Human Molecular Genetics, 2001, Vol. 10, No. 11 1215-1220
© 2001 Oxford University Press
Mutations in the 
2 subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis
1Department of Cardiovascular Medicine and 2Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, 3Royal Manchester Children’s Hospital, Manchester, UK, 4Paediatric Cardiology, Southampton General Hospital, Southampton, UK and 5Paediatric Cardiology, John Radcliffe Hospital, Oxford, UK
Received 2 March 2001; Revised and Accepted 2 April 2001.
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Familial hypertrophic cardiomyopathy (HCM) has been widely studied as a genetic model of cardiac hypertrophy and sudden cardiac death. HCM has been defined as a disease of the cardiac sarcomere, but mutations in the known contractile protein disease genes are not found in up to one-third of cases. Further, no consistent changes in contractile properties are shared by these mutant proteins, implying that an abnormality of force generation may not be the underlying mechanism of disease. Instead, all of the sarcomeric mutations appear to result in inefficient use of ATP, suggesting that an inability to maintain normal ATP levels may be the central abnormality. To test this hypothesis we have examined candidate genes involved in energy homeostasis in the heart. We now describe mutations in PRKAG2, encoding the
2 subunit of AMP-activated protein kinase (AMPK), in two families with severe HCM and aberrant conduction from atria to ventricles in some affected individuals (pre-excitation or Wolff–Parkinson–White syndrome). The mutations, one missense and one in-frame single codon insertion, occur in highly conserved regions. Because AMPK provides a central sensing mechanism that protects cells from exhaustion of ATP supplies, we propose that these data substantiate energy compromise as a unifying pathogenic mechanism in all forms of HCM. This conclusion should radically redirect thinking about this disorder and also, by establishing energy depletion as a cause of myocardial dysfunction, should be relevant to the acquired forms of heart muscle disease that HCM models. |
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Familial hypertrophic cardiomyopathy (HCM) is a relatively common autosomal dominant disorder characterized by myocardial hypertrophy and a high incidence of sudden death in some affected families (1,2). HCM has come to be considered as a ‘disease of the sarcomere’, as multiple different mutant alleles have been described in nine genes encoding cardiac contractile proteins (3–5). Biochemical and biophysical analyses have, however, shown that there is no unifying abnormality of cardiac contractility resulting from these different mutations (for a review, see ref. 5); some mutant proteins appear to depress contractility (e.g. missense mutations in ß-myosin heavy chain) (6) whereas others enhance calcium sensitivity and contractility (e.g. mutant
-tropomyosin or cardiac troponin I) (7,8). This suggests that the disease phenotype is not simply a direct consequence of altered contractility per se and that a more fundamental abnormality of myocardial function must be sought. One feature that the different classes of HCM-causing mutations do share is an inefficiency of ATP utilization (5,9,10). We predict that ATP wastage leading to a relative depletion of ATP in the cardiac myocyte may, in circumstances of increased demand, lead to a failure of energy-dependent homeostatic mechanisms. In particular, interference with calcium re-uptake in the myocyte would trigger calcium-dependent hypertrophic signalling as well as a tendency to lethal arrhythmias. Support for this hypothesis comes from the observation that a number of phenocopies of HCM have been defined at the molecular level recently and shown to be syndromes associated with abnormalities of ATP generation in the myocardium (e.g. mitochondrial mutations, Friedreich’s ataxia and VLCAD deficiency) (11–13).
Pathogenic mutations in the known HCM disease genes are only found in 
60–70% of probands with familial HCM (unpublished data), suggesting that other disease genes remain to be identified. However, most of the remaining candidate sarcomeric protein genes have been screened directly and have yielded either no mutations in HCM (e.g. in troponin C) (14 and unpublished data) or only rare mutations (e.g. in titin and actin) (15,16), suggesting that mutations in contractile protein genes may not account for the shortfall. If the hypothesized role of inefficient ATP usage in ‘sarcomeric’ HCM is correct, genes encoding proteins involved in energy homeostasis in the myocyte could also be considered as strong candidates in this disorder. A particularly attractive candidate in this context is the AMP-activated protein kinase (AMPK) (17). AMPK, which has both protein kinase and transcriptional regulatory roles (18), is a heterotrimeric protein composed of a catalytic subunit and two regulatory subunits (ß and ). It shows homology to the SNF1 transcription factor complex which has a central role in the regulation of glucose metabolism in yeast (19). When activated it functions to protect the cell from critical depletion of ATP by activating glycolysis and fatty acid uptake during hypoxic stress or extreme metabolic demand (17,20). The 2 protein is the dominant isoform of the regulatory subunit of AMPK in the heart. This is encoded by the gene PRKAG2, which has recently been mapped to human chromosome 7q36 (21). This chromosomal region includes a mapped locus for HCM associated with electrophysiological pre-excitation or Wolff–Parkinson–White (WPW) syndrome (22), a feature of HCM perhaps not likely to be explained by defects in structural contractile proteins. We now report PRKAG2 mutations in two families with HCM associated with pre-excitation in some affected individuals.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Clinical findings
To test the hypothesis that mutations affecting the AMPK
2 subunit cause HCM we studied 23 families with HCM in which contractile protein mutations had not been identified (having screened the genes encoding ß-myosin heavy chain, the regulatory myosin light chain, cardiac troponin T, myosin binding protein C and cardiac actin); amongst these families, one (WA) also showed features of pre-excitation. We subsequently selected family HA for study as members also manifested HCM with pre-excitation. Family WA (Fig. 1A and Table 1) shows autosomal transmission through three generations with five individuals affected by HCM, three of whom have died of the condition. Of note, individuals I:1 and II:2 died prematurely with early cardiac dilatation and III:2 has been referred for cardiac transplantation. Individual II:1 has a short PR interval on electrocardiogram (ECG) suggestive of pre-excitation, and individual III:1, who died suddenly at age 38 during the course of this study, had previously undergone an ablation of an accessory pathway for symptomatic WPW syndrome. In family HA (Fig. 1B and Table 1) the proband, I:1, presented early in life with HCM, which progressed to a dilated phase requiring cardiac transplantation at age 19. One affected child (II:1, 8 years) has HCM with pre-excitation on the resting ECG; the other (II:2, 4 years) was diagnosed clinically at birth after presenting with a murmur and pre-excitation and has since had symptomatic WPW syndrome.
|
|
Exon-intron sequences of PRKAG2
The published cDNA sequence and genomic structure (21) (GenBank accession no. AF087875) were compared with the genomic sequence obtained from two bacterial artificial chromosome clones in public domain DNA databases (accession nos AC006358 and AC006966) to obtain additional intronic sequences. Intronic oligonucleotide primers were designed for the amplification of each of the 12 exons and flanking splice-sites of PRKAG2.
