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in the PHKA1 gene encoding the muscle isoform of the a subunit have been described in only four patients now. The three mutations identified in previously described patients include an E1112X nonsense mutation [Wehner et al, 1994], a splice site mutation [Bruno et al, 1998], and a D229V missense mutation [Burwinkel et al, 2003], and are thought to result in loss of PHKA1 function. This is in agreement with the 695delC mutation identified in our patient which results in premature termination of translation at amino acid position 242, leading at most to the formation of a truncated PHKA1 peptide.…”

Section: Discussionmentioning

confidence: 99%

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Myopathy and phosphorylase kinase deficiency caused by a mutation in thePHKA1 gene

Wuyts¹,

Reyniers²,

Ceuterick³

et al. 2005

Am. J. Med. Genet.

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Phosphorylase kinase (PhK) deficiency is the underlying cause of variable clinical symptoms depending on the tissues involved. Until today, only a few cases of myopathy associated with muscle PhK deficiency caused by a mutation in the gene encoding the alpha subunit of phosphorylase kinase (PHKA1) have been reported. We describe a male patient with myopathy and absent muscle PhK activity caused by a frameshift mutation in the gene encoding the alpha subunit of PhK on chromosome Xq12-q13.

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“…In these cases, and contrary to what happens in GSD II, glycogen does not accumulate within lysosomes but is free in the cytoplasm of cardiomyocytes, and the disease seems to be restricted to the heart. The molecular basis of this disorder has been a puzzle until recently because none of the several isozymes of PHK is heart-specific or predominantly expressed in the heart (8). The riddle was solved when, in three unrelated sporadic patients, Burwinkel et al (9) found an identical heterozygous pathogenic mutation (R531Q) in the gene encoding the ␥2-subunit of AMP-activated protein kinase (PRKAG2).…”

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Fatal Infantile Cardiac Glycogenosis with Phosphorylase Kinase Deficiency and a Mutation in the γ2-Subunit of AMP-Activated Protein Kinase

et al. 2007

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A 10-wk-old infant girl with severe hypertrophy of the septal and atrial walls by cardiac ultrasound, developed progressive ventricular wall thickening and died of aspiration pneumonia at 5 mo of age. Postmortem examination revealed ventricular hypertrophy and massive atrial wall thickening due to glycogen accumulation. A skeletal muscle biopsy showed increased free glycogen and decreased activity of phosphorylase b kinase (PHK). The report of a pathogenic mutation (R531Q) in the gene (PRKAG2) encoding the ␥2 subunit of AMP-activated protein kinase (AMPK) in three infants with congenital hypertrophic cardiomyopathy, glycogen storage, and "pseudo PHK deficiency" prompted us to screen this gene in our patient. We found a novel (R384T) heterozygous mutation in PRKAG2, affecting an arginine residue in the N-terminal AMPbinding domain. Like R531Q, this mutation reduces the binding of AMP and ATP to the isolated nucleotide-binding domains, and prevents activation of the heterotrimer by metabolic stress in intact cells. The mutation was not found in DNA from the patient's father, the only available parent, and is likely to have arisen de novo. Our studies confirm that mutations in PRKAG2 can cause fatal infantile cardiomyopathy, often associated with apparent PHK deficiency. T he most common cause of cardiac glycogenosis in infancy is Pompe disease (glycogen storage disease type II, GSD II), due to deficiency of the lysosomal enzyme acid ␣-1,4-glucosidase (1). The only other glycogenosis causing massive and rapidly fatal cardiomegaly in infants is a variant of phosphorylase b kinase (PHK) deficiency, which has been reported only in a handful of patients (2-7). In these cases, and contrary to what happens in GSD II, glycogen does not accumulate within lysosomes but is free in the cytoplasm of cardiomyocytes, and the disease seems to be restricted to the heart. The molecular basis of this disorder has been a puzzle until recently because none of the several isozymes of PHK is heart-specific or predominantly expressed in the heart (8). The riddle was solved when, in three unrelated sporadic patients, Burwinkel et al. (9) found an identical heterozygous pathogenic mutation (R531Q) in the gene encoding the ␥2-subunit of AMP-activated protein kinase (PRKAG2). This finding prompted us to revisit an infant with fatal infantile cardiac glycogenosis and PHK deficiency that we had briefly described in 1998. We found a novel heterozygous mutation in PRKAG2, thus confirming the seemingly paradoxical association between an enzyme defect and a mutation in an unrelated gene. PATIENTS AND METHODSPatient. This baby girl was born at term by caesarian section (due to fetal bradycardia) to nonconsanguineous parents without any family history of cardiac disease or fetal loss. A cardiac ultrasound at 10 wk of age showed severe hypertrophy of both septal (1.52 cm) and atrial (1 cm) walls (Fig. 1, A and B). Left ventricular ejection fraction was 81%, and peak instantaneous left ventricular outflow gradient was 75 mm Hg. Electrocard...

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Muscle glycogenosis with low phosphorylase kinase activity: mutations in PHKA1, PHKG1 or six other candidate genes explain only a minority of cases

Cited by 47 publications

References 56 publications

Nrf2-Mediated Regulation of Skeletal Muscle Glycogen Metabolism

Nrf2-Mediated Regulation of Skeletal Muscle Glycogen Metabolism

Myopathy and phosphorylase kinase deficiency caused by a mutation in thePHKA1 gene

Fatal Infantile Cardiac Glycogenosis with Phosphorylase Kinase Deficiency and a Mutation in the γ2-Subunit of AMP-Activated Protein Kinase

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