Identification of a Gene Responsible for Familial Wolff–Parkinson–White Syndrome
Michael H. Gollob, M.D., Martin S. Green, M.D., Anthony S.-L. Tang, M.D., Tanya Gollob, R.N., Akihiko Karibe, M.D., Al-Sayegh Hassan, M.D., Ferhaan Ahmad, M.D., Ryan Lozado, B.S., Gopi Shah, M.D., Lameh Fananapazir, M.D., Linda L. Bachinski, Ph.D., Terry Tapscott, B.S., Oscar Gonzales, B.S., David Begley, M.D., Saidi Mohiddin, M.D., and Robert Roberts, M.D.
Background The Wolff–Parkinson–White syndrome, witha prevalence in Western countries of 1.5 to 3.1 per 1000 persons,causes considerable morbidity and may cause sudden death. Weidentified two families in which the Wolff–Parkinson–Whitesyndrome segregated as an autosomal dominant disorder.
Methods We studied 70 members of the two families (57 in Family1 and 13 in Family 2). The subjects underwent 12-lead electrocardiographyand two-dimensional echocardiography. Genotyping mapped thegene responsible to 7q34–q36, a locus previously identifiedto be responsible for an inherited form of Wolff–Parkinson–Whitesyndrome. Candidate genes were identified, sequenced, and analyzedin normal and affected family members to identify the disease-causinggene.
Results A total of 31 members (23 from Family 1 and 8 from Family2) had the Wolff–Parkinson–White syndrome. Affectedmembers of both families had ventricular preexcitation withconduction abnormalities and cardiac hypertrophy. The maximalcombined two-point lod score was 9.82 at a distance of 5 cMfrom marker D7S636, which confirmed the linkage of the genein both families to 7q34–q36. Haplotype analysis indicatedthat there were no alleles in common in the two families atthis locus, suggesting that the two families do not have a commonfounder. We identified a missense mutation in the gene thatencodes the 2 regulatory subunit of AMP-activated protein kinase(PRKAG2). The mutation results in the substitution of glutaminefor arginine at residue 302 in the protein.
Conclusions The identification of this genetic defect has importantimplications for elucidating the pathogenesis of ventricularpreexcitation. Further understanding of how this molecular defectleads to supraventricular arrhythmias could influence the developmentof specific therapies for other forms of supraventricular arrhythmia.
The Wolff–Parkinson–White syndrome is the secondmost common cause of paroxysmal supraventricular tachycardiain most parts of the world and is the most common cause in China,being responsible for more than 70 percent of cases.1 In Westerncountries, the prevalence of the Wolff–Parkinson–Whitesyndrome is 1.5 to 3.1 per 1000 persons.2,3,4 Tachycardias associatedwith the syndrome are usually paroxysmal and may produce symptomsof presyncope, syncope, and shortness of breath and cause suddendeath. Conduction through an accessory pathway and the associationof the Wolff–Parkinson–White syndrome with supraventriculartachycardia have led to the creation of an in vivo reentry modelfor arrhythmias.5 Research on the Wolff–Parkinson–Whitesyndrome has appropriately focused on the atrioventricular pathways,which led to ablation as an effective therapy.6 We evaluatedtwo families with familial Wolff–Parkinson–Whitesyndrome in which the probands presented with syncope and theelectrocardiographic features of the syndrome. A clinical evaluationof members of both families was followed by linkage analysisto identify the chromosomal location of the causative gene.
Methods
Clinical Evaluation
Written informed consent was obtained from all participantsaccording to the guidelines of Baylor College of Medicine; theNational Heart, Lung, and Blood Institute of the National Institutesof Health; and the University of Ottawa Heart Institute. Subjectswere evaluated by means of a detailed analysis of their medicalhistory, a physical examination, 12-lead electrocardiography,and two-dimensional echocardiography. A total of 57 membersof Family 1 and 13 members of Family 2 were examined. Two subjectsin Family 1 and six subjects in Family 2 underwent invasiveelectrophysiologic study.
