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Michael H Gollob - One of the best experts on this subject based on the ideXlab platform.
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the PRKAG2 cardiac syndrome
2020Co-Authors: Wael Alqarawi, Michael H Gollob, Martin S GreenAbstract:PRKAG2 cardiac syndrome is an inherited condition characterized by different forms of arrhythmia. It is associated with ventricular hypertrophy, pre-excitation, atrial arrhythmias, and conduction disease. Typically, it presents in young adulthood and can occasionally lead to sudden cardiac death. The PRKAG2 syndrome patients may have a combination of specific ECG features that will be discussed in this chapter.
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chronic ampk activity dysregulation produces myocardial insulin resistance in the human arg302gln PRKAG2 glycogen storage disease mouse model
EJNMMI research, 2013Co-Authors: Stephanie Thorn, Michael H Gollob, Maryellen Harper, Rob S Beanlands, Robert A Dekemp, Jean N DasilvaAbstract:Background The cardiac PRKAG2 mutation in the γ2-subunit of adenosine monophosphate activated kinase (AMPK) is characterized by excessive glycogen deposition, hypertrophy, frequent arrhythmias, and progressive conduction system disease. We investigated whether myocardial glucose uptake (MGU) was augmented following insulin stimulation in a mouse model of the PRKAG2 cardiac syndrome.
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abstract 16614 reduced glucose uptake and increased glycogen synthase is observed early in a mouse model of the human arg302gln PRKAG2 cardiac syndrome
Circulation, 2011Co-Authors: Stephanie Thorn, Michael H Gollob, Rob S Beanlands, Robert A Dekemp, Jennifer M Renaud, Ran Klein, Tyler Dumouchel, Jean N DasilvaAbstract:Background: The PRKAG2 cardiac syndrome is characterized by frequent heart arrhythmias, excessive cardiac glycogen deposition and cardiomyopathy due to a mutation in the gamma2 subunit of AMP-activ...
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in vivo assessment of myocardial glucose uptake by positron emission tomography in adults with the PRKAG2 cardiac syndrome
Circulation-cardiovascular Imaging, 2009Co-Authors: Jennifer M Renaud, Stephanie Thorn, Rob S Beanlands, Robert A Dekemp, Jean N Dasilva, Martin S Green, Linda Garrard, Keiichiro Yoshinaga, Arun Abraham, Michael H GollobAbstract:Background— The PRKAG2 cardiac syndrome is an inherited metabolic disease of the heart characterized by excessive myocardial glycogen deposition. The biochemical alterations associated with this co...
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modulating phenotypic expression of the PRKAG2 cardiac syndrome
Circulation, 2008Co-Authors: Michael H GollobAbstract:The PRKAG2 cardiac syndrome is a rare, autosomal-dominant genetic disease of the heart. Genetic defects in the PRKAG2 gene, encoding the regulatory subunit of AMP-activated protein kinase (AMPK), lead to a diverse cardiac phenotype of variable clinical expressivity.1 Typically, affected patients present in late adolescence with frequent paroxysms of supraventricular arrhythmias, demonstrate ventricular preexcitation on 12-lead ECG, and commonly progress to high-grade conduction system disease requiring a permanent pacemaker by their fourth or fifth decade of life. A significant proportion of patients develop mild to severe cardiac hypertrophy with progression to dilated cardiomyopathy. Phenotypic variability within a family is common, suggesting an influence of genetic modifiers. In addition, specific mutations of the PRKAG2 gene may predict clinical expression. Mutations giving rise to atrial fibrillation and conduction disease only, severe neonatal cardiomyopathy with death, or skeletal myopathy with a cardiac phenotype have all been described.2–4 Article p 144 Most intriguing, the arrhythmogenic nature and cardiomyopathic process of this disease are not caused by primary genetic defects in cardiac ion channels or structural proteins. Rather, the PRKAG2 cardiac syndrome is a disease of cardiac metabolism. AMPK enzymatic activity serves a critical role in regulating cellular glucose and fatty acid metabolic pathways. …
Roger K Wolff - One of the best experts on this subject based on the ideXlab platform.
