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(Circulation. 1995;91:1633-1640.)
© 1995 American Heart Association, Inc.

Articles

Gene for Progressive Familial Heart Block Type I Maps to Chromosome 19q13

Paul A. Brink, MD; Alet Ferreira, MS; Johanna C. Moolman, MS; Hettie W. Weymar, RCT; Pieter-Luttig van der Merwe, MD; Valerie A. Corfield, PhD

From the Department of Internal Medicine, University of Stellenbosch Medical School and Tygerberg Hospital (P.A.B.); the University of Stellenbosch and Medical Research Council Centre for Molecular and Cellular Biology, Department of Medical Physiology and Biochemistry, University of Stellenbosch Medical School (A.F., J.C.M., V.A.C.); the Section of Cardiology, Department of Medicine, Tygerberg Hospital (H.W.W); and the Section of Cardiology, Department of Pediatrics, Tygerberg Hospital, University of Stellenbosch Medical School (P.-L.van der M.), Tygerberg, South Africa.

	Abstract

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Background Progressive familial heart block type I (PF-HBI) is a dominantly inherited cardiac bundle-branch conduction disorder that has been traced through nine generations of a large South African kindred. Similar conduction disorders have been reported elsewhere; however, the cause of these diseases is unknown. The aim of the present study was to determine by linkage analysis the approximate chromosomal position of the gene causing PFHBI, thereby allowing family-based diagnosis and the development of positional cloning strategies to identify the causative gene.

Methods and Results Eighty-six members of three pedigrees, 39 members of which were affected with PFHBI, were genotyped at four linked polymorphic marker loci mapped to chromosome 19, bands q13.2-q13.3 (chromosome 19q13.2-13.3). Maximum two-point logarithm of the odds scores (which represent the logarithm of the odds ratio of detecting linkage versus nonlinkage) generated were 6.49 (=0) for the kallikrein locus, 5.72 (=0.01) for the myotonic dystrophy locus, 3.44 (=0) for the creatine kinase muscle-type locus and 4.51 (=0.10) for the apolipoprotein C2 locus. The maximum multipoint logarithm of the odds score was 11.6, with the 90% support interval positioning the PFHBI locus within a 10 cM distance centering on the kallikrein 1 locus.

Conclusions The gene for PFHBI maps to an area of approximately 10 cM on chromosome 19q13.2-13.3. There are several candidate genes in this interval; although a recombination event ruled out the myotonic dystrophy locus from direct involvement with PFHBI, the proximity of these two loci may be relevant to the observed cardiac abnormalities of myotonic dystrophy. The results provide a means of DNA-based diagnosis in the families studied and a foundation for cloning studies to identify the causative gene.

Key Words: conduction • bundle-branch block • mapping • genes

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Progressive familial heart block type I (PFHBI) is an autosomal dominantly inherited cardiac bundle-branch disorder that may progress to complete heart block.^{1 2 3 4} It is defined on ECG by evidence of bundle-branch disease, ie, right bundle-branch block, left anterior or posterior hemiblock, or complete heart block with broad QRS complexes.¹ Progression has been shown from a normal ECG to right bundle-branch block and from the latter to complete heart block.^{2 3} These ECG features differentiate PFHBI from progressive familial heart block type II (PFHBII), in which the onset of complete heart block is associated with narrow complexes.¹ Electrocardiographically the changes represent, respectively, bundle-branch disease (PFHBI) and atrioventricular nodal disease with an atrioventricular block and an idionodal escape rhythm (PFHBII). PFHBI is manifested symptomatically when complete heart block supervenes, either with dyspnea, syncopal episodes, or sudden death.¹ Treatment, which is best managed by regular ECG follow-up, is by the timely implantation of a pacemaker.

Several branches of a large kindred in South Africa have been identified in which PFHBI is segregating and whose family members descend from one ancestor who emigrated from Portugal in 1696.¹ It has been estimated that there may be between 1000 and 9000 gene carriers among the descendants.^{1 5 6} Although the global incidence of PFHBI is unclear, the disease is probably not confined to South Africa. At least 13 reports suggest that similar familial conduction diseases, ie, with right bundle-branch block or right bundle-branch block and complete heart block appearing in the same family, exist elsewhere, although designated differently.¹⁰

The pathophysiology of these diseases is unknown; however, linkage analysis and positional cloning^{7 8 9} offer a means of identification of disease-causing genes. Characterization of genes that predispose individuals to the development of electrophysiological disturbances may help elucidate the functioning at the molecular level of the cardiac conduction system, whether normal or abnormal.