Identification of PRKAG2 mutations
Individual PRKAG2 exons amplified from genomic DNA of unrelated probands were screened for variants by heteroduplex analysis using a denaturing HPLC (DHPLC) apparatus. An abnormality on the DHPLC trace indicative of heteroduplex formation was identified in exon 5 from the proband of family WA. Direct sequencing of the PCR product, and later of the subcloned mutant allele, revealed the insertion of a TTA codon after the codon for arginine 109 (Fig. 1A). This mutation predicts the insertion of an additional leucine residue without disruption of the reading frame or of the splicing of exon 5 to exon 6 (the junction of which generates the normal codon for glutamate at residue 110); normal splicing was confirmed by RT–PCR. This mutation, which we denote Exon5:InsLeu, introduces a BsaXI restriction enzyme site. This restriction fragment length polymorphism was used to confirm the identity of the mutation, its cosegregation with disease in the affected members of the family and its absence from over 240 normal control chromosomes (Fig. 1A).
A heteroduplex abnormality was also identified in exon 7 from the proband of family HA. Direct sequencing of this PCR product revealed an A
G transition predicting a His142Arg missense mutation (Fig. 1B). This variant introduces an AciI restriction enzyme site, which was again used to confirm the identity of the mutation, its presence in each of the three affected individuals and its absence from over 240 normal chromosomes.
Additional support for the disease-causing role of these variants is provided by an analysis of evolutionary sequence conservation (Fig. 2). The leucine insertion is situated in a highly conserved region of the protein, between an invariant basic residue (arginine or lysine in all homologues including the yeast Snf4p protein) and an invariant acidic residue (glutamate in all AMPK isoforms; aspartate in Drosophila and yeast Snf4 proteins). Similarly, His142 is conserved as far back as Drosophila Snf4 and the disease-causing mutation replaces it with arginine, which has a more basic side chain. Strikingly, the His142Arg missense mutation affects a residue in the second cystathionine-ß-synthase (CBS) domain, which is in the same position as Arg200 in the first CBS motif of the AMPK 3, mutation of which has recently been shown to cause a skeletal myopathy with glycogen storage abnormalities in the pig (23) (Fig. 2). The position of these mutations in the AMPK 2 primary amino acid sequence is illustrated in Figure 3.
|
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
We believe that these data are sufficient to confirm the causal role of the mutations in the PRKAG2 gene in the two families. Each mutation results in a significant change within a conserved region of the protein sequence, cosegregates with disease with complete penetrance, and is absent from the control population. Further, the residue affected by the missense mutation occupies a position of demonstrated importance in the CBS domain structure of other proteins. Finally, while implication of a gene with a primary role in energy homeostasis as a cause of HCM is entirely novel, it does in fact fit with prior observations regarding the pathophysiology of this condition.
The cardiac phenotype is extremely similar in the two families and is notable in a number of ways. Firstly, the cardiomyopathy is severe, with early onset and poor prognosis, with symptomatic presentation in childhood in family HA and multiple sudden deaths in early adult life in family WA. Secondly, massive hypertrophy is present in some individuals (WA I:1 and WA II:1) and markedly increased wall thickness persists despite cavity dilation in others. Thirdly, there is an unusually marked propensity towards early dilatation of the ventricle; although this complication usually occurs in only a minority of individuals with HCM, the majority of adults in these families either died of heart failure or required cardiac transplantation at an early age. Fourthly, as was described in the family previously mapped to this locus on chromosome 7, pre-excitation indicated by short PR interval on the ECG and, in some instances, by symptomatic supra-ventricular tachycardias, is present in some individuals in both families (Fig. 4). Formal electrophysiological studies confirmed an accessory pathway in WA III:1, and the association of pre-excitation with conduction disease in individual WA III:2 is also highly characteristic of the WPW and HCM phenotype (24). Our data to date suggest that PRKAG2 mutations may be expected where HCM and WPW co-exist but may not be a frequent cause of HCM where no features of pre-excitation are found in affected individuals.
|
The dramatic phenotypic impact of these mutations confirms the importance of the AMP-activated kinase as the ‘cellular fuel gauge’ (17). The precise impact of these mutations on the structure and function of the AMPK
2 subunit, and the subsequent effect on the heterotrimer, will need further evaluation. Presumably the autosomal dominant phenotype reflects a dominant negative disruption of AMPK activity whereby mutant subunits are incorporated but then alter the activity and/or regulation of AMPK in the myocardium. Comparable dominant negative actions have been described for an engineered subunit mutant (25). Structurally, the subunits of AMPK consist primarily of four consecutive CBS domains (20). The Exon5:InsLeu mutation inserts an amino acid in the link between CBS1 and CBS2, and His142Arg alters a residue within CBS2 (Fig. 3). The latter mutation alters the same position within the CBS consensus motif (26) as the Arg200Gln missense mutation in the pig AMPK 3 CBS1 domain, which causes skeletal myopathy (23), and the Asp444Asn mutation in human CBS, which leads to homocystinuria (27). We conclude that this position has particular importance within the CBS motif and note that it lies towards the end of the ß2 sheet in the CBS domain of the inosine monophosphate dehydrogenase structure (28).
AMPK activity is suppressed in the absence of AMP due to an autoinhibitory region on the subunit blocking the catalytic site. As ATP is consumed the level of AMP is increased by the conversion of 2ADP
ATP + AMP by adenylate kinase, such that a climbing AMP/ATP ratio is an extremely sensitive signal of energy depletion in times of stress (17). AMP activates the enzyme by competing with the kinase domain for binding to the autoinhibitory region and stimulates further activation by an upstream kinase (AMPKK). In the model of Cheung et al. (29), AMP is bound via interactions with both the autoinhibitory region and the subunit. Thus, mutations in may act to weaken AMP binding and hence reduce activation of AMPK. Although this remains unproven, the disease-causing Arg200Gln mutation in the pig 3 subunit has been found to give decreased AMPK activity in skeletal muscle (23). Thus the mutations in families WA and HA may lead to a decreased AMP-activated level of kinase activity and hence a reduced responsiveness to ATP depletion.
In addition, mammalian AMPK subunits have a close homology with transcription factors involved in repression/derepression of genes encoding glucose-metabolizing enzymes in yeast (19) and localize to the cell nucleus as well as the cytoplasm (18). The subunit homologue in yeast is the Snf4p component of the SNF1 transcription factor complex. It is therefore likely that AMPK also has transcriptional roles in man that may similarly be perturbed by these mutations in the 2 subunit.