Ventricular preexcitation was diagnosed on the basis of thepresence of a short PR interval (<120 msec) with a widenedQRS complex (>110 msec) or an abnormal initial QRS vector(a delta wave). In the case of subjects who had a pacemaker,base-line 12-lead electrocardiograms were obtained from theirmedical records, when possible. Sinoatrial abnormalities andconduction disease were diagnosed if chronotropic incompetenceor high-grade sinoatrial or atrioventricular block was presenton the electrocardiogram. Left ventricular hypertrophy was diagnosedif the thickness of the septal wall or the left ventricularfree wall was at least 13 mm.
Chromosomal Mapping and Identification of Candidate Genes
Peripheral blood was obtained from each family member we evaluated.DNA was extracted from white cells, and lymphocytes were isolatedfor the development of transformed cell lines.7 Genotyping wascarried out with short tandem-repeat polymorphisms from the7q34–q36 region. We examined a total of 12 markers fromthe Genethon linkage map, and 2 additional polymorphic repeatswere identified from the published sequence of P1-derived artificialchromosomes in the region. An autosomal dominant pattern ofinheritance was assumed, and penetrance was estimated to be99 percent on the basis of the observed pattern of inheritance.The frequencies of the disease allele and the normal allelewere assumed to be 0.0001 and 0.9999, respectively. The allelefrequencies in the case of markers were calculated to be 1/n,where n is the number of alleles observed in the two pedigrees.Two-point linkage analysis was performed with version 5.2 ofthe linkage program.8 Once the disease-causing locus was identified,we used a candidate-gene approach to identify the responsiblegene.
We identified sequences of P1-derived artificial chromosomesfrom the Human Genome Project by searching draft sequences containingGenethon markers mapped to the region. We identified two additionalinformative polymorphic markers from these sequences to narrowthe critical region. We then entered each sequence into theNational Center for Biotechnology Information BLAST search program(http://www.ncbi.nlm.nih.gov/BLAST/) to identify candidate genes,one of which was the gene that encodes the 2 subunit of AMP-activatedprotein kinase (PRKAG2).
Identification of the Mutation in the PRKAG2 Gene
Exon–intron boundaries for protein-encoding sequencesof PRKAG2 (GenBank accession number, AJ249976) complementaryDNA (cDNA) were identified in the GenBank data base with useof the BLAST search program within the following P1-derivedartificial chromosome clones: RP11-79612 (cDNA bp 1 to 205;GenBank accession number, AC074257), RP5-1127D14 (bp 557 to843; GenBank accession number, AC006358), and RP4-563H24 (bp844 to 1800; GenBank accession number, AC006966). Intronic primerswere derived on the basis of these sequences. Primer sequencesare available with the electronic version of the article (Appendix )and at http://www.bcmcardiofellows.org. Fragments of genomicDNA were amplified by the polymerase chain reaction (PCR), andthe products were purified with use of the QIAquik PCR purificationkit (Qiagen, Valencia, Calif.). In the case of protein-encodingsequences (bp 206 to 556) that were not identified in the GenBankdata base, RNA was isolated from lymphoblastoid cells with arandom primer and reverse-transcribed with use of the Prostarsystem (Stratagene, Cedar Creek, Tex.). Direct sequencing reactionswere performed in both the sense and antisense directions onan automated sequencer (Prism 377, Perkin–Elmer AppliedBiosystems, Foster City, Calif.) with use of a technique involvingdye-labeled terminators.9
Appendix. Primer Sequences Used for the Amplification and Sequencing of PRKAG2.
Results
Clinical Evaluation
Analysis of Families 1 and 2 (Figure 1) showed that the modeof transmission of the Wolff–Parkinson–White syndromewas consistent with an autosomal dominant pattern of inheritance.Transmission occurred with high penetrance but with a variabledegree of expression. Initial clinical presentations includedreports of palpitations, presyncope, and syncope. The onsetof clinical symptoms typically occurred in late adolescenceor the third decade of life. All 24 subjects (16 from Family1 and 8 from Family 2) for whom base-line 12-lead electrocardiogramswere available had evidence of ventricular preexcitation. Paroxysmalatrial fibrillation or flutter occurred in association withthe Wolff–Parkinson–White syndrome in 44 percentof the subjects in Family 1 and 38 percent of the subjects inFamily 2. Twelve members of Family 1 had had recurrent syncope.A total of eight subjects underwent invasive electrophysiologicstudies, and a total of 10 anomalous conduction pathways wereidentified. Two of the eight (Subjects III-5 and IV-1 in Family2) had two accessory connections, or tracts. Typical accessorypathways, including two right-sided pathways and one posterolateralpathway, were identified. Five of the eight family members whowere studied had evidence of preexcitation with decrementalconduction properties.