We have previously reported exclusion of 68 loci, representing 35% of the genome, from linkage to PFHBI.¹⁰ In this paper we report linkage of PFHBI to chromosome 19, bands q13.2-q13.3 (chromosome 19q13.2-13.3). The gene encoding myotonin protein kinase (DMK), which is implicated as a cause of myotonic dystrophy, lies within this region.^{11 12 13} Myotonic dystrophy is a disease that is itself complicated by heart block and other conduction abnormalities.

	Methods

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Subjects and Clinical Evaluation
Subjects were drawn from three pedigrees identified through previous studies.^{1 5 6} A consolidated pedigree of one large South African kindred, pedigree 2, which could be traced back nine generations, and in which PFHBI segregates, is shown in Fig 1A. These data incorporate the previously reported pedigrees 2, 3, 4, and 8¹⁰ and other family members who have since come to our attention. The previously reported pedigrees 1 and 5¹⁰ (Fig 1B) have not as yet been linked to the larger pedigree. However, because most members of all three pedigrees live in or originate from the same geographical area, the Eastern Cape in South Africa, and given the rarity of the disease, we expect a common ancestor.

View larger version (33K): [in this window] [in a new window]   Figure 1. Diagrams of pedigrees in which PFHBI segregates. A, Pedigree 2, a nine-generation kindred. B, Pedigrees 1 and 5, two smaller families that could not be linked to the main pedigree. Affected individuals had either right bundle-branch block, complicated right bundle-branch block, or complete heart block, as described in the text.

The diagnosis of PFHBI followed strict criteria, based on ECG-defined right bundle-branch block, complicated right bundle-branch block, or complete heart block with broad complexes in the absence of disease that might cause a similar defect, as previously described.¹⁰ Sinus bradycardia in isolation was regarded as normal. The Minnesota code was adhered to in making ECG diagnoses.¹⁴ Whenever available, members of the pedigrees were entered into the study irrespective of age.

DNA Analysis
Genomic DNA was extracted from lymphocytes or Epstein-Barr virus–transformed cell lines as previously described.¹⁵ To retrospectively obtain a repeat sample from a patient who died during the period of study, we extracted DNA from archival postmortem tissue sections using a method modified from Shibata et al.¹⁶ Individual sections 5 to 10 µm thick were cut from trimmed, buffered, formalin-fixed, paraffin-embedded tissue and placed in 500-µL Eppendorf tubes. The samples were deparaffinized by extraction with 1 mL of xylene followed by microcentrifugation. This extraction procedure was repeated and 1 mL of 95% ethanol was added to the residue. After microcentrifugation the ethanol wash was repeated, and the pellet was desiccated before suspension in 40 µL water. The solution was boiled for 10 minutes and microcentrifuged for 5 minutes, and 3 µL of supernatant was used to confirm polymerase chain reaction–based detection of the trinucleotide repeat at the myotonic dystrophy (DM) locus, as detailed below. Genotyping was performed at the apolipoprotein C2 (APOC2) locus,¹⁷ the creatine kinase muscle-type (CKMM) locus,¹⁸ the DM locus,^{11 12 13} and the kallikrein 1 (KLK1) locus,¹⁹ which span chromosome 19q13.2-13.3. The microsatellite dinucleotide repeat polymorphisms at the APOC2 and KLK1 loci and the CTG trinucleotide repeat at the DM locus were analyzed by polymerase chain reaction–based assays. Primers were synthesized from published sequences (DNA Synthesis Laboratory, University of Cape Town, South Africa) for the APOC2¹⁷ and DM¹¹ loci or purchased from Research Genetics for the KLK1¹⁹ locus. Each reaction was performed in a 10-µL volume that contained 300 ng of genomic DNA; 40 pmol of each primer; 67 µmol/L each of dATP, dGTP, and dTTP; 2.5 µmol/L of dCTP; 1.5 nCi of [-³²P]-dCTP; 2.5 µmol/L of MgCl₂; and 0.75 U of Taq polymerase in the buffer supplied by the manufacturer (Promega). The reaction mixes were overlaid with 25 µL of mineral oil to prevent evaporation. Cycling parameters in a polymerase chain reaction machine (ESU Electronics) were an initial incubation at 93°C for 2 minutes followed by 30 cycles at 93°C for 110 seconds, 57°C for 120 seconds, and 72°C for 140 seconds. After the addition of 6 µL of loading dye (95% formamide, 0.05% bromophenol blue, 0.05% xylene cyanole, 20 mmol/L EDTA), 6 µL of the amplification products were electrophoresed on 6% denaturing polyacrylamide gels. The gels were fixed and dried and the autoradiographs were exposed overnight at -70°C. The sizes of the different alleles were determined by reference to a sequencing ladder.