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genetic variation in a metabolic signaling pathway and colon and rectal cancer risk mtor pten stk11 rpkaa1 PRKAG2 tsc1 tsc2 pi3k and akt1
Carcinogenesis, 2010Co-Authors: Martha L Slattery, Jennifer S Herrick, Abbie Lundgreen, Francis A Fitzpatrick, Karen Curtin, Roger K WolffAbstract:Serine/threonine protein kinase 11 (STK11) and phosphatase tensin homolog deleted on chromosome 10 (PTEN) link insulin sensitivity and metabolic signaling to inflammation and other hormonal factors and colorectal cancer. We evaluate genetic variation in nine genes in a candidate pathway as follows: STK11 (3 tagSNPs), PTEN (9 tagSNPs), FRAP1 (mTOR) (4 tagSNPs), TSC1 (14 tagSNPs), TSC2 (8 tagSNPs), Akt1 (2 tagSNPs), PIK3CA (7 tagSNPs), PRKAA1 (13 tagSNPs) and PRKAG2 (68 tagSNPs) in two population-based case–control studies of colon (n = 1574 cases, 1940 controls) and rectal (n = 91 cases, 999 controls) cancer. FRAP1, PRKAA1, PRKAG2 and TSC2 genes were significantly associated with colon cancer; risk estimates ranged from 1.21 [95% confidence interval (CI) 1.05–1.38] for FRAP1rs1057079 for the AG/GG genotype to 1.51 (95% CI 1.09–2.09) for PRKAG2rs9648723 CC genotype. PIK3CA, PRKAG2, PTEN, STK11 and TSC1 were significantly associated with rectal cancer overall. The strongest association was observed for PIK3CA rs7651265 GG genotype (odds ratio 2.32 95% CI 1.02–5.30). FRAP1 was associated with microsatellite instability (MSI)+ colon tumors; PRKAA1, CpG island methylator phenotype (CIMP)+ and MSI+ colon tumors; PRKAG2 and KRAS2 colon tumors; TSC1 and CIMP+ and MSI+ colon tumors; TSC2 with MSI+ colon tumors; PIK3CA with KRAS2-mutated rectal tumors; PRKAG2 (rs6964824) with KRAS2- and TP53-mutated rectal tumors and with PRKAG2 (rs412396 and rs4725431) with CIMP+ rectal tumors. These data suggest that genetic variation in a predefined candidate pathway for colorectal cancer contributes to both colon and rectal cancer risk. Associations appear to be strongest for CIMP+ and MSI+ tumors.
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genetic variation in a metabolic signaling pathway and colon and rectal cancer risk mtor pten stk11 rpkaa1 PRKAG2 tsc1 tsc2 pi3k and akt1
Carcinogenesis, 2010Co-Authors: Martha L Slattery, Jennifer S Herrick, Abbie Lundgreen, Francis A Fitzpatrick, Karen Curtin, Roger K WolffAbstract:Serine/threonine protein kinase 11 (STK11) and phosphatase tensin homolog deleted on chromosome 10 (PTEN) link insulin sensitivity and metabolic signaling to inflammation and other hormonal factors and colorectal cancer. We evaluate genetic variation in nine genes in a candidate pathway as follows: STK11 (3 tagSNPs), PTEN (9 tagSNPs), FRAP1 (mTOR) (4 tagSNPs), TSC1 (14 tagSNPs), TSC2 (8 tagSNPs), Akt1 (2 tagSNPs), PIK3CA (7 tagSNPs), PRKAA1 (13 tagSNPs) and PRKAG2 (68 tagSNPs) in two population-based case–control studies of colon (n = 1574 cases, 1940 controls) and rectal (n = 91 cases, 999 controls) cancer. FRAP1, PRKAA1, PRKAG2 and TSC2 genes were significantly associated with colon cancer; risk estimates ranged from 1.21 [95% confidence interval (CI) 1.05–1.38] for FRAP1rs1057079 for the AG/GG genotype to 1.51 (95% CI 1.09–2.09) for PRKAG2rs9648723 CC genotype. PIK3CA, PRKAG2, PTEN, STK11 and TSC1 were significantly associated with rectal cancer overall. The strongest association was observed for PIK3CA rs7651265 GG genotype (odds ratio 2.32 95% CI 1.02–5.30). FRAP1 was associated with microsatellite instability (MSI)+ colon tumors; PRKAA1, CpG island methylator phenotype (CIMP)+ and MSI+ colon tumors; PRKAG2 and KRAS2 colon tumors; TSC1 and CIMP+ and MSI+ colon tumors; TSC2 with MSI+ colon tumors; PIK3CA with KRAS2-mutated rectal tumors; PRKAG2 (rs6964824) with KRAS2- and TP53-mutated rectal tumors and with PRKAG2 (rs412396 and rs4725431) with CIMP+ rectal tumors. These data suggest that genetic variation in a predefined candidate pathway for colorectal cancer contributes to both colon and rectal cancer risk. Associations appear to be strongest for CIMP+ and MSI+ tumors.
