Journal of Heredity Advance Access published online on November 12, 2007
Journal of Heredity, doi:10.1093/jhered/esm090
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Evaluation of 15 Candidate Genes for Dilated Cardiomyopathy in the Newfoundland Dog
From the Small Animal Teaching Hospital, University of Liverpool, Leahurst, Chester High Road, Neston, CH64 7TE, United Kingdom (Wiersma and Dukes-McEwan); the Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3508 TD Utrecht, The Netherlands (Wiersma, Stabej, and Leegwater); the Centre for Integrated Genomic Medical Research, Division of Epidemiology and Health Sciences, The University of Manchester, Manchester, M13 9PT, United Kingdom (Wiersma and Ollier); and the Department of Molecular Cell Biology, American University of the Caribbean, #1 University Drive at Jordan Road, Cupecoy, St Maarten, Dutch Antilles (van Oost)
Address correspondence to A. C. Wiersma at the address above, or e-mail: a.c.wiersma{at}uu.nl.
Dilated cardiomyopathy (DCM) is a disease of the myocardium, which causes heart failure and premature death. It has been described in humans and several domestic animals. In the Newfoundland dog, DCM is an autosomal dominant disease with late onset and reduced penetrance. We analyzed 15 candidate genes for their involvement in DCM in the Newfoundland dog. Polymorphic microsatellite markers and single Nucleotide Polymorphisms were genotyped in 4 families of Newfoundland dogs segregating dilated cardiomyopathy for the genes encoding 
-cardiac actin (ACTC), caveolin (CAVI), cysteine-rich protein 3 (CSRP3), LIM-domain binding factor 3 (LDB3), desmin (DES), lamin A/C (LMNA), myosin heavy polypeptide 7 (MYH7), delta-sarcoglycan (SGCD), troponin I (TNNTI3), troponin T (TNNT2), alpha-tropomyosin (TPMI), titin (TTN) and vinculin (VCL). A Logarithm of the odds (LOD) score of less than –2.0 in 2-point linkage analysis indicated exclusion of all but 2 genes, encoding CSRP3 and DES. A (LOD) score between –1.5 and –2.0 for CSRP3 and DES makes these genes unlikely causes of DCM in this dog breed. For the phospholamban (PLN) and titin cap (TTN) genes, a direct mutation screening approach was used. DNA sequence analysis of all exons showed no evidence that these genes are involved in DCM in the Newfoundland dog.
Dilated cardiomyopathy (DCM) in humans is characterized by dilatation and increased sphericity of the left ventricle of the heart accompanied by reduced systolic function (Burkett and Hershberger 2005). After a presymptomatic period in which compensatory mechanisms take place, congestive heart failure and arrhythmias will start to cause clinical signs and will eventually lead to premature mortality (Seidman JG and Seidman C 2001). In humans, up to 35% of cases of DCM may have a hereditary background (Grünig et al. 1998), but the underlying genetic cause has not been identified in most patients.
DCM is seen in other species as well, such as mouse (Zhao et al. 2002), hamster (Nigro et al. 1997), and the dog. Canine DCM has mostly been described in breeds of larger dogs, for example, the Dobermann (Domanjko-Petric et al. 2002), Newfoundland dog (Tidholm and Jonsson 1996), Great Dane (Meurs et al. 2001), and Irish Wolfhound (Brownlie and Cobb 1999). DCM in the Newfoundland dog has been described as an autosomal dominant disease (Dukes-McEwan 1999a; Dukes-McEwan and Jackson 2002), with a late onset and a reduced penetrance. The disease is progressive and incurable. The median age of onset of clinical signs is approximately 8 years of age and the median age of death 9 years (Dukes-McEwan 2000). The first clinical signs are often acute and include weakness, exercise intolerance, coughing, weight loss, accumulation of fluid in the abdomen, and sudden (premature) death (Tidholm and Jonsson 1996).
A number of genes have been identified in human, hamster, and mouse as causal for DCM. These genes mainly encode proteins of the cytoskeleton of the cardiac myocyte, divided between the sarcomere (the contractile unit of the cardiac myocyte) and extrasarcomeric proteins. Candidate genes that encode sarcomeric proteins include -cardiac actin (ACTC) (Olson et al. 1998), cysteine-rich protein 3 (CSRP3) (Knoll et al. 2002), LIM-domain binding factor 3 (LDB3, also known as Cypher or ZASP) (Arimura et al. 2004), myosin heavy polypeptide 7 (MYH7) (Kamisago et al. 2000), titin cap (TCAP) (Hayashi et al. 2004), -tropomyosin (TPM1) (Olson et al. 2001), troponin I (TNNI3) (Murphy et al. 2004), troponin T (TNNT2) (Kamisago et al. 2000), titin (TTN) (Itoh-Satoh et al. 2002), and vinculin (VCL) (Olson et al. 2002). Extrasarcomeric proteins involved in DCM include caveolin 1 (CAV1) (Zhao et al. 2002), desmin (DES) (Li et al. 1999), lamin A/C (LMNA) (Burke and Stewart 2002), phospholamban (PLN) (MacLennan and Kranias 2003; Stabej, Leegwater, Stokhof, et al. 2005), and sarcoglycan 
(SGCD) (Nigro et al. 1997).
