Alternative titles; symbols
HGNC Approved Gene Symbol: PRKAG2
SNOMEDCT: 1230303001, 74390002; ICD10CM: I45.6;
Cytogenetic location: 7q36.1 Genomic coordinates (GRCh38): 7:151,556,127-151,877,115 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q36.1 | Cardiomyopathy, hypertrophic 6 | 600858 | Autosomal dominant | 3 |
| Glycogen storage disease of heart, lethal congenital | 261740 | Autosomal dominant | 3 | |
| Wolff-Parkinson-White syndrome | 194200 | Autosomal dominant | 3 |
AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that is activated by various cellular stresses that increase AMP levels and decrease ATP levels. Once activated, AMPK switches on catabolic pathways and switches off many ATP-consuming processes. AMPK is a heterotrimeric complex consisting of a catalytic alpha subunit (e.g., PRKAA1, 602739), a noncatalytic beta subunit (e.g., PRKAB1, 602740), and a noncatalytic gamma subunit (e.g., PRKAG2). AMPK is evolutionarily conserved, and orthologs for all 3 subunits are found throughout eukaryotes (review by Sanz, 2008).
By searching an EST database with PRKAG1 (602742) as the probe, followed by PCR screening of cDNA libraries, Lang et al. (2000) identified a cDNA encoding PRKAG2. Sequence analysis predicted that the 328-amino acid protein, which is 76% identical to PRKAG1, contains 4 conserved cystathionine-beta-synthase domains but lacks N-linked glycosylation sites. Lang et al. (2000) noted that the entire PRKAG2 amino acid sequence is identical to a part of the 569-amino acid PRKAG2 sequence reported by Cheung et al. (2000), suggesting the existence of different promoters. They designated the long and short PRKAG2 isoforms PRKAG2a and PRKAG2b, respectively. Genomic sequence analysis determined that PRKAG2b spans 80 kb and contains 12 exons. Northern blot analysis detected a specific 2.4-kb PRKAG2b transcript that was most abundantly expressed in heart, followed by testis and placenta; it was not expressed in liver and thymus. A 3.8-kb PRKAG2a transcript was expressed in liver, but not in heart, placenta, or thymus, and a 3.0-kb PRKAG2a transcript was expressed at extremely high levels in heart and at lower levels in skeletal muscle, kidney, spleen, and testis.
Stapleton et al. (1997) identified human ESTs encoding human AMPK-gamma-2. They noted that the AMPK-gamma-2 gene was mapped to 7q35-q36 by Genethon. By radiation hybrid analysis, Lang et al. (2000) mapped the PRKAG2 gene to 7q36.
Wolff-Parkinson-White Syndrome
In 2 apparently unrelated families with autosomal dominant Wolff-Parkinson-White syndrome (WPW; 194200), Gollob et al. (2001) identified a heterozygous mutation in the PRKAG2 gene (R302Q; 602743.0001).
Hypertrophic Cardiomyopathy 6
Blair et al. (2001) identified heterozygous mutations in the PRKAG2 gene in 2 families with severe hypertrophic cardiomyopathy (CMH6; 600858), in which some affected individuals also displayed Wolff-Parkinson-White ventricular preexcitation. Both mutations, H142A (602743.0002) and a 3-bp insertion (602743.0003), occur in highly conserved regions. Because AMPK provides a central sensing mechanism that protects cells from exhaustion of ATP supplies, Blair et al. (2001) proposed that energy compromise may provide a unifying pathogenic mechanism in all forms of CMH.
Sinha et al. (2000) reported a family in which 12 persons had ventricular preexcitation, 6 of whom also had cardiac hypertrophy. Three patients underwent successful ablation of typical accessory atrioventricular bundles, with subsequent loss of preexcitation. Gollob et al. (2001) demonstrated the presence of the R302Q mutation of PRKAG2 in this kindred.