At the CKMM locus the NcoI and TaqI restriction length polymorphisms¹⁸ were detected by Southern blot hybridization using methods previously described²⁰ or by a polymerase chain reaction–based method using published primer sequences.²¹ The EcoR1 polymorphism at the DM locus was examined for possible expansion of the CTG repeat to pathological levels by Southern blot hybridization.²²

Statistical Analysis
MLINK (two-point) and LINKMAP (multipoint) from the LINKAGE group of programs were used to calculate LOD (which represent the logarithm of the odds ratio of detecting linkage versus nonlinkage) scores²³ from marker, disease status, and pedigree information using the following parameters. To obtain the penetrance value, input for the LIPED²⁴ program was constructed to reflect apparent penetrance and used in an iterative fashion to find the penetrance value that maximized the likelihood,²⁵ as previously described.¹⁰ A maximal value was obtained at a penetrance of 96%. A more conservative value of 90% was used in the actual linkage calculations. Because an affectation ratio of 0.45 or more was obtained upon examination of the number of affected individuals born in each decade since 1900, we concluded that assuming 90% penetrance would not influence linkage results negatively. The same phenotypic parameters were used for possible PFHBI homozygotes as for heterozygotes. The assumptions on which estimates of the prevalence of PFHBI (0.002) were based were reported previously.¹⁰ No allowance was made for phenocopies because the prevalence of similar cardiac conduction disturbances reported in the general population is low.¹⁰

To perform the multipoint analysis for the large multigeneration families with multiallelic markers, we used the following simplifying measures. In pedigree 2, all individuals in the line of descent of the PFHBI allele were coded as affected, with the exception of individuals I.01 and I.02, who were designated as being of unknown phenotype.⁶ All individuals who married into the family were coded as unaffected. These modifications resulted in LOD score changes only after the second decimal digit when tested on a two-point analysis rerun. Alleles were then collapsed into three-allele systems for the DM and KLK1 loci and a four-allele system for the APOC2 locus. The individual alleles obviously segregating with PFHBI were maintained as separate alleles at the DM and KLK1 loci. Only the TaqI restriction length polymorphism (ie, a biallelic polymorphism) was used at the CKMM locus. Allele frequencies were adjusted to incorporate these modifications and the simplified data were analyzed on a VAX 6000-410 computer system using published gene order and genetic distances.^{19 26 27 28}

	Results

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Clinical Evaluation
Table 1 displays the clinical characteristics of subjects with PFHBI who were genotyped and in the additional affected first-degree relatives who were unavailable for genotyping. Of a total of 51 family members assessed, 22 had complete heart block, 25 had right bundle-branch block or right bundle-branch block and left posterior hemiblock or left anterior hemiblock, and 4 (individuals VIII.26 and VII.44 in pedigree 2 and I.01 and I.02 in pedigree 5) displayed no ECG abnormalities but had affected children.

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of Subjects With Progressive Familial Heart Block Type I Genotyped in the Study and Their Affected First-Degree Relatives

Linkage of PFHBI to Chromosome 19q13
Eighty-six members of three pedigrees, 39 members of which were affected with PFHBI, were genotyped at four linked polymorphic marker loci mapped to chromosome 19q13.2-13.3. Results of pairwise linkage analysis between PFHBI and marker loci are summarized in Table 2. The highest LOD score was obtained for KLK1 (Z_max, 6.49 at =0). Marker locus APOC2 (Z_max, 4.51 at =0.10) showed several recombinants, while in separate individuals CKMM (Z_max, 3.44 at =0.05) and DM (Z_max, 5.72 at =0.01) each showed a single recombinant. These genes span a distance of about 12 cM in the following order: centromere-APOC2-CKMM-DM-KLK1-telomere.²⁶

View this table: [in this window] [in a new window]   Table 2. Two-Point Logarithm of the Odds Scores of Progressive Familial Heart Block Type I and Chromosome 19 Markers by Pedigree

The maximum LOD score for a multipoint analysis occurred at KLK1 (LOD 11.6) (Fig 2). The 1-LOD-down 90% support interval²⁹ defined an area of 10 cM centering on the KLK1 locus as being likely to contain the PFHBI gene. This distance may include the DM locus.