Figure 1. Pedigrees of Two Families with Familial Wolff–Parkinson–White Syndrome.
The members of each family who died suddenly of an undetermined cause (SD) or from cardiac causes (SCD) and the age at death are shown. Solid symbols denote affected family members, circles female family members, squares male family members, and symbols with a slash deceased family members.
In addition to preexcitation, other forms of conduction diseasewere seen. Three young women (Subjects V-3 and V-4 in Family1 and Subject V-1 in Family 2) had resting heart rates of lessthan 50 beats per minute and an inadequate heart-rate responseto exercise. Progression to high-grade sinoatrial or atrioventricularblock requiring the implantation of a pacemaker occurred in76 percent of the affected members of both families who wereolder than 30 years of age. Cardiac hypertrophy was identifiedin 8 of 31 affected subjects (26 percent) who were evaluated.In two members of Family 1 (Subjects IV-1 and IV-16) hypertrophyprogressed to left ventricular dysfunction (ejection fraction,<40 percent). In one member of Family 2 who had left ventricularhypertrophy (Subject IV-4) severe left ventricular dysfunctiondeveloped that required cardiac transplantation at the age of42 years. Six patients died before the age of 40 years, butwhether they had the Wolff–Parkinson–White syndromeor other features of the phenotype is unknown, since neithermedical records nor postmortem findings were available.
Chromosomal Location and Haplotype Analysis
In determining the chromosomal location of the gene responsiblefor familial Wolff–Parkinson–White syndrome in Family1, we first assessed whether there was linkage to 7q34–q36,a locus previously identified as the site of a gene responsiblefor a familial form of hypertrophic cardiomyopathy and the Wolff–Parkinson–Whitesyndrome.10 The maximal two-point lod score was 9.82 for markerD7S636 at a distance of 0 cM. The maximal two-point lod scorewas 1.64 for marker D7S2439 in the analysis involving Family2. The maximal combined lod score for both families was 9.82at a distance of 5 cM from marker D7S636. Combined haplotypeanalysis indicated a shared region among affected members flankedby markers D7S2461 and D7S483 corresponding to a genetic distanceof less than 2.6 cM. Haplotype analysis with the use of a totalof 10 polymorphic-repeat markers and 1 single-nucleotide polymorphismfor Family 1 and Family 2 indicated that there were no allelesin common segregating at this locus, suggesting the two familiesdo not share a recent common founder. The distinct haplotypeof affected members in each family is shown in Figure 2.
Figure 2. Haplotypes, Recombination, and Genetic Map of the PRKAG2 Genomic Region in Family 1 and Family 2.
Panel A shows the results of haplotype analysis of nine members of Family 1 involving numerous polymorphic-repeat markers and one single-nucleotide polymorphism in the 3' untranslated region (3' SNP) of PRKAG2. MG7 and MG1 are novel markers identified on the basis of the sequence of P1-derived artificial chromosomes. In Subject IV-29, a crossover occurred between D7S2439 and D7S483, marking the distal limit of the shared region in this family. In Panel B, the results of haplotype analysis of six members of Family 2 involving the same polymorphic markers indicate that a crossover occurred between D7S2439 and MG1 in Subject III-3, marking the proximal limit of the shared region in this family. All affected members of both families had the R302Q mutation in PRKAG2. All affected members of Family 2 had a mutation (the substitution of adenine for guanine) at bp 1912 in the 3' untranslated region of PRKAG2, whereas none of the affected members of Family 1 had this mutation. Panel C shows the distance (in centimorgans) of each marker shown in Panels A and B from the region of interest. Black bars in Panels A and B show the region shared by all the affected members of both families. In Panel C, an integrated map of the PRKAG2 genomic region shows the genetic distances in centimorgans derived from the Genethon linkage map and the approximate positions of the crossovers (arrows). The drawing is not to scale. The accession numbers of the sequenced P1-derived artificial chromosomes are shown above the bold lines.