Reports that dominant mutations in PRKAG2, an enzyme that modulates glucose uptake and glycolysis, can cause hypertrophic cardiomyopathy challenged the hypothesis that hypertrophic cardiomyopathy is a disease of the sarcomere. In addition to cardiac hypertrophy, individuals with PRKAG2 mutations frequently manifest electrophysiologic abnormalities, particularly Wolff-Parkinson-White syndrome (Gollob et al., 2001), atrial fibrillation, and progressive development of atrioventricular conduction block. Although atrial fibrillation is common in CMH patients and becomes increasingly prevalent with disease duration, neither accessory pathway nor conduction system diseases are typical features of CMH. To understand the mechanisms by which PRKAG2 defects cause disease, Arad et al. (2002) defined additional novel mutations (T400N, 602743.0004; N488I, 602743.0005) and examined the clinical manifestations found in affected individuals. A previously unrecognized and unusual histopathology was identified in hearts with PRKAG2 defects, which prompted biochemical analyses of the functional consequences of human PRKAG2 mutations on Snf4, the yeast homolog of the gamma-2 protein kinase subunit. Arad et al. (2002) concluded that their data indicated that PRKAG2 defects do not cause CMH, but rather a novel glycogen storage disease of the heart. They found that although the cardiac pathology caused by the PRKAG2 mutations R302Q, T400N, and N488I included myocyte enlargement and minimal interstitial fibrosis, these mutations were not associated with myocyte and myofibrillar disarray, the pathognomonic features of hypertrophic cardiomyopathy caused by sarcomere protein mutations. Instead, PRKAG2 mutations caused pronounced vacuole formation within myocytes. Several lines of evidence indicated that these vacuoles are filled with glycogen-associated granules. Analyses of the effects of human PRKAG2 mutations on Snf1/Snf4 kinase function demonstrated constitutive activity, which could foster glycogen accumulation. Thus, this disorder is a metabolic storage disease in which hypertrophy, ventricular preexcitation, and conduction system defects coexist. Support for the hypothesis that human PRKAG2 missense mutations cause an increase in AMP kinase activity and stimulate carbohydrate accumulation also comes from analyses of RN- pigs (Milan et al., 2000; Hamilton et al., 2001). RN- pigs produce 'acid meat' that is of inferior quality due to increased muscle glycogen content. The porcine RN- mutation is analogous to the human PRKAG2 mutation arg302-to-gln (602743.0001).
Arad et al. (2005) analyzed the PRKAG2 gene in 35 patients with hypertrophic cardiomyopathy who were negative for mutations in known sarcomere-protein genes, and identified a heterozygous missense mutation (Y487H; 602743.0008) in 1 proband with moderate hypertrophy and an extremely short PR interval.
In a 38-year-old man with hypertrophic cardiomyopathy, severe conduction system abnormalities, and mild skeletal muscle glycogenosis, who was negative for mutation in the LMNA gene (150330), Laforet et al. (2006) identified heterozygosity for a mutation in the PRKAG2 gene (602743.0011). The authors suggested that PRKAG2 could be a candidate for unexplained skeletal muscle glycogenosis associated with cardiac abnormalities.
In a child with idiopathic cardiac hypertrophy and presumed sporadic cardiomyopathy, who was negative for mutations in 9 of the known CMH genes, Morita et al. (2008) identified heterozygosity for a missense mutation in the PRKAG2 gene (H530R; 602743.0009).
Kelly et al. (2009) reported a father, son, and daughter with hypertrophic cardiomyopathy in whom they identified heterozygosity for a missense mutation in the PRKAG2 gene (E506Q; 602743.0010). Endomyocardial tissue from the son showed a normal amount of glycogen present in the myocytes by staining and electron microscopy. Kelly et al. (2009) stated that 8 affected members of a family reported by Bayrak et al. (2006) with a PRKAG2 mutation at the same codon (E506K) had ventricular preexcitation and mild left ventricular hypertrophy; endomyocardial biopsy of the adult proband showed profound intracellular vacuolization and marked interstitial fibrosis. Noting that in the patients reported by Burwinkel et al. (2005), the approximately 4- to 6-fold increase in cardiac mass was associated with only a 3-fold increase in glycogen content and an absence of more organized cellular aggregations of glycogen, Kelly et al. (2009) concluded that CMH due to PRKAG2 mutations may have a degree of cardiac hypertrophy exceeding that expected from observed amounts of glycogen deposition.
Glyogen Storage Disease of Heart, Lethal Congenital
In 3 of 5 patients with fatal congenital heart glycogenosis (261740), 1 of whom had previously been reported by Regalado et al. (1999), Burwinkel et al. (2005) identified heterozygosity for an arg531-to-gln mutation in the PRKAG2 gene (R531Q; 602743.0007). The patients died of hemodynamic and respiratory failure secondary to hypertrophic nonobstructive cardiomyopathy but also had Wolff-Parkinson-White syndrome-like conduction anomalies. Biochemical characterization of the mutant protein showed a greater than 100-fold reduction of binding affinities for the regulatory nucleotides AMP and ATP but an enhanced basal activity and increased phosphorylation of the alpha subunit. Burwinkel et al. (2005) noted that the molecular abnormalities of the R531Q mutant protein are more pronounced than those of other PRKAG2 mutants, which likely accounts for the more severe phenotype with fetal onset, extreme cardiomegaly, and a fatal outcome in infancy.
In a female infant with severe cardiac hypertrophy due to glycogen accumulation who died at 5 months of age, Akman et al. (2007) identified heterozygosity for a missense mutation in the PRKAG2 gene (R384T; 602743.0012).