View larger version (12K): [in this window] [in a new window]   Figure 2. LINKMAP plot of chromosome 19, band q13, showing the relative likelihoods for the various locations of the PFHBI gene with reference to a fixed order of linked DNA markers. On the basis of the 1-LOD-down support interval, the most likely location for the locus for PFHBI is distal to the CKMM locus, encompassing a 10 cM length centering on the KLK1 locus.

Recombination Event at the DM Locus
At the DM locus, one recombination event was seen between individual VIII.46 and IX.25 in pedigree 2 (Fig 3). The latter, who was affected with PFHBI, inherited from his affected father the same length CTG repeat (allele 14) and EcoRI polymorphism (allele 2) at the DM locus as his unaffected sibling IX.24, who showed no evidence of recombination events. Because the DMK gene was a candidate for the cause of PFHBI, it was important to confirm the recombination event in IX.25. Unfortunately, this child had died at the age of 2 years, so a new blood sample was unobtainable. However, genomic DNA was extracted from formalin-fixed, paraffin-embedded postmortem material. The CTG repeat at the DM locus was polymerase chain reaction–amplified from this source and a genotype of 13:14 was confirmed. The mother (VIII.45) was not affected with PFHBI, as assessed by ECG testing, and to date no ancestral links between her and the PFHBI families have been found. Eighteen of the 37 PFHBI-affected individuals were heterozygous for alleles within the normal range of the myotonic dystrophy–causing trinucleotide repeat. All possessed a 5-repeat–length allele and one other allele of up to 21 repeats. One subject, IX.25, in whom the recombination event was seen, was heterozygous with alleles of 13- and 14-repeat lengths. The remaining affected individuals were apparently homozygous for the 5-repeat–length allele, a result compatible with their parents' genotype. Furthermore, in none of the affected individuals with the single 5-repeat–length band was there evidence of triplet repeat expansion, which might have been undetectable by polymerase chain reaction–based amplification, upon Southern blot analysis of the DM locus (results not shown).

View larger version (32K): [in this window] [in a new window]   Figure 3. Genotypes of apolipoprotein C2 locus, creatine kinase muscle-type locus, myotonic dystrophy locus, and kallikrein 1 locus in pedigrees with PFHBI. Abridged kindred structures are shown for pedigree 2; the symbols correspond to the key in Fig 1. The haplotypes were constructed from the results of the combination of alleles inherited at each locus in the order of the genotypes listed above (APOCII, CKMM, DM, and KLK1, respectively). Genotypes indicated by a slash indicate two indistinguishable alternatives, and haplotypes in brackets could not be assigned with certainty because of pedigree position. - indicates not tested.

To refine the chromosomal position of the recombination event and facilitate molecular diagnosis, haplotypes for the four marker loci genotyped were deduced (Fig 3). The haplotype of affected individuals at the CKMM, DM, and KLK1 combined locus was 4:5:7, with the exception of a subset of pedigree 2, VII.36 and children (2:5:7), and individual IX.25, who displayed a 4:14:7 haplotype inherited from his phase-known affected father. As discussed above, a recombination event appeared to have occurred between DM and KLK1 in IX.25, suggesting that the PFHBI locus lies telomeric to the DM locus.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In this study, PFHBI, a familial cardiac bundle-branch conduction disorder, was genetically mapped to a group of four linked loci on chromosome 19q13.2-13.3. Multipoint mapping has positioned the gene to within a 10 cM distance, centering on the KLK1 locus. In the families investigated, markers may now be used to support ECG-based diagnosis. This is important to the identification of persons in whom routine clinical follow-up would be advisable because of the progressive nature of the disease.^{1 2 3 4} Furthermore, fine mapping and attempts to identify the causative gene by positional cloning can be initiated. In pedigree 2, unaffected siblings VIII.59 and VIII.60 and their affected sister VIII.58 all carry the 4:5:7 (CKMM:DM:KLK1) haplotype inherited from their affected father, who is homozygous at these loci. Additionally, detection of frequent recombination events between APOC2 and rarer events between CKMM and DM and the disease currently precludes unequivocal identification of the disease-causing chromosomal region in all branches of the pedigree. Fine mapping with other markers across this region should allow identification of an invariant disease haplotype, resolving molecular diagnosis and confirming the presence of a founder effect.