Perhaps the most important implication of these findings is that they offer substantial support to the hypothesis that inability to maintain adequate levels of ATP is the unifying abnormality in familial HCM and, indeed, related phenotypes. Just as ATP wastage through inefficient chemo-mechanical transduction in the sarcomere or ATP deficiency due to ß-oxidation or mitochondrial electron transport chain defects can leave the cardiomyocyte exposed to critical energy insufficiency, so, presumably, can failure of the AMPK system to initiate protective metabolic compensation during periods of excess demand. Once activated, AMPK inhibits enzymes in biosynthetic and ATP-consuming pathways (e.g. creatine kinase and HMGco-A reductase) and activates rate-limiting enzymes in glycolytic and fatty acid metabolism pathways to promote ATP production. We postulate that in this and other forms of HCM, periods of increased cardiac demand render the myocyte unable to maintain highly energy-dependent homeostatic pathways, particularly the SERCA2 calcium re-uptake pump (10), resulting in increased intracellular calcium leading to hypertrophy and vulnerability to arrhythmia. The marked progression to dilation (which is the end result of myocyte death) suggests that the energetic defect may be more severe with AMPK 2 mutations than other forms of HCM, such that cardiomyocytes are exposed to sufficiently disordered metabolism and calcium homeostasis as to initiate apoptosis, resulting ultimately in loss of contractile function and heart failure. The particular phenotype of pre-excitation suggests the presence of aberrant conduction pathways bypassing the atrio-ventricular node. This may perhaps be a consequence of disruption of AMPK’s role as a transcription factor regulating an as yet unknown gene. Alternatively, it is possible that deficiencies in energy homeostasis per se can cause pre-excitation, as the WPW syndrome has been described in a number of instances of mitochondrial mutation (30–32).
In conclusion, we believe that the identification of AMPK 2 mutations in HCM strongly supports the proposal that the unifying pathophysiology in this condition is energy compromise. Demonstration of the central role of abnormalities of ATP homeostasis suggests novel avenues for potential therapy, which would be equally applicable in all forms of HCM. For example, the requirement to protect the heart from excess energy demand lends support to the proposed protective effect of high-dose beta blockade in HCM (33). Equally, it may be possible to enhance energy production or to directly manipulate components of the AMPK system. In this regard, we believe that understanding the pathogenesis in those families in which HCM results from AMPK 2 mutations may be of wide relevance to all forms of the disease. Potentially of even greater importance is that progressive abnormalities in cardiac energetics are found in acquired forms of dilated cardiomyopathy and heart failure and have been shown to predict prognosis (34). Thus a more complete understanding of the protective mechanisms in the normal heart is an important goal and one which should be facilitated by further study of AMPK mutant alleles and their phenotypes.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Family members were ascertained through our clinical practice or the practice of referring physicians, and evaluated by physical examination, ECG and echocardiography, allowing the diagnosis of FHC to be made in those clinically affected. Blood or mouth wash samples were collected in each affected individual and other available members of the families and processed for genomic DNA preparation using standard protocols.
Mutation analysis
Oligonucleotides were designed from flanking intronic sequence for all exons of the PRKAG2 gene. Amplifications were performed with ‘touchdown’ PCR using high fidelity polymerases from 50 ng of genomic DNA using standard conditions. Annealing temperatures were optimized for each exon and touched down from 7.5°C above the final annealing temperature in 0.5°C decrements. Products of each PCR reaction were checked on 1.5% agarose gels. Mutation analysis was undertaken using temperature-modulated heteroduplex analysis (TMHA) on an automated HPLC instrument equipped with a DNASep column (Transgenomic). Mobile phase gradients and melting temperatures for TMHA of each amplimer were calculated using the Wavemaker software package. Crude PCR products were denatured at 95°C and gradually re-annealed before application to the TMHA apparatus. Exons with an abnormal TMHA profile were sequenced using an ABI377 (Applied Biosystems), following product purification by QIAquick PCR purification (Qiagen) or, in the case of family WA, subcloned prior to sequencing, and compared with published genomic sequence of the PRKAG2 gene (GenBank accession no. AF087875). Mutations were confirmed by restriction enzyme digestion of PCR-amplified exons prior to separation on an agarose gel.
|
ACKNOWLEDGEMENTS |
|---|
We thank the families for their participation in this study, Dr Graham Goode for providing clinical information, the Clinical Genetics Laboratory at the Churchill Hospital, Oxford and Katherine Lygate and Philip Townsend for help in manuscript preparation. This work was supported by the British Heart Foundation (programme grant RG/97008 and project grant PG/99196) and the Wellcome Trust.
|
FOOTNOTES |
|---|
+ These authors contributed equally to this work
To whom correspondence should be addressed at: Department of Cardiovascular Medicine, University of Oxford, Level 5, John Radcliffe Hospital, Oxford OX3 9DU, UK. Tel: +44 1865 220257; Fax: +44 1865 768844; Email: hugh.watkins@cardiov.ox.ac.uk
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
1 Maron, B.J., Gardin, J.M., Flack, J.M., Gidding, S.S., Kurosaki, T.T. and Bild, D.E. (1995) Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation, 92, 785–789.
2 Spirito, P., Seidman, C.E., McKenna, W.J. and Maron, B.J. (1997) The management of hypertrophic cardiomyopathy. N. Engl. J. Med., 336, 775–785.
3 Thierfelder, L., Watkins, H., MacRae, C., Lamas, R., McKenna, W., Vosberg, H.P., Seidman, J.G. and Seidman, C.E. (1994) -tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell, 77, 701–712.[Web of Science][Medline]
4 Bonne, G., Carrier, L., Richard, P., Hainque, B. and Schwartz, K. (1998) Familial hypertrophic cardiomyopathy: from mutations to functional defects. Circ. Res., 83, 580–593.
5 Redwood, C.S., Moolman-Smook, J.C. and Watkins, H. (1999) Properties of mutant contractile proteins that cause hypertrophic cardiomyopathy. Cardiovasc. Res., 44, 20–36.
6 Lankford, E.B., Epstein, N.D., Fananapazir, L. and Sweeney, H.L. (1995) Abnormal contractile properties of muscle fibers expressing ß-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy. J. Clin. Invest., 95, 1409–1414.
7 Bottinelli, R., Coviello, D.A., Redwood, C.S., Pellegrino, M.A., Maron, B.J., Spirito, P., Watkins, H. and Reggiani, C. (1998) A mutant tropomyosin that causes hypertrophic cardiomyopathy is expressed in vivo and associated with an increased calcium sensitivity. Circ. Res., 82, 106–115.