Martha L Slattery - One of the best experts on this subject based on the ideXlab platform.
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genetic variation in a metabolic signaling pathway and colon and rectal cancer risk mtor pten stk11 rpkaa1 PRKAG2 tsc1 tsc2 pi3k and akt1
Carcinogenesis, 2010Co-Authors: Martha L Slattery, Jennifer S Herrick, Abbie Lundgreen, Francis A Fitzpatrick, Karen Curtin, Roger K WolffAbstract:Serine/threonine protein kinase 11 (STK11) and phosphatase tensin homolog deleted on chromosome 10 (PTEN) link insulin sensitivity and metabolic signaling to inflammation and other hormonal factors and colorectal cancer. We evaluate genetic variation in nine genes in a candidate pathway as follows: STK11 (3 tagSNPs), PTEN (9 tagSNPs), FRAP1 (mTOR) (4 tagSNPs), TSC1 (14 tagSNPs), TSC2 (8 tagSNPs), Akt1 (2 tagSNPs), PIK3CA (7 tagSNPs), PRKAA1 (13 tagSNPs) and PRKAG2 (68 tagSNPs) in two population-based case–control studies of colon (n = 1574 cases, 1940 controls) and rectal (n = 91 cases, 999 controls) cancer. FRAP1, PRKAA1, PRKAG2 and TSC2 genes were significantly associated with colon cancer; risk estimates ranged from 1.21 [95% confidence interval (CI) 1.05–1.38] for FRAP1rs1057079 for the AG/GG genotype to 1.51 (95% CI 1.09–2.09) for PRKAG2rs9648723 CC genotype. PIK3CA, PRKAG2, PTEN, STK11 and TSC1 were significantly associated with rectal cancer overall. The strongest association was observed for PIK3CA rs7651265 GG genotype (odds ratio 2.32 95% CI 1.02–5.30). FRAP1 was associated with microsatellite instability (MSI)+ colon tumors; PRKAA1, CpG island methylator phenotype (CIMP)+ and MSI+ colon tumors; PRKAG2 and KRAS2 colon tumors; TSC1 and CIMP+ and MSI+ colon tumors; TSC2 with MSI+ colon tumors; PIK3CA with KRAS2-mutated rectal tumors; PRKAG2 (rs6964824) with KRAS2- and TP53-mutated rectal tumors and with PRKAG2 (rs412396 and rs4725431) with CIMP+ rectal tumors. These data suggest that genetic variation in a predefined candidate pathway for colorectal cancer contributes to both colon and rectal cancer risk. Associations appear to be strongest for CIMP+ and MSI+ tumors.