Identification of the Mutation in the PRKAG2 Gene
After we determined that PRKAG2 was in the critical genomicregion, we amplified and sequenced from genomic DNA affectedand unaffected family members. A sequence variation (the substitutionof adenine for guanine) was identified that corresponded tobp 995 of the PRKAG2 cDNA sequence in all affected members inFamily 1. This change results in a change in the amino acidat residue 302 from arginine to glutamine (R302Q). The identicalsequence variation was subsequently found in all affected membersof Family 2. Unaffected relatives in both families had no evidenceof this sequence variation. The same PCR product from genomicDNA was sequenced in 300 chromosomes from control subjects selectedfrom the general population, which showed no evidence of sequencevariation. The existence of the R302Q mutation was independentlyconfirmed by analysis of the results of restriction-enzyme digestion(Figure 3). Taken together, the findings indicate that thismutation in PRKAG2 is likely to cause familial Wolff–Parkinson–Whitesyndrome. An additional sequence variation (the substitutionof adenine for guanine) was identified at bp 1912 in the 3'untranslated region of PRKAG2 that was present in all affectedmembers of Family 2, but not Family 1. This finding furtherconfirms that these two families are unrelated. We have analyzedthe protein-encoding sequence of PRKAG2 in genomic DNA fromfive patients with sporadic cases of the Wolff–Parkinson–Whitesyndrome and did not detect any mutations.
Figure 3. Sequence Analysis and Secondary Confirmation of the PRKAG2 Mutation.
Sequence analysis of the sense strand of genomic DNA from an affected member of Family 1 indicates the substitution of adenine (A) for guanine (G) at bp 995 of PRKAG2 complementary DNA. This results in the substitution of glutamine for arginine (R302Q) in the PRKAG2 protein (arrow in Panel A). The mutation contained within a 190-bp amplicon abolishes an Hpy188I restriction-enzyme site, resulting in the persistence of this fragment in affected members after restriction-enzyme digestion (Panel B).
Discussion
We studied two families in which the probands presented withthe Wolff–Parkinson–White syndrome. Of the totalof 70 family members whom we examined, 31 were affected in fivegenerations. The trait is inherited in an autosomal dominantpattern with complete penetrance and variable degrees of expression.All affected subjects had electrocardiographic evidence of preexcitation.Certain features occurred more commonly in our subjects thanin those with sporadic Wolff–Parkinson–White syndrome.Paroxysmal atrial fibrillation and flutter were present in 44percent of the subjects in Family 1 and 38 percent of the subjectsin Family 2, an incidence that is significantly higher thanthe incidence of 15 to 20 percent that has been reported forsporadic Wolff–Parkinson–White syndrome.11,12 Inaddition, conduction abnormalities and cardiac hypertrophy areuncommonly associated with sporadic Wolff–Parkinson–Whitesyndrome but were commonly seen in the two families that westudied.13 Electrophysiological studies showed a higher thanexpected incidence of preexcitation with decremental conductionproperties.14,15 Six subjects died suddenly from cardiac causesbefore the age of 40 years. Although definitive diagnoses couldnot be confirmed in these obligate gene carriers, this findingsuggests that the risk of sudden death is higher in patientswith familial Wolff–Parkinson–White syndrome thanin patients with sporadic cases. Nevertheless, the Wolff–Parkinson–Whitesyndrome is a well-recognized cause of sudden death, and instudies of young survivors of sudden cardiac arrest who didnot have gross structural heart disease, the syndrome was presentin up to 33 percent of patients.16,17
In both families the gene responsible mapped to 7q34–q36,which had been previously documented to be the locus responsiblefor disease in a family with combined hypertrophic cardiomyopathyand the Wolff–Parkinson–White syndrome.10 Usingthe candidate-gene approach, we identified the gene PRKAG2,which encodes the 2 regulatory subunit of AMP-activated proteinkinase. The genetic defect is a point mutation resulting inthe substitution of glutamine for arginine (R302Q). That themutation was responsible for the phenotype in these familieswas confirmed by the following findings: the mutation was presentin all affected members of two unrelated families, the mutationwas absent in all unaffected members of both families as wellas in 300 chromosomes from control subjects, and the substitutedarginine is highly conserved across several species, reflectingthe functional biologic importance of this amino acid.