8 Elliott, K., Watkins, H. and Redwood, C.S. (2000) Altered regulatory properties of human cardiac troponin I mutants that cause hypertrophic cardiomyopathy. J. Biol. Chem., 275, 22069–22074.
9 Sweeney, H.L., Feng, H.S., Yang, Z. and Watkins, H. (1998) Functional analyses of troponin T mutations that cause hypertrophic cardiomyopathy: insights into disease pathogenesis and troponin function. Proc. Natl Acad. Sci. USA, 95, 14406–14410.
10 Spindler, M., Saupe, K.W., Christe, M.E., Sweeney, H.L., Seidman, C.E., Seidman, J.G. and Ingwall, J.S. (1998) Diastolic dysfunction and altered energetics in the MHC403/+ mouse model of familial hypertrophic cardiomyopathy. J. Clin. Invest., 101, 1775–1783.[Web of Science][Medline]
11 Puccio, H. and Koenig, M. (2000) Recent advances in the molecular pathogenesis of Friedreich ataxia. Hum. Mol. Genet., 9, 887–892.
12 Merante, F., Tein, I., Benson, L. and Robinson, B.H. (1994) Maternally inherited hypertrophic cardiomyopathy due to a novel T-to-C transition at nucleotide 9997 in the mitochondrial tRNA (glycine) gene. Am. J. Hum. Genet., 55, 437–446.[Web of Science][Medline]
13 Bonnet, D., Martin, D., De Lonlay, P., Villain, E., Jouvet, P., Rabier, D., Brivet, M. and Saudubray, J.M. (1999) Arrhythmias and conduction defects as presenting symptoms of fatty acid oxidation disorders in children. Circulation, 100, 2248–2253.
14 Kimura, A., Harada, H., Park, J.E., Nishi, H., Satoh, M., Takahashi, M., Hiroi, S., Sasaoka, T., Ohbuchi, N., Nakamura, T. et al. (1997) Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nat. Genet., 16, 379–382.[Web of Science][Medline]
15 Satoh, M., Takahashi, M., Sakamoto, T., Hiroe, M., Marumo, F. and Kimura, A. (1999) Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene. Biochem. Biophys. Res. Commun., 262, 411–417.[Web of Science][Medline]
16 Olson, T.M., Doan, T.P., Kishimoto, N.Y., Whitby, F.G., Ackerman, M.J. and Fananapazir, L. (2000) Inherited and de novo mutations in the cardiac actin gene cause hypertrophic cardiomyopathy. J. Mol. Cell. Cardiol., 32, 1687–1694.[Web of Science][Medline]
17 Hardie, D.G. and Carling, D. (1997) The AMP-activated protein kinase—fuel gauge of the mammalian cell? Eur. J. Biochem., 246, 259–273.[Web of Science][Medline]
18 Salt, I., Celler, J.W., Hawley, S.A., Prescott, A., Woods, A., Carling, D. and Hardie, D.G. (1998) AMP-activated protein kinase: greater AMP dependence, and preferential nuclear localization, of complexes containing the 2 isoform. Biochem. J., 334, 177–187.
19 Wilson, W.A., Hawley, S.A. and Hardie, D.G. (1996) Glucose repression/derepression in budding yeast: SNF1 protein kinase is activated by phosphorylation under derepressing conditions, and this correlates with a high AMP:ATP ratio. Curr. Biol., 6, 1426–1434.[Web of Science][Medline]
20 Kemp, B.E., Mitchelhill, K.I., Stapleton, D., Michell, B.J., Chen, Z.P. and Witters, L.A. (1999) Dealing with energy demand: the AMP-activated protein kinase. Trends Biochem. Sci., 24, 22–25.[Web of Science][Medline]
21 Lang, T., Yu, L., Tu, Q., Jiang, J., Chen, Z., Xin, Y., Liu, G. and Zhao, S. (2000) Molecular cloning, genomic organization, and mapping of PRKAG2, a heart abundant 2 subunit of 5'-AMP-activated protein kinase, to human chromosome 7q36. Genomics, 70, 258–263.[Web of Science][Medline]
22 MacRae, C.A., Ghaisas, N., Kass, S., Donnelly, S., Basson, C.T., Watkins, H.C., Anan, R., Thierfelder, L.H., McGarry, K., Rowland, E. et al. (1995) Familial hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome maps to a locus on chromosome 7q3. J. Clin. Invest., 96, 1216–1220.
23 Milan, D., Jeon, J.T., Looft, C., Amarger, V., Robic, A., Thelander, M., Rogel-Gaillard, C., Paul, S., Iannuccelli, N., Rask, L. et al. (2000) A mutation in PRKAG3 associated with excess glycogen content in pig skeletal muscle. Science, 288, 1248–1251.
24 Khair, G.Z., Soni, J.S. and Bamrah, V.S. (1985) Syncope in hypertrophic cardiomyopathy. II. Coexistence of atrioventricular block and Wolff-Parkinson-White syndrome. Am. Heart J., 110, 1083–1086.[Web of Science][Medline]
25 Woods, A., Azzout-Marniche, D., Foretz, M., Stein, S.C., Lemarchand, P., Ferre, P., Foufelle, F. and Carling, D. (2000) Characterization of the role of AMP-activated protein kinase in the regulation of glucose-activated gene expression using constitutively active and dominant negative forms of the kinase. Mol. Cell. Biol., 20, 6704–6711.
26 Bateman, A. (1997) The structure of a domain common to archaebacteria and the homocystinuria disease protein. Trends Biochem. Sci., 22, 12–13.[Web of Science][Medline]
27 Kluijtmans, L.A., Boers, G.H., Stevens, E.M., Renier, W.O., Kraus, J.P., Trijbels, F.J., van den Heuvel, L.P. and Blom, H.J. (1996) Defective cystathionine ß-synthase regulation by S-adenosylmethionine in a partially pyridoxine responsive homocystinuria patient. J. Clin. Invest., 98, 285–289.[Web of Science][Medline]
28 Colby, T.D., Vanderveen, K., Strickler, M.D., Markham, G.D. and Goldstein, B.M. (1999) Crystal structure of human type II inosine monophosphate dehydrogenase: implications for ligand binding and drug design. Proc. Natl Acad. Sci. USA, 96, 3531–3536.
29 Cheung, P.C., Salt, I.P., Davies, S.P., Hardie, D.G. and Carling, D. (2000) Characterization of AMP-activated protein kinase -subunit isoforms and their role in AMP binding. Biochem. J., 346, 659–669.