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genetic variation in a metabolic signaling pathway and colon and rectal cancer risk mtor pten stk11 rpkaa1 PRKAG2 tsc1 tsc2 pi3k and akt1
Carcinogenesis, 2010Co-Authors: Martha L Slattery, Jennifer S Herrick, Abbie Lundgreen, Francis A Fitzpatrick, Karen Curtin, Roger K WolffAbstract:Serine/threonine protein kinase 11 (STK11) and phosphatase tensin homolog deleted on chromosome 10 (PTEN) link insulin sensitivity and metabolic signaling to inflammation and other hormonal factors and colorectal cancer. We evaluate genetic variation in nine genes in a candidate pathway as follows: STK11 (3 tagSNPs), PTEN (9 tagSNPs), FRAP1 (mTOR) (4 tagSNPs), TSC1 (14 tagSNPs), TSC2 (8 tagSNPs), Akt1 (2 tagSNPs), PIK3CA (7 tagSNPs), PRKAA1 (13 tagSNPs) and PRKAG2 (68 tagSNPs) in two population-based case–control studies of colon (n = 1574 cases, 1940 controls) and rectal (n = 91 cases, 999 controls) cancer. FRAP1, PRKAA1, PRKAG2 and TSC2 genes were significantly associated with colon cancer; risk estimates ranged from 1.21 [95% confidence interval (CI) 1.05–1.38] for FRAP1rs1057079 for the AG/GG genotype to 1.51 (95% CI 1.09–2.09) for PRKAG2rs9648723 CC genotype. PIK3CA, PRKAG2, PTEN, STK11 and TSC1 were significantly associated with rectal cancer overall. The strongest association was observed for PIK3CA rs7651265 GG genotype (odds ratio 2.32 95% CI 1.02–5.30). FRAP1 was associated with microsatellite instability (MSI)+ colon tumors; PRKAA1, CpG island methylator phenotype (CIMP)+ and MSI+ colon tumors; PRKAG2 and KRAS2 colon tumors; TSC1 and CIMP+ and MSI+ colon tumors; TSC2 with MSI+ colon tumors; PIK3CA with KRAS2-mutated rectal tumors; PRKAG2 (rs6964824) with KRAS2- and TP53-mutated rectal tumors and with PRKAG2 (rs412396 and rs4725431) with CIMP+ rectal tumors. These data suggest that genetic variation in a predefined candidate pathway for colorectal cancer contributes to both colon and rectal cancer risk. Associations appear to be strongest for CIMP+ and MSI+ tumors.
Ferhaan Ahmad - One of the best experts on this subject based on the ideXlab platform.
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patient with a PRKAG2 mutation who developed immunoglobulin a nephropathy a case report
European Heart Journal - Case Reports, 2019Co-Authors: Michael C Giudici, Ferhaan Ahmad, Danniele G HolandaAbstract:Background PRKAG2 syndrome (PS) is a rare, early-onset autosomal dominant inherited disease caused by mutations in PRKAG2, the gene encoding the regulatory γ2 subunit of adenosine monophosphate-activated protein kinase. PRKAG2 syndrome is associated with many cardiac manifestations, including pre-excitation, arrhythmias, left ventricular hypertrophy, and chronotropic incompetence frequently leading to early pacemaker placement. A meta-analysis of genome-wide association data in subjects with chronic kidney disease (CKD) identified a susceptibility locus in an intron of PRKAG2, which has been replicated in other studies. However, CKD has not been reported in patients with PS or mutations in PRKAG2. Case summary We report a case of a woman diagnosed at age 27 with PS when she presented with atrial fibrillation and pre-excitation on electrocardiogram. By age 35, she had developed mild renal insufficiency and a biopsy demonstrated IgA nephropathy (IGAN). Discussion This is the first reported case of IGAN in a patient with PS. We discuss both PS and IGAN and the potential mechanisms by which they could be related.
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transgenic knockdown of cardiac sodium glucose cotransporter 1 sglt1 attenuates PRKAG2 cardiomyopathy whereas transgenic overexpression of cardiac sglt1 causes pathologic hypertrophy and dysfunction in mice
Journal of the American Heart Association, 2014Co-Authors: Ferhaan Ahmad, Mohun Ramratnam, Ravi K Sharma, Stephen Dauria, So Jung Lee, David C Wang, Xue Yin N HuangAbstract:Background The expression of a novel cardiac glucose transporter, SGLT1, is increased in glycogen storage cardiomyopathy secondary to mutations in PRKAG2 . We sought to determine the role of SGLT1 in the pathogenesis of PRKAG2 cardiomyopathy and its role in cardiac structure and function. Methods and Results Transgenic mice with cardiomyocyte-specific overexpression of human T400N mutant PRKAG2 cDNA (TGT400N) and transgenic mice with cardiomyocyte-specific RNA interference knockdown of SGLT1 (TGSGLT1-DOWN) were crossed to produce double-transgenic mice (TGT400N/TGSGLT1-DOWN). Tet-off transgenic mice conditionally overexpressing cardiac SGLT1 in the absence of doxycycline were also constructed (TGSGLT-ON). Relative to TGT400N mice, TGT400N/TGSGLT1-DOWN mice exhibited decreases in cardiac SGLT1 expression (63% decrease, P <0.05), heart/body weight ratio, markers of cardiac hypertrophy, and cardiac glycogen content. TGT400N/TGSGLT1-DOWN mice had less left ventricular dilation at age 12 weeks compared to TGT400N mice. Relative to wildtype (WT) mice, TGSGLT1-ON mice exhibited increases in heart/body weight ratio, glycogen content, and markers of cardiac hypertrophy at ages 10 and 20 weeks. TGSGLT1-ON mice had increased myocyte size and interstitial fibrosis, and progressive left ventricular dysfunction. When SGLT1 was suppressed after 10 weeks of overexpression (TGSGLT1-ON/OFF), there was a reduction in cardiac hypertrophy and improvement in left ventricular failure. Conclusions Cardiac knockdown of SGLT1 in a murine model of PRKAG2 cardiomyopathy attenuates the disease phenotype, implicating SGLT1 in the pathogenesis. Overexpression of SGLT1 causes pathologic cardiac hypertrophy and left ventricular failure that is reversible. This is the first report of cardiomyocyte-specific transgenic knockdown of a target gene.