Arad et al. (2003) constructed transgenic mice overexpressing the PRKAG2 cDNA with or without a missense N488I human mutation (602743.0005). The transgenic mice showed elevated AMP-activated protein kinase activity, accumulated large amounts of cardiac glycogen, developed dramatic left ventricular hypertrophy, and exhibited ventricular preexcitation and sinus node dysfunction. Electrophysiologic testing demonstrated alternative atrioventricular conduction pathways consistent with Wolff-Parkinson-White syndrome. Cardiac histopathology revealed that the annulus fibrosis, which normally insulates the ventricles from inappropriate excitation by the atria, was disrupted by glycogen-filled myocytes. Arad et al. (2003) concluded that these data establish that PRKAG2 mutations cause a glycogen storage cardiomyopathy, provide an anatomic explanation for electrophysiologic findings, and implicate disruption of the annulus fibrosis by glycogen-engorged myocytes as the cause of preexcitation in Pompe (232300), Danon (300257), and other glycogen storage diseases.
Sidhu et al. (2005) generated transgenic mice expressing the human PRKAG2 gene containing the arg302-to-gln (R302Q; 602743.0001) mutation and observed a phenotype identical to that of Wolff-Parkinson-White syndrome, including preexcitation, inducible orthodromic AV reentrant tachycardia, cardiac hypertrophy, and excessive cardiac glycogen. The primary molecular defect was loss of cardiac AMPK activity, which appeared to be due to disruption of the gamma-2 subunit binding site for AMP.
Wolff-Parkinson-White Syndrome
In 2 families with Wolff-Parkinson-White syndrome (WPW; 194200), Gollob et al. (2001) identified a G-to-A transition at nucleotide 995 of the PRKAG2 gene, resulting in an arg302-to-gln (R302Q) missense mutation.
Familial Hypertrophic Cardiomyopathy 6
In a kindred previously reported by Sinha et al. (2000), in which 12 individuals had ventricular preexcitation and 6 of those also had cardiac hypertrophy (CMH6; 600858), Gollob et al. (2001) demonstrated the presence of the R302Q mutation in the PRKAG2 gene.
In 43 affected individuals from 4 unrelated families with cardiac hypertrophy, 1 of which was previously reported by Mehdirad et al. (1999), Arad et al. (2002) identified the R302Q mutation in exon 7 of the PRKAG2 gene. Most of the patients had hypertrophy associated with WPW (65%) and/or other conduction system disease (atrioventricular block, 37%; sinus bradycardia, 12%); however, 5 patients from 2 of the families had only WPW without cardiac hypertrophy. Twenty (47%) of the 43 affected individuals had undergone pacemaker implantation. Histopathology revealed enlarged myocytes but no myofiber disarray, and there were large, isolated cytosolic vacuoles within cardiomyocytes; electron microscopy showed the vacuoles to be filled with densely packed fine granular and fibrillar electron-dense material. Arad et al. (2002) noted that such pathologic findings in the heart were typical of those seen in type IV glycogenosis (232500) and polyglucosan body disease (263570) and had also been found in hearts of patients with adult-onset Pompe disease (232300).
In 3 affected members of a family with early-onset hypertrophic cardiomyopathy (CMH6; 600858), 2 of whom also displayed Wolff-Parkinson-White ventricular preexcitation with a 'very large and bizarre' QRS pattern, Blair et al. (2001) identified heterozygosity for an A-G transition in exon 7 of the PRKAG2 gene, resulting in a his142-to-arg (H142R) substitution at a highly conserved residue in the second cystathionine-beta-synthase domain. The mutation was not found in more than 240 control chromosomes. One patient underwent cardiac transplantation at 19 years of age.
In 5 affected members of a 3-generation family with severe hypertrophic cardiomyopathy (CMH6; 600858), Blair et al. (2001) identified heterozygosity for a 3-bp insertion (TTA) after the codon for arginine-109 in exon 5 of the PRKAG2 gene, predicting the insertion of a leucine residue. Three of the 5 patients underwent sudden death at 32 years, 38 years, and 51 years of age; 1 of those had symptomatic Wolff-Parkinson-White ventricular preexcitation requiring treatment with ablation. The 2 remaining patients also had conduction and electrocardiographic abnormalities: atrial fibrillation with left ventricular bundle branch block and atrioventricular block requiring pacemaker insertion, and a short PR interval with broad QRS and T wave inversion, respectively.
In a 42-year-old woman with cardiac hypertrophy associated with Wolff-Parkinson-White ventricular preexcitation and sinus bradycardia requiring pacemaker implantation (CMH6; 600858), Arad et al. (2002) identified heterozygosity for a 1289C-A transversion in the PRKAG2 gene, resulting in a thr400-to-asn (T400N) substitution at a highly conserved residue. The mutation was not found in her unaffected mother or sister or in 200 control samples; no DNA was available from her deceased and reportedly unaffected father.