30 Aggarwal, P., Gill-Randall, R., Wheatley, T., Buchalter, M.B., Metcalfe, J. and Alcolado, J.C. (2001) Identification of mtDNA mutation in a pedigree with gestational diabetes, deafness, Wolff-Parkinson-White syndrome and placenta accreta. Hum. Hered., 51, 114–116.[Web of Science][Medline]
31 Yamagata, K., Tomida, C., Umeyama, K., Urakami, K., Ishizu, T., Hirayama, K., Gotoh, M., Iitsuka, T., Takemura, K., Kikuchi, H. et al. (2000) Prevalence of Japanese dialysis patients with an A-to-G mutation at nucleotide 3243 of the mitochondrial tRNA(Leu(UUR)) gene. Nephrol. Dial. Transplant., 15, 385–388.
32 Mourmans, J., Wendel, U., Bentlage, H.A., Trijbels, J.M., Smeitink, J.A., de Coo, I.F., Gabreels, F.J., Sengers, R.C. and Ruitenbeek, W. (1997) Clinical heterogeneity in respiratory chain complex III deficiency in childhood. J. Neurol. Sci., 149, 111–117.[Web of Science][Medline]
33 Ostman-Smith, I., Wettrell, G. and Riesenfeld, T. (1999) A cohort study of childhood hypertrophic cardiomyopathy: improved survival following high-dose ß-adrenoceptor antagonist treatment. J. Am. Coll. Cardiol., 34, 1813–1822.
34 Neubauer, S., Horn, M., Cramer, M., Harre, K., Newell, J.B., Peters, W., Pabst, T., Ertl, G., Hahn, D., Ingwall, J.S. et al. (1997) Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation, 96, 2190–2196.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  I. Ostman-Smith, A. Wisten, E. Nylander, E.-L. Bratt, A. de-Wahl Granelli, A. Oulhaj, and E. Ljungstrom Electrocardiographic amplitudes: a new risk factor for sudden death in hypertrophic cardiomyopathy Eur. Heart J., November 5, 2009; (2009) ehp443v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Bos, J. A. Towbin, and M. J. Ackerman Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. J. Am. Coll. Cardiol., July 14, 2009; 54(3): 201 - 211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Mounier, L. Lantier, J. Leclerc, A. Sotiropoulos, M. Pende, D. Daegelen, K. Sakamoto, M. Foretz, and B. Viollet Important role for AMPK{alpha}1 in limiting skeletal muscle cell hypertrophy FASEB J, July 1, 2009; 23(7): 2264 - 2273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kelly and C. Semsarian Multiple Mutations in Genetic Cardiovascular Disease: A Marker of Disease Severity? Circ Cardiovasc Genet, April 1, 2009; 2(2): 182 - 190. [Full Text] [PDF]
|
|
|
|
 |
|
 S R Lalani, J V Thakuria, G F Cox, X Wang, W Bi, M S Bray, C Shaw, S W Cheung, A C Chinault, B A Boggs, et al. 20p12.3 microdeletion predisposes to Wolff-Parkinson-White syndrome with variable neurocognitive deficits J. Med. Genet., March 1, 2009; 46(3): 168 - 175. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G S Soor, A Luk, E Ahn, J R Abraham, A Woo, A Ralph-Edwards, and J Butany Hypertrophic cardiomyopathy: current understanding and treatment objectives J. Clin. Pathol., March 1, 2009; 62(3): 226 - 235. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Cambronero, F. Marin, V. Roldan, D. Hernandez-Romero, M. Valdes, and G. Y.H. Lip Biomarkers of pathophysiology in hypertrophic cardiomyopathy: implications for clinical management and prognosis Eur. Heart J., January 9, 2009; (2009) ehn538v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. M. Hess, W. McKenna, and H.-P. Schultheiss CHAPTER 18 Myocardial Disease ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Shinzato, M. Enoki, H. Sato, K. Nakamura, T. Matsui, and Y. Kamagata Specific DNA Binding of a Potential Transcriptional Regulator, Inosine 5'-Monophosphate Dehydrogenase-Related Protein VII, to the Promoter Region of a Methyl Coenzyme M Reductase I-Encoding Operon Retrieved from Methanothermobacter thermautotrophicus Strain {Delta}H Appl. Envir. Microbiol., October 15, 2008; 74(20): 6239 - 6247. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rosner and M. Hengstschlager Cytoplasmic and nuclear distribution of the protein complexes mTORC1 and mTORC2: rapamycin triggers dephosphorylation and delocalization of the mTORC2 components rictor and sin1 Hum. Mol. Genet., October 1, 2008; 17(19): 2934 - 2948. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H Watkins, H Ashrafian, and W J McKenna The genetics of hypertrophic cardiomyopathy: Teare redux Heart, October 1, 2008; 94(10): 1264 - 1268. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Momcilovic, S. H. Iram, Y. Liu, and M. Carlson Roles of the Glycogen-binding Domain and Snf4 in Glucose Inhibition of SNF1 Protein Kinase J. Biol. Chem., July 11, 2008; 283(28): 19521 - 19529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Olivotto, F. Girolami, M. J. Ackerman, S. Nistri, J. M. Bos, E. Zachara, S. R. Ommen, J. L. Theis, R. A. Vaubel, F. Re, et al. Myofilament Protein Gene Mutation Screening and Outcome of Patients With Hypertrophic Cardiomyopathy Mayo Clin. Proc., June 1, 2008; 83(6): 630 - 638. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Deshmukh, J. T. Treebak, Y. C. Long, B. Viollet, J. F. P. Wojtaszewski, and J. R. Zierath Role of Adenosine 5'-Monophosphate-Activated Protein Kinase Subunits in Skeletal Muscle Mammalian Target of Rapamycin Signaling Mol. Endocrinol., May 1, 2008; 22(5): 1105 - 1112. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Wolf, M. Arad, F. Ahmad, A. Sanbe, S. A. Bernstein, O. Toka, T. Konno, G. Morley, J. Robbins, J.G. Seidman, et al. Reversibility of PRKAG2 Glycogen-Storage Cardiomyopathy and Electrophysiological Manifestations Circulation, January 15, 2008; 117(2): 144 - 154. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. D. Folmes, L. A. Witters, M. F. Allard, M. E. Young, and J. R. B. Dyck The AMPK {gamma}1 R70Q mutant regulates multiple metabolic and growth pathways in neonatal cardiac myocytes Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3456 - H3464. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Charron, M. Genest, P. Richard, M. Komajda, and G. Pochmalicki A familial form of conduction defect related to a mutation in the PRKAG2 gene Europace, August 1, 2007; 9(8): 597 - 600. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Viana, M. C. Towler, D. A. Pan, D. Carling, B. Viollet, D. G. Hardie, and P. Sanz A Conserved Sequence Immediately N-terminal to the Bateman Domains in AMP-activated Protein Kinase {gamma} Subunits Is Required for the Interaction with the beta Subunits J. Biol. Chem., June 1, 2007; 282(22): 16117 - 16125. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Mulligan, A. A. Gonzalez, A. M. Stewart, H. V. Carey, and K. W. Saupe Upregulation of AMPK during cold exposure occurs via distinct mechanisms in brown and white adipose tissue of the mouse J. Physiol., April 15, 2007; 580(2): 677 - 684. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ashrafian and H. Watkins Reviews of Translational Medicine and Genomics in Cardiovascular Disease: New Disease Taxonomy and Therapeutic Implications: Cardiomyopathies: Therapeutics Based on Molecular Phenotype J. Am. Coll. Cardiol., March 27, 2007; 49(12): 1251 - 1264. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Townley and L. Shapiro Crystal Structures of the Adenylate Sensor from Fission Yeast AMP-Activated Protein Kinase Science, March 23, 2007; 315(5819): 1726 - 1729. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Arad, C. E. Seidman, and J.G. Seidman AMP-Activated Protein Kinase in the Heart: Role During Health and Disease Circ. Res., March 2, 2007; 100(4): 474 - 488. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-J. Lee, D. Feliers, M. M. Mariappan, K. Sataranatarajan, L. Mahimainathan, N. Musi, M. Foretz, B. Viollet, J. M. Weinberg, G. G. Choudhury, et al. A role for AMP-activated protein kinase in diabetes-induced renal hypertrophy Am J Physiol Renal Physiol, February 1, 2007; 292(2): F617 - F627. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N J Spencer-Jones, D Ge, H Snieder, U Perks, R Swaminathan, T D Spector, N D Carter, and S D O'Dell AMP-kinase {alpha}2 subunit gene PRKAA2 variants are associated with total cholesterol, low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol in normal women J. Med. Genet., December 1, 2006; 43(12): 936 - 942. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. W. Dolinsky and J. R. B. Dyck Role of AMP-activated protein kinase in healthy and diseased hearts Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2557 - H2569. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Bayrak, E. Komurcu-Bayrak, B. Mutlu, G. Kahveci, Y. Basaran, and N. Erginel-Unaltuna Ventricular pre-excitation and cardiac hypertrophy mimicking hypertrophic cardiomyopathy in a Turkish family with a novel PRKAG2 mutation Eur J Heart Fail, November 1, 2006; 8(7): 712 - 715. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Richard, E. Villard, P. Charron, and R. Isnard The Genetic Bases of Cardiomyopathies J. Am. Coll. Cardiol., October 27, 2006; 48(9_Suppl_A): A79 - A89. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Li, D. L. Coven, E. J. Miller, X. Hu, M. E. Young, D. Carling, A. J. Sinusas, and L. H. Young Activation of AMPK {alpha}- and {gamma}-isoform complexes in the intact ischemic rat heart Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1927 - H1934. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Yu, M. F. Hirshman, N. Fujii, J. M. Pomerleau, L. E. Peter, and L. J. Goodyear Muscle-specific overexpression of wild type and R225Q mutant AMP-activated protein kinase {gamma}3-subunit differentially regulates glycogen accumulation Am J Physiol Endocrinol Metab, September 1, 2006; 291(3): E557 - E565. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. B. Dyck and G. D. Lopaschuk AMPK alterations in cardiac physiology and pathology: enemy or ally? J. Physiol., July 1, 2006; 574(1): 95 - 112. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Y. Ho and C. E. Seidman A Contemporary Approach to Hypertrophic Cardiomyopathy Circulation, June 20, 2006; 113(24): e858 - e862. [Full Text] [PDF]
|
|
|
|
|
|
L. Song, S. R. DePalma, M. Kharlap, A. G. Zenovich, A. Cirino, R. Mitchell, B. McDonough, B. J. Maron, C. E. Seidman, J.G. Seidman, et al. Novel Locus for an Inherited Cardiomyopathy Maps to Chromosome 7 Circulation, May 9, 2006; 113(18): 2186 - 2192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Davies, D. J. Wells, K. Liu, H. R. Whitrow, T. D. Daniel, R. Grignani, C. A. Lygate, J. E. Schneider, G. Noel, H. Watkins, et al. Characterization of the role of {gamma}2 R531G mutation in AMP-activated protein kinase in cardiac hypertrophy and Wolff-Parkinson-White syndrome Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1942 - H1951. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Hattori, K. Akimoto, T. Nishikimi, H. Matsuoka, and K. Kasai Activation of AMP-Activated Protein Kinase Enhances Angiotensin II-Induced Proliferation in Cardiac Fibroblasts Hypertension, February 1, 2006; 47(2): 265 - 270. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ignoul and J. Eggermont CBS domains: structure, function, and pathology in human proteins Am J Physiol Cell Physiol, December 1, 2005; 289(6): C1369 - C1378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Ahmad, M. Arad, N. Musi, H. He, C. Wolf, D. Branco, A. R. Perez-Atayde, D. Stapleton, D. Bali, Y. Xing, et al. Increased {alpha}2 Subunit-Associated AMPK Activity and PRKAG2 Cardiomyopathy Circulation, November 15, 2005; 112(20): 3140 - 3148. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Chandra, M. L. Tschirgi, and J. C. Tardiff Increase in tension-dependent ATP consumption induced by cardiac troponin T mutation Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2112 - H2119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Yang, C. J. McMahon, L. R. Smith, J. Bersola, A. M. Adesina, J. P. Breinholt, D. L. Kearney, W. J. Dreyer, S. W. Denfield, J. F. Price, et al. Danon Disease as an Underrecognized Cause of Hypertrophic Cardiomyopathy in Children Circulation, September 13, 2005; 112(11): 1612 - 1617. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Zou, M. Shen, M. Arad, H. He, B. Lofgren, J. S. Ingwall, C. E. Seidman, J. G. Seidman, and R. Tian N488I Mutation of the {gamma}2-Subunit Results in Bidirectional Changes in AMP-Activated Protein Kinase Activity Circ. Res., August 19, 2005; 97(4): 323 - 328. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kaab and E. Schulze-Bahr Susceptibility genes and modifiers for cardiac arrhythmias Cardiovasc Res, August 15, 2005; 67(3): 397 - 413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-P. Hong, M. Momcilovic, and M. Carlson Function of Mammalian LKB1 and Ca2+/Calmodulin-dependent Protein Kinase Kinase {alpha} as Snf1-activating Kinases in Yeast J. Biol. Chem., June 10, 2005; 280(23): 21804 - 21809. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. T. Murphy, J. Mogensen, K. McGarry, A. Bahl, A. Evans, E. Osman, P. Syrris, G. Gorman, M. Farrell, J. L. Holton, et al. Adenosine monophosphate-activated protein kinase disease mimicks hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome: Natural history J. Am. Coll. Cardiol., March 15, 2005; 45(6): 922 - 930. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Thomson and S. E. Gordon Diminished overload-induced hypertrophy in aged fast-twitch skeletal muscle is associated with AMPK hyperphosphorylation J Appl Physiol, February 1, 2005; 98(2): 557 - 564. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Arad, B. J. Maron, J. M. Gorham, W. H. Johnson Jr., J. P. Saul, A. R. Perez-Atayde, P. Spirito, G. B. Wright, R. J. Kanter, C. E. Seidman, et al. Glycogen Storage Diseases Presenting as Hypertrophic Cardiomyopathy N. Engl. J. Med., January 27, 2005; 352(4): 362 - 372. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Sidhu, Y. S. Rajawat, T. G. Rami, M. H. Gollob, Z. Wang, R. Yuan, A.J. Marian, F. J. DeMayo, D. Weilbacher, G. E. Taffet, et al. Transgenic Mouse Model of Ventricular Preexcitation and Atrioventricular Reentrant Tachycardia Induced by an AMP-Activated Protein Kinase Loss-of-Function Mutation Responsible for Wolff-Parkinson-White Syndrome Circulation, January 4, 2005; 111(1): 21 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. Maron, J.G. Seidman, and C. E. Seidman Proposal for contemporary screening strategies in families with hypertrophic cardiomyopathy J. Am. Coll. Cardiol., December 7, 2004; 44(11): 2125 - 2132. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Scheuer Fueling the Hypertrophied Heart Hypertension, November 1, 2004; 44(5): 623 - 624. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Wernicke, C. Thiel, C. M. Duja-Isac, K. V. Essin, M. Spindler, D. J. R. Nunez, R. Plehm, N. Wessel, A. Hammes, R.-J. Edwards, et al. {alpha}-Tropomyosin mutations Asp175Asn and Glu180Gly affect cardiac function in transgenic rats in different ways Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2004; 287(3): R685 - R695. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Y. M. Chan, C.-L. M. Soltys, M. E. Young, C. G. Proud, and J. R. B. Dyck Activation of AMP-activated Protein Kinase Inhibits Protein Synthesis Associated with Hypertrophy in the Cardiac Myocyte J. Biol. Chem., July 30, 2004; 279(31): 32771 - 32779. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Estevez, M. Pusch, C. Ferrer-Costa, M. Orozco, and T. J. Jentsch Functional and structural conservation of CBS domains from CLC chloride channels J. Physiol., June 1, 2004; 557(2): 363 - 378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Force, K. Kuida, M. Namchuk, K. Parang, and J. M. Kyriakis Inhibitors of Protein Kinase Signaling Pathways: Emerging Therapies for Cardiovascular Disease Circulation, March 16, 2004; 109(10): 1196 - 1205. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Yu, N. Fujii, M. F. Hirshman, J. M. Pomerleau, and L. J. Goodyear Cloning and characterization of mouse 5'-AMP-activated protein kinase {gamma}3 subunit Am J Physiol Cell Physiol, February 1, 2004; 286(2): C283 - C292. [Abstract] [Full Text]
|
|
|
|
|
|
M. Mahlapuu, C. Johansson, K. Lindgren, G. Hjalm, B. R. Barnes, A. Krook, J. R. Zierath, L. Andersson, and S. Marklund Expression profiling of the {gamma}-subunit isoforms of AMP-activated protein kinase suggests a major role for {gamma}3 in white skeletal muscle Am J Physiol Endocrinol Metab, February 1, 2004; 286(2): E194 - E200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J Mogensen, A Perrot, P S Andersen, O Havndrup, I C Klausen, M Christiansen, P Bross, H Egeblad, H Bundgaard, K J Osterziel, et al. Clinical and genetic characteristics of {alpha} cardiac actin gene mutations in hypertrophic cardiomyopathy J. Med. Genet., January 1, 2004; 41(1): e10 - 10. [Full Text] [PDF]
|
|
|
|
|
|
B. J. Maron, W. J. McKenna, G. K. Danielson, L. J. Kappenberger, H. J. Kuhn, C. E. Seidman, P. M. Shah, W. H. Spencer III, P. Spirito, F. J. Ten Cate, et al. American College of Cardiology/European Society of Cardiology Clinical Expert Consensus Document on Hypertrophic Cardiomyopathy: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines J. Am. Coll. Cardiol., November 5, 2003; 42(9): 1687 - 1713. [Full Text] [PDF]
|
|
|
|
|
|
Writing Committee Members, B. J. Maron, W. J. McKenna, G. K. Danielson, L. J. Kappenberger, H. J. Kuhn, C. E. Seidman, P. M. Shah, W. H. Spencer III, P. Spirito, et al. American College of Cardiology/European Society of Cardiology Clinical Expert Consensus Document on Hypertrophic Cardiomyopathy: A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines Eur. Heart J., November 1, 2003; 24(21): 1965 - 1991. [Full Text] [PDF]
|
|
|
|
|
|
W. Yin, J. Mu, and M. J. Birnbaum Role of AMP-activated Protein Kinase in Cyclic AMP-dependent Lipolysis In 3T3-L1 Adipocytes J. Biol. Chem., October 31, 2003; 278(44): 43074 - 43080. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Arad, I. P. Moskowitz, V. V. Patel, F. Ahmad, A. R. Perez-Atayde, D. B. Sawyer, M. Walter, G. H. Li, P. G. Burgon, C. T. Maguire, et al. Transgenic Mice Overexpressing Mutant PRKAG2 Define the Cause of Wolff-Parkinson-White Syndrome in Glycogen Storage Cardiomyopathy Circulation, June 10, 2003; 107(22): 2850 - 2856. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G. Crilley, E. A. Boehm, E. Blair, B. Rajagopalan, A. M. Blamire, P. Styles, W. J. McKenna, I. Ostman-Smith, K. Clarke, and H. Watkins Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy J. Am. Coll. Cardiol., May 21, 2003; 41(10): 1776 - 1782. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Roberts and A. J. Marian Can an energy-deficient heart grow bigger and stronger? J. Am. Coll. Cardiol., May 21, 2003; 41(10): 1783 - 1785. [Full Text] [PDF]