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activation of cardiac hypertrophic signaling pathways in a transgenic mouse with the human PRKAG2 thr400asn mutation
Biochimica et Biophysica Acta, 2010Co-Authors: Sanjay K Banerjee, Xue Yin N Huang, Kenneth R Mcgaffin, Ferhaan AhmadAbstract:Human mutations in PRKAG2, the gene encoding the gamma2 subunit of AMP activated protein kinase (AMPK), cause a glycogen storage cardiomyopathy. In a transgenic mouse with cardiac specific expression of the Thr400Asn mutation in PRKAG2 (TG(T400N)), we previously reported initial cardiac hypertrophy (ages 2-8 weeks) followed by dilation and failure (ages 12-20 weeks). We sought to elucidate the molecular mechanisms of cardiac hypertrophy. TG(T400N) mice showed significantly increased cardiac mass/body mass ratios up to approximately 3-fold beginning at age 2 weeks. Cardiac expression of ANP and BNP were approximately 2- and approximately 5-fold higher, respectively, in TG(T400N) relative to wildtype (WT) mice at age 2 weeks. NF-kappaB activity and nuclear translocation of the p50 subunit were increased approximately 2- to 3-fold in TG(T400N) hearts relative to WT during the hypertrophic phase. Phosphorylated Akt and p70S6K were elevated approximately 2-fold as early as age 2 weeks. To ascertain whether these changes in TG(T400N) mice were a consequence of increased AMPK activity, we crossbred TG(T400N) with TG(alpha2DN) mice, which express a dominant negative, kinase dead mutant of the AMPK alpha2 catalytic subunit and have low myocardial AMPK activity. Genetic reversal of AMPK overactivity led to a reduction in hypertrophy, nuclear translocation of NF-kappaB, phosphorylated Akt, and p70S6K. We conclude that inappropriate activation of AMPK secondary to the T400N PRKAG2 mutation is associated with the early activation of NF-kappaB and Akt signaling pathway, which mediates cardiac hypertrophy.
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abstract 2295 a novel cardiac glucose transporter sglt1 mediates increased glucose uptake in PRKAG2 cardiomyopathy
Circulation, 2009Co-Authors: Sanjay K Banerjee, David Wang, Nuria M Pastorsoler, Kenneth R Mcgaffin, Ferhaan AhmadAbstract:INTRODUCTION: Mutations in PRKAG2, the gene encoding the γ2 subunit of AMP activated protein kinase (AMPK), lead to a cardiomyopathy characterized by cardiac hypertrophy, increased cardiac glucose ...
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reversibility of PRKAG2 glycogen storage cardiomyopathy and electrophysiological manifestations
Circulation, 2008Co-Authors: Cordula M Wolf, Ferhaan Ahmad, Michael Arad, Atsushi Sanbe, Scott Bernstein, Okan Toka, Tetsuo Konno, Gregory E Morley, Jeffrey M Robbins, J G SeidmanAbstract:Background— PRKAG2 mutations cause glycogen-storage cardiomyopathy, ventricular preexcitation, and conduction system degeneration. A genetic approach that utilizes a binary inducible transgenic system was used to investigate the disease mechanism and to assess preventability and reversibility of disease features in a mouse model of glycogen-storage cardiomyopathy. Methods and Results— Transgenic (Tg) mice expressing a human N488I PRKAG2 cDNA under control of the tetracycline-repressible α-myosin heavy chain promoter underwent echocardiography, ECG, and in vivo electrophysiology studies. Transgene suppression by tetracycline administration caused a reduction in cardiac glycogen content and was initiated either prenatally (TgOFF(E-8 weeks)) or at different time points during life (TgOFF(4–16 weeks), TgOFF(8–20 weeks), and TgOFF(>20 weeks)). One group never received tetracycline, expressing transgene throughout life (TgON). TgON mice developed cardiac hypertrophy followed by dilatation, ventricular preexcita...