The same mutation occurred in the two families despite the absenceof a common founder. The absence of a common founder is basedon the following evidence: the two families were not known tobe related, they did not share alleles segregating in the vicinityof the PRKAG2 gene, and the single-nucleotide polymorphism identifiedat bp 1912 of PRKAG2 was present in all affected members ofFamily 2, but not Family 1. Nucleotide substitutions tend notto occur at random. Substitutions of adenine for guanine, asoccurred in the mutation identified in the two families we studied,are 10 to 40 times as frequent as other base substitutions.18The substitution in PRKAG2 occurred at a CG doublet, and thesedoublets are often referred to as "hot spots" for mutation.19
The PRKAG2 gene consists of 569 amino acids with a calculatedmolecular mass of 63 kd.20 The subunit of the AMP-activatedprotein kinase heterotrimer functions as the AMP-binding site,thus regulating the activity of the protein. However, it isnot possible to determine whether the R302Q mutation directlyaffects AMP binding, since the sequence of the AMP-binding siteis not known.21
AMP-activated protein kinase functions as a metabolic sensorin cells, responding to cellular energy demands by regulatingdiverse ATP-using pathways and ATP-generating pathways.22 Inthe presence of an elevated ratio of AMP to ATP, AMP-activatedprotein kinase is activated by the direct binding of AMP, whichexposes a threonine of the catalytic unit. The threonine isthen phosphorylated by an upstream kinase (AMP-activated proteinkinase kinase).20 Activation decreases the use of ATP for nonessentialfunctions and stimulates ATP-generating pathways, conservingATP for more vital cellular requirements (Figure 4). The PRKAG2isoform has a high level of expression in cardiac tissue, andit is also present in skeletal muscle, the brain, the placenta,the liver, the kidneys, and the pancreas.20
Figure 4. Regulation and Function of AMP-Activated Protein Kinase.
In response to an elevated ratio of AMP to ATP, AMP-activated protein kinase is activated by both direct AMP binding and phosphorylation by AMP-activated protein kinase kinase (AMPKK). AMP-activated protein kinase may also be activated in response to the increase in cyclic AMP (cAMP) and resultant increase in the AMP:ATP ratio induced by -adrenergic stimulation. The diverse functions of AMP-activated protein kinase include the inactivation of nonessential ATP-consuming pathways, the regulation of the activity of creatine kinase, and the restoration of ATP levels through increased fatty-acid oxidation to meet vital cellular needs such as ion-channel activity and sarcomeric contraction. In addition, AMP-activated protein kinase may migrate to the nucleus and regulate gene transcription.
The Wolff–Parkinson–White syndrome is thought tobe due to accessory pathways derived from muscle fibers thatprovided direct continuity between atrial and ventricular myocardiumduring cardiogenesis.23 The molecular defect that we found mayin some way inhibit the normal regression of muscle fibers duringatrioventricular septation. Although the propensity for arrhythmiasin patients with familial Wolff–Parkinson–Whitesyndrome is well known, the mechanism that triggers these episodesat the molecular level is not understood. The activation ofAMP-activated protein kinase in response to -adrenergic stimulationcould account for the development of tachyarrhythmias duringexercise or metabolic stress.24,25
It is unclear whether the R302Q mutation acts as an activatingor inactivating mutation. However, the mutation probably leadsto an alteration in the phosphorylation of downstream substrateswithin the heart. Potential targets are likely to include enzymesinvolved in energy metabolism and ion-channel proteins. An importanttask will be to identify the proteins whose phosphorylationis affected by this mutation. Although AMP-activated proteinkinase affects gene expression,26,27 its role during cardiacdevelopment is unknown. The identification of this genetic defecthas important implications for the diagnosis and treatment ofthe Wolff–Parkinson–White syndrome. The relationbetween the role of AMP-activated protein kinase in cardiacelectrophysiology and the management of supraventricular arrhythmiasand conduction disease remains to be elucidated.