A survey of known genes in the defined area focused attention on the intriguing proximity of the PFHBI locus to the one encoding myotonin protein kinase, which is implicated in causing myotonic dystrophy.^{11 12 13} PFHBI and myotonic dystrophy have similar cardiac complications, namely bundle-branch blocks or intraventricular conduction disturbances.^{30 31 32 33} Myotonic dystrophy is caused by instability of a CTG triplet repeat in the 3' untranslated region of the DMK gene,^{11 12 13 34 35} with affected individuals having copy numbers ranging from 50 to more than 2000 repeats. The recombination event between PFHBI and the DM locus and the absence of a pathologically expanded CTG repeat in PFHBI-affected individuals effectively excluded direct involvement of the DMK gene in PFHBI. However, it has been proposed that it is through its effects on chromosome structure that triplet repeat expansion within the DMK gene interferes with the expression of multiple neighboring genes, resulting in the highly variable clinical presentation that is a hallmark of myotonic dystrophy.^{34 36 37} It can be speculated that one of these adjacent genes is involved in the specific cardiac conduction disturbances characteristic of myotonic dystrophy, and that when this gene harbors a particular mutation it causes the clinical features of PFHBI. Consequently, identifying the exact relationship of the PFHBI locus to the DMK locus may help elucidate the mechanisms of both diseases. Additional family members not previously available will be genotyped for possible other recombination events in the targeted region.

The exclusion of the DMK gene as a direct cause of PFHBI allows consideration of other candidate genes in the defined area. The highest LOD score obtained in the study, and one with no recombination events, was at the KLK1 locus, which forms part of a linked group of kallikreins.¹⁹ The kallikreins, generally considered important intravascularly, have been shown to be present in cardiac tissue in the rat.³⁸ Some of the cardiac effects of the tissue renin-angiotensin system may be mediated through a kallikrein³⁸ and could be involved in the pathophysiology of PFHBI. Included in the kallikrein gene cluster is the R-ras gene,³⁹ a member of the ras gene superfamily.⁴⁰ The description of a possible association of the H-ras proto-oncogene with the long QT syndrome,⁴¹ which is characterized by cardiac arrhythmias, justifies consideration of R-ras as a candidate for involvement in PFHBI. A plausible mechanism may be through a role in abnormal growth or differentiation of the conduction system, a possibility proposed by Brink and Torrington in their initial description of PFHBI.¹

In general, the chromosome 19q13.2-13.3 region seems particularly rich in genes with known cardiac functions or associations with cardiac pathology. The histidine-rich calcium-binding protein⁴² is a luminal sarcoplasmic reticulum protein. It is thought that sarcoplasmic reticulum proteins may play a role in binding calcium; mutations in this gene could therefore affect intracellular calcium homeostasis. The apolipoproteins, by virtue of their connection with atherosclerosis, are often associated with cardiac dysfunction.⁴³ However, multiple recombination events at the APOC2 locus effectively excluded not only this gene as a candidate but apolipoprotein genes C1 and E as well, because all three genes are clustered within a 50-kilobase region of chromosome 19q13.2-13.3.⁴⁴ Similarly, the candidature of creatine kinase muscle-type, the enzyme product that plays a key role in cellular energy metabolism,⁴⁵ was excluded by the presence of one recombination event. The gene for troponin T also resides in the candidate region.⁴⁶ The troponin complex plays an important role in linking excitation to contraction of the sarcomere.⁴⁷ Its role in conduction tissue is uncertain, but it is known that conduction tissue is modified muscle and that it possesses rudimentary sarcomeric structures. Several other genes of unknown function^{37 48} and HTF (HpaII tiny fragments) islands,⁴⁹ generally associated with the 5' end of expressed genes,⁵⁰ have been identified in this extensively studied and gene-rich area of chromosome 19.

These results not only allow selective follow-up of individuals at risk for PFHBI, on the basis of genotypic analysis in the families studied, but define the chromosomal location of a gene causing cardiac pacing abnormalities. Additionally, establishment of the position of the loci for PFHBI and myotonic dystrophy relative to each other may shed light on the pathophysiology of both diseases. Eventually, finding and characterizing the gene that causes PFHBI may help unravel the underlying molecular mechanisms of the cardiac conduction system.

	Footnotes

 
Reprint requests to Valerie A. Corfield, US/MRC Centre for Molecular and Cellular Biology, PO Box 19063, Tygerberg 7505, Republic of South Africa.

Received May 17, 1994; revision received October 5, 1994; accepted October 24, 1994.

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