Michael Arad - One of the best experts on this subject based on the ideXlab platform.
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reversibility of PRKAG2 glycogen storage cardiomyopathy and electrophysiological manifestations
Circulation, 2008Co-Authors: Cordula M Wolf, Ferhaan Ahmad, Michael Arad, Atsushi Sanbe, Scott Bernstein, Okan Toka, Tetsuo Konno, Gregory E Morley, Jeffrey M Robbins, J G SeidmanAbstract:Background— PRKAG2 mutations cause glycogen-storage cardiomyopathy, ventricular preexcitation, and conduction system degeneration. A genetic approach that utilizes a binary inducible transgenic system was used to investigate the disease mechanism and to assess preventability and reversibility of disease features in a mouse model of glycogen-storage cardiomyopathy. Methods and Results— Transgenic (Tg) mice expressing a human N488I PRKAG2 cDNA under control of the tetracycline-repressible α-myosin heavy chain promoter underwent echocardiography, ECG, and in vivo electrophysiology studies. Transgene suppression by tetracycline administration caused a reduction in cardiac glycogen content and was initiated either prenatally (TgOFF(E-8 weeks)) or at different time points during life (TgOFF(4–16 weeks), TgOFF(8–20 weeks), and TgOFF(>20 weeks)). One group never received tetracycline, expressing transgene throughout life (TgON). TgON mice developed cardiac hypertrophy followed by dilatation, ventricular preexcita...
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increased alpha2 subunit associated ampk activity and PRKAG2 cardiomyopathy
Circulation, 2005Co-Authors: Ferhaan Ahmad, Michael Arad, Antonio R Perezatayde, Deeksha Bali, Nicolas Musi, Cordula M Wolf, Dorothy Branco, David Stapleton, Yanqiu Xing, Rong TianAbstract:Background— AMP-activated protein kinase (AMPK) regulatory γ2 subunit (PRKAG2) mutations cause a human cardiomyopathy with cardiac hypertrophy, preexcitation, and glycogen deposition. PRKAG2 cardiomyopathy is recapitulated in transgenic mice overexpressing mutant PRKAG2 N488I in the heart (TGγ2N488I). AMPK is a heterotrimeric kinase consisting of 1 catalytic (α) and 2 regulatory (β and γ) subunits. Two α-subunit isoforms, α1 and α2, are expressed in the heart; however, the contribution of AMPK utilization of these subunits to PRKAG2 cardiomyopathy is unknown. Mice overexpressing a dominant-negative α2 subunit of AMPK (TGα2DN) provide a tool for selectively inhibiting α2, but not α1, subunit-associated AMPK activity. Methods and Results— In compound-heterozygous TGγ2N488I/TGα2DN mice, AMPK activity associated with α2 but not α1 was decreased compared with TGγ2N488I. The TGα2DN transgene reduced the disease phenotype of TGγ2N488I, partially or completely normalizing the ECG, cardiac function, cardiac morpho...