Supported in part by a grant (86-2216) from the American HeartAssociation and by a grant from the Effie and Wollard Cain Foundation.
Presented in part at the 22nd Annual Meeting of the North AmericanSociety of Pacing and Electrophysiology, Boston, May 3, 2001.
We are indebted to the families who participated in the study;to Donna Orchard, R.N., for technical assistance; and to DebbieGraustein and Moira Long for assistance in the preparation ofthe manuscript.
Source Information
From the Section of Cardiology, Baylor College of Medicine, Houston (M.H.G., T.G., A.K., F.A., R.L., G.S., L.L.B., R.R.); the University of Ottawa Heart Institute, Ottawa, Ont., Canada (M.S.G., A.S.-L.T., A.-S.H.); and the Inherited Heart Disease Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. (L.F.).
Other authors were Terry Tapscott, B.S., and Oscar Gonzales, B.S. (Section of Cardiology, Baylor College of Medicine, Houston); and David Begley, M.D., and Saidi Mohiddin, M.D. (Inherited Heart Disease Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.).
Address reprint requests to Dr. Roberts at the Department of Medicine, Section of Cardiology, 6550 Fannin, MS SM 677, Baylor College of Medicine, Houston, TX 77030, or at rroberts{at}bcm.tmc.edu.
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Committee Members, , Blomstrom-Lundqvist, C., Scheinman, M. M., Aliot, E. M., Alpert, J. S., Calkins, H., Camm, A. J., Campbell, W. B., Haines, D. E., Kuck, K. H., Lerman, B. B., Miller, D. D., Shaeffer, C. W. Jr, Stevenson, W. G., Tomaselli, G. F., Task Force Members, , Antman, E. M., Smith, S. C. Jr, Alpert, J. S., Faxon, D. P., Fuster, V., Gibbons, R. J., Gregoratos, G., Hiratzka, L. F., Hunt, S. A., Jacobs, A. K., Russell, R. O. Jr, ESC Committee for Practice Guidelines Members, , Priori, S. G., Blanc, J.-J., Budaj, A., Burgos, E. F., Cowie, M., Deckers, J. W., Garcia, M. A. A., Klein, W. W., Lekakis, J., Lindahl, B., Mazzotta, G., Morais, J. C. A., Oto, A., Smiseth, O., Trappe, H.-J.
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Blomstrom-Lundqvist, C., Scheinman, M. M., Aliot, E. M., Alpert, J. S., Calkins, H., Camm, A. J., Campbell, W. B., Haines, D. E., Kuck, K. H., Lerman, B. B., Miller, D. D., Shaeffer, C. W. Jr, Stevenson, W. G., Tomaselli, G. F., Antman, E. M., Smith, S. C. Jr, Alpert, J. S., Faxon, D. P., Fuster, V., Gibbons, R. J., Gregoratos, G., Hiratzka, L. F., Hunt, S. A., Jacobs, A. K., Russell, R. O. Jr, Priori, S. G., Blanc, J.-J., Budaj, A., Burgos, E. F., Cowie, M., Deckers, J. W., Garcia, M. A. A., Klein, W. W., Lekakis, J., Lindahl, B., Mazzotta, G., Morais, J. C. A., Oto, A., Smiseth, O., Trappe, H.-J., Committee Members, , Task Force Members, , ESC Committee for Practice Guidelines Members,
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Watkins, H.
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Daniel, T., Carling, D.
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Gollob, M.H., Roberts, R.
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Maron, B. J.
(2002). Hypertrophic Cardiomyopathy: A Systematic Review. JAMA
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(2001). Novel PRKAG2 Mutation Responsible for the Genetic Syndrome of Ventricular Preexcitation and Conduction System Disease With Childhood Onset and Absence of Cardiac Hypertrophy. Circulation
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Anderson, K. P., Vidaillet, H. J. Jr., Josephson, M. E., Gollob, M. H., Green, M. S., Roberts, R.
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A correction has been published: N Engl J Med 2001;345(7):552.
2 regulatory subunit of AMP-activated protein kinase (PRKAG2). The mutation results in the substitution of glutamine for arginine at residue 302 in the protein. 
-adrenergic stimulation could account for the development of tachyarrhythmias during exercise or metabolic stress.24,25 
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