|
|
|
|
|
|
P. Richard, P. Charron, L. Carrier, C. Ledeuil, T. Cheav, C. Pichereau, A. Benaiche, R. Isnard, O. Dubourg, M. Burban, et al. Hypertrophic Cardiomyopathy: Distribution of Disease Genes, Spectrum of Mutations, and Implications for a Molecular Diagnosis Strategy Circulation, May 6, 2003; 107(17): 2227 - 2232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J Mogensen, A Bahl, T Kubo, N Elanko, R Taylor, and W J McKenna Comparison of fluorescent SSCP and denaturing HPLC analysis with direct sequencing for mutation screening in hypertrophic cardiomyopathy J. Med. Genet., May 1, 2003; 40(5): e59 - 59. [Full Text] [PDF]
|
|
|
|
|
|
K. R. Hallows, G. P. Kobinger, J. M. Wilson, L. A. Witters, and J. K. Foskett Physiological modulation of CFTR activity by AMP-activated protein kinase in polarized T84 cells Am J Physiol Cell Physiol, May 1, 2003; 284(5): C1297 - C1308. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Miller, J. Maycock, E. White, M. Peckham, and S. Calaghan Heterologous expression of wild-type and mutant {beta}-cardiac myosin changes the contractile kinetics of cultured mouse myotubes J. Physiol., April 1, 2003; 548(1): 167 - 174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Jongbloed, C. L. Marcelis, P. A. Doevendans, J. M. Schmeitz-Mulkens, W. G. Van Dockum, J. P. Geraedts, and H. J. Smeets Variable clinical manifestation of a novel missense mutation in the alpha-tropomyosin (TPM1) gene in familial hypertrophic cardiomyopathy J. Am. Coll. Cardiol., March 19, 2003; 41(6): 981 - 986. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Watkins Genetic Clues to Disease Pathways in Hypertrophic and Dilated Cardiomyopathies Circulation, March 18, 2003; 107(10): 1344 - 1346. [Full Text] [PDF]
|
|
|
|
|
|
J. Mogensen, A. Bahl, and W. J McKenna Hypertrophic cardiomyopathy--the clinical challenge of managing a hereditary heart condition Eur. Heart J., March 2, 2003; 24(6): 496 - 498. [Full Text] [PDF]
|
|
|
|
|
|
K. R. Hallows, J. E. McCane, B. E. Kemp, L. A. Witters, and J. K. Foskett Regulation of Channel Gating by AMP-activated Protein Kinase Modulates Cystic Fibrosis Transmembrane Conductance Regulator Activity in Lung Submucosal Cells J. Biol. Chem., January 3, 2003; 278(2): 998 - 1004. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Daniel and D. Carling Functional Analysis of Mutations in the gamma 2 Subunit of AMP-activated Protein Kinase Associated with Cardiac Hypertrophy and Wolff-Parkinson-White Syndrome J. Biol. Chem., December 20, 2002; 277(52): 51017 - 51024. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Seidman Genetic Causes of Inherited Cardiac Hypertrophy: Robert L. Frye Lecture Mayo Clin. Proc., December 1, 2002; 77(12): 1315 - 1319. [Abstract] [PDF]
|
|
|
|
|
|
P. Robinson, M. Mirza, A. Knott, H. Abdulrazzak, R. Willott, S. Marston, H. Watkins, and C. Redwood Alterations in Thin Filament Regulation Induced by a Human Cardiac Troponin T Mutant That Causes Dilated Cardiomyopathy Are Distinct from Those Induced by Troponin T Mutants That Cause Hypertrophic Cardiomyopathy J. Biol. Chem., October 18, 2002; 277(43): 40710 - 40716. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Veinot, P.M. Elliott, B. Sachdev, W.J. McKenna, T. Takenaka, H. Teraguchi, C. Tei, and P. Lee Prevalence of Anderson-Fabry Disease in Male Patients With Late Onset Hypertrophic Cardiomyopathy * Response Circulation, October 8, 2002; 106 (15): e73 - e73. [Full Text] [PDF]
|
|
|
|
|
|
M. Arad, J.G. Seidman, and C. E. Seidman Phenotypic diversity in hypertrophic cardiomyopathy Hum. Mol. Genet., October 1, 2002; 11(20): 2499 - 2506. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Fatkin and R. M. Graham Molecular Mechanisms of Inherited Cardiomyopathies Physiol Rev, October 1, 2002; 82(4): 945 - 980. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. P. Kelly Peroxisome Proliferator-Activated Receptor {alpha} as a Genetic Determinant of Cardiac Hypertrophic Growth: Culprit or Innocent Bystander? Circulation, March 5, 2002; 105(9): 1025 - 1027. [Full Text] [PDF]
|
|
|
|
|
|
E. Blair, C. Redwood, M. de Jesus Oliveira, J.C. Moolman-Smook, P. Brink, V.A. Corfield, I. Ostman-Smith, and H. Watkins Mutations of the Light Meromyosin Domain of the {beta}-Myosin Heavy Chain Rod in Hypertrophic Cardiomyopathy Circ. Res., February 22, 2002; 90(3): 263 - 269. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H. Gollob, J. J. Seger, T. N. Gollob, T. Tapscott, O. Gonzales, L. Bachinski, and R. Roberts Novel PRKAG2 Mutation Responsible for the Genetic Syndrome of Ventricular Preexcitation and Conduction System Disease With Childhood Onset and Absence of Cardiac Hypertrophy Circulation, December 18, 2001; 104(25): 3030 - 3033. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ashrafian, H. Watkins, S. F. Nagueh, L. L. Bachinski, D. Meyer, R. Hill, W. A. Zoghbi, J. W. Tam, M. A. Quinones, R. Roberts, et al. Myocardial Dysfunction in Hypertrophic Cardiomyopathy Response Circulation, December 18, 2001; 104 (25): e165 - e165. [Full Text] [PDF]
|
|
|
|
|
|
P. P. Dzeja, E. L. Holmuhamedov, C. Ozcan, D. Pucar, A. Jahangir, and A. Terzic Mitochondria: Gateway for Cytoprotection Circ. Res., October 26, 2001; 89(9): 744 - 746. [Full Text] [PDF]
|
|
|
|
 |
|
 H. Watkins Hypertrophic cardiomyopathy: from molecular and genetic mechanisms to clinical management Eur. Heart J. Suppl., October 1, 2001; 3(suppl_L): L43 - L50. [Abstract] [PDF]
|
|
|
|
|
|
E. Blair, C. Redwood, M. de Jesus Oliveira, J.C. Moolman-Smook, P. Brink, V.A. Corfield, I. Ostman-Smith, and H. Watkins Mutations of the Light Meromyosin Domain of the {beta}-Myosin Heavy Chain Rod in Hypertrophic Cardiomyopathy Circ. Res., February 22, 2002; 90(3): 263 - 269. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||