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glycogen storage diseases presenting as hypertrophic cardiomyopathy
The New England Journal of Medicine, 2005Co-Authors: Michael Arad, Antonio R Perezatayde, B J Maron, P Spirito, Joshua M Gorham, Walter H Johnson, Philip J Saul, Gregory B Wright, Ronald J Kanter, Christine E SeidmanAbstract:background Unexplained left ventricular hypertrophy often prompts the diagnosis of hypertrophic cardiomyopathy, a sarcomere-protein gene disorder. Because mutations in the gene for AMP-activated protein kinase g 2 ( PRKAG2 ) cause an accumulation of cardiac glycogen and left ventricular hypertrophy that mimics hypertrophic cardiomyopathy, we hypothesized that hypertrophic cardiomyopathy might also be clinically misdiagnosed in patients with other mutations in genes regulating glycogen metabolism. methods Genetic analyses performed in 75 consecutive unrelated patients with hypertrophic cardiomyopathy detected 40 sarcomere-protein mutations. In the remaining 35 patients, PRKAG2 , lysosome-associated membrane protein 2 ( LAMP2 ), a -galactosidase ( GLA ), and acid a -1,4-glucosidase ( GAA ) genes were studied. results Gene defects causing Fabry’s disease ( GLA ) and Pompe’s disease ( GAA ) were not found, but two LAMP2 and one PRKAG2 mutations were identified in probands with prominent hypertrophy and electrophysiological abnormalities. These results prompted the study of two additional, independent series of patients. Genetic analyses of 20 subjects with massive hypertrophy (left ventricular wall thickness, ≥30 mm) but without electrophysiological abnormalities revealed mutations in neither LAMP2 nor PRKAG2 . Genetic analyses of 24 subjects with increased left ventricular wall thickness and electrocardiograms suggesting ventricular preexcitation revealed four LAMP2 and seven PRKAG2 mutations. Clinical features associated with defects in LAMP2 included male sex, severe hypertrophy, early onset (at 8 to 17 years of age), ventricular preexcitation, and asymptomatic elevations of two serum proteins. conclusions LAMP2 mutations typically cause multisystem glycogen-storage disease (Danon’s disease) but can also present as a primary cardiomyopathy. The glycogen-storage cardiomyopathy produced by LAMP2 or PRKAG2 mutations resembles hypertrophic cardiomyopathy but is distinguished by electrophysiological abnormalities, particularly ventricular preexcitation.
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transgenic mice overexpressing mutant PRKAG2 define the cause of wolff parkinson white syndrome in glycogen storage cardiomyopathy
Circulation, 2003Co-Authors: Michael Arad, Ferhaan Ahmad, Ivan P Moskowitz, Vickas V Patel, Antonio R Perezatayde, Douglas B Sawyer, Mark Walter, Guo H Li, Patrick G Burgon, Colin T MaguireAbstract:Background— Mutations in the γ2 subunit (PRKAG2) of AMP-activated protein kinase produce an unusual human cardiomyopathy characterized by ventricular hypertrophy and electrophysiological abnormalities: Wolff-Parkinson-White syndrome (WPW) and progressive degenerative conduction system disease. Pathological examinations of affected human hearts reveal vacuoles containing amylopectin, a glycogen-related substance. Methods and Results— To elucidate the mechanism by which PRKAG2 mutations produce hypertrophy with electrophysiological abnormalities, we constructed transgenic mice overexpressing the PRKAG2 cDNA with or without a missense N488I human mutation. Transgenic mutant mice showed elevated AMP-activated protein kinase activity, accumulated large amounts of cardiac glycogen (30-fold above normal), developed dramatic left ventricular hypertrophy, and exhibited ventricular preexcitation and sinus node dysfunction. Electrophysiological testing demonstrated alternative atrioventricular conduction pathways co...
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constitutively active amp kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy
Journal of Clinical Investigation, 2002Co-Authors: Michael Arad, Antonio R Perezatayde, Ronald J Kanter, Woodrow D Benson, William J Mckenna, Elizabeth Sparks, K Mcgarry, J G Seidman, Christine E SeidmanAbstract:Mutations in PRKAG2, the gene for the γ2 regulatory subunit of AMP-activated protein kinase, cause cardiac hypertrophy and electrophysiologic abnormalities, particularly preexcitation (Wolff-Parkinson-White syndrome) and atrioventricular conduction block. To understand the mechanisms by which PRKAG2 defects cause disease, we defined novel mutations, characterized the associated cardiac histopathology, and studied the consequences of introducing these mutations into the yeast homologue of PRKAG2, Snf4. Although the cardiac pathology caused by PRKAG2 mutations Arg302Gln, Thr400Asn, and Asn488Ile include 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 these vacuoles were 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. Taken together, our data indicate that PRKAG2 mutations do not cause hypertrophic cardiomyopathy but rather lead to a novel myocardial metabolic storage disease, in which hypertrophy, ventricular pre-excitation and conduction system defects coexist.