In 24 affected individuals from a large family with hypertrophic cardiomyopathy mapping to chromosome 7q3 (CMH6; 600858), originally reported by MacRae et al. (1995), Arad et al. (2002) identified heterozygosity for a 1553A-T transversion in the PRKAG2 gene, resulting in an asn488-to-ile (N488I) substitution at a highly conserved residue. The mutation segregated with disease in the family and was not found in 200 control samples. Three of the patients with hypertrophy also had Wolff-Parkinson-White ventricular preexcitation and several others had various forms of conduction disease; 1 mutation-positive individual had WPW and conduction disease without cardiac hypertrophy.
In affected members of a 3-generation family segregating Wolff-Parkinson-White syndrome (WPW; 194200), Gollob et al. (2001) identified a 1681C-G transversion in exon 15 of the PRKAG2 gene, resulting in an arg531-to-gly (R531G) substitution. The proband had experienced recurrent syncope since the age of 2, at which age he was noted to have ventricular preexcitation on resting ECG. He subsequently developed paroxysms of atrial fibrillation with ventricular escape rhythms of right bundle branch block morphology before developing chronic atrial fibrillation. Echocardiography at the age of 43 demonstrated normal ventricular architecture. Three other immediate relatives were affected.
In 3 sporadic, unrelated patients with lethal congenital glycogen storage disease of the heart (261740), 2 of whom were previously reported ('patient A' by Regalado et al., 1999 and 'patient E' by Buhrer et al., 2003), Burwinkel et al. (2005) identified heterozygosity for a 1592G-A transition of the PRKAG2 gene, resulting in an arg531-to-gln (R531Q) substitution. Biochemical characterization of the mutant protein showed a greater than 100-fold reduction of binding affinities for the regulatory nucleotides AMP and ATP but an enhanced basal activity and increased phosphorylation of the alpha-subunit. Burwinkel et al. (2005) noted that the molecular abnormalities of the R531Q mutant protein are more pronounced than those of other PRKAG2 mutants, which likely accounts for the more severe phenotype.
In a brother and sister with hypertrophic cardiomyopathy (CMH6; 600858), Arad et al. (2005) identified heterozygosity for a tyr487-to-his (Y487H) substitution in the PRKAG2 gene. Their maternal uncle had undergone sudden cardiac death. The proband had moderate hypertrophy with a left ventricular wall thickness of 13 mm and an extremely short PR interval (0.09 msec).
In a child with idiopathic cardiac hypertrophy and presumed sporadic cardiomyopathy (CMH6; 600858), who was negative for mutations in 9 of the known CMH genes, Morita et al. (2008) identified heterozygosity for an A-to-G transition in the PRKAG2 gene, resulting in a his530-to-arg (H530R) substitution. (The parents were not studied.) The mutation was not found in unrelated individuals matched by ancestral origin or in more than 1,000 control chromosomes.
In a father, son, and daughter with hypertrophic cardiomyopathy (CMH6; 600858), Kelly et al. (2009) identified heterozygosity for a glu506-to-gln (E506Q) substitution in exon 14 of the PRKAG2 gene. The father had undergone cardiac transplantation at 29 years of age for cardiomyopathy; the 6-year-old daughter, who had 'prominent forces' on electrocardiography, was shown to have left ventricular mass in the 90th percentile for body surface area by 2-D echocardiography. The son presented at 6 months of age with a cardiac murmur and was found to have ventricular preexcitation and severe biventricular CMH requiring septal myectomy. Endomyocardial biopsy samples from the son did not demonstrate significant glycogen accumulation.
In a 38-year-old man with hypertrophic cardiomyopathy, severe conduction system abnormalities, and mild skeletal muscle glycogenosis (CMH6; 600858), Laforet et al. (2006) identified heterozygosity for a 1732T-C transition in the PRKAG2 gene, resulting in a ser548-to-pro (S548P) substitution at a highly conserved residue in the fourth CBS domain. The mutation was not found in his unaffected brother or in 200 control chromosomes.
In a female infant with severe cardiac hypertrophy due to glycogen accumulation (261740) who died at 5 months of age, Akman et al. (2007) identified heterozygosity for a c.1151 G-C transversion in the PRKAG2 gene, resulting in an arg384-to-thr (R384T) substitution at a highly conserved residue within the second cystathionine beta-synthase motif. The mutation was not found in DNA from the patient's father, the only available parent, and was likely to have arisen de novo. Functional analysis demonstrated a 17- and a 26-fold decrease in binding of AMP and ATP, respectively, with the R384T mutant compared to wildtype, and the mutant prevented activation of the heterotrimer by metabolic stress in intact cells.
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