A low-resolution genome scan was performed previously in Newfoundland dog families from the United Kingdom that segregate the disease (Dukes-McEwan and Jackson 2002). Pedigree and segregation analysis showed that the most likely mode of inheritance was autosomal dominant, with reduced (age-related) penetrance (Dukes-McEwan 1999). Approximately 35% of the genome could be excluded (LOD < –2.0 in 2-point linkage analysis), and 20% was unlikely to harbor the DCM gene (LOD < –1.0). In this paper, we describe the evaluation of 15 candidate genes in these Newfoundland dog families that segregate DCM.
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Materials and Methods |
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Four families of Newfoundland dogs with DCM were available, derived from the British population of this breed (Figure 1). DNA and phenotypes were available of 74 dogs. Clinical and Doppler echocardiographic examinations were performed by a veterinary cardiologist (J.D.-M.) and were used to establish the phenotype. Criteria for the diagnosis of DCM (Dukes-McEwan 1999b) included at least 2 of the following: depressed systolic function (actively excluding other systemic conditions which could secondarily result in this phenotype); increased sphericity of the left ventricle; left ventricular chamber dimensions above reference values for the breed and weight of dog (Dukes-McEwan et al. 2003). Other congenital or acquired cardiac disease was excluded. The presence of a cardiac dysrhythmia, such as atrial fibrillation, although common, was not included as a diagnostic criterion. Criteria for normal Newfoundlands included left ventricular M-mode dimensions and volumes (Simpson's rule) within reference ranges for the weight of dog and normal systolic function (defined as M-mode fractional shortening of more than 20% and Simpson's rule derived ejection fraction of more than 50%). Of the 74 available dogs (27 males and 47 females), 38 were classified as affected (17 males and 21 females). Serial evaluations were performed (12–24 months apart). Some dogs showed echocardiographic abnormalities that were equivocal, such as isolated left ventricular enlargement or depressed contractility (Dukes-McEwan 1999b). These were labeled "unknown" unless they progressed to an unequivocal phenotype of DCM.
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Mutation Detection
For PLN and TCAP, genes with each only 2 coding exons of small size, a direct mutation screening was used. From our Newfoundland pedigree, 4 dogs with DCM and 4 healthy dogs were selected for DNA sequencing. These were DCM dogs A-6, A-23, B-17, and B-25 (Figure 1) and healthy dogs A-1 (tested last at 12 years of age), A-9 (9 years), B-5 (8 years), and B-21 (11 years). DNA sequence analysis for PLN was performed as described previously (Stabej, Leegwater, Stokhof, et al. 2005). Briefly, 3 fragments of genomic sequence were analyzed, containing both exons of the gene and 6 putative promoter elements. For TCAP, 2 fragments of genomic sequence (Table 1) were analyzed. Genomic DNA fragments of the dogs were polymerase chain reaction (PCR) amplified at 94 °C for 10 min, 35x (94 °C for 30 s, annealing temperature [Ta] °C for 30 s, and 72 °C for 30 s), 72 °C for 10 min, and 4°
(see Table 1 for Ta and primer sequences) on PTC-100 Programmable Thermal Controller (MJ Research, Inc, Waltham, MA). Subsequently, 1 µl of 1:15 diluted PCR product was used in a Tercycle big dye reaction (Applied Biosystems, Foster City, CA), as recommended by the manufacturer. The products were purified with Sephadex G50 Superfine (Amersham Biosciences, Buckinghamshire, UK) and were analyzed with an ABI PRISM 3100 Genetic Analyzer (Applied Biosystems). The DNA sequences of each fragment were aligned and screened for mutations using the Staden Package (Staden et al. 1998).
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Microsatellites
Polymorphic microsatellites were available for 11 of our candidate genes: ACTC (2 microsatellites), CAV1 (1), CSRP3 (1), DES (1), LMNA (1), MYH7 (1), SGCD (2), TNNI3 (3), TPM1 (1), TTN (1), and VCL (1) (Table 2). Genotyping PCR conditions were 94 °C for 12 min, 35x (94 °C for 10 s, Ta °C for 15 s, and 72 °C for 30 s), and 72 °C for 20 min (Ta listed in Table 2). For some microsatellites, a protocol employing a common labeled primer was used (Table 2); the F-primer was tailed with an M13-sequence (GTTTTCCCAGTCACGAC--- [5'-3']) and the corresponding PCR was performed with 3 primers: the M13-tailed F-primer, a 6-FAM-labeled M13 primer, and the R-primer. A 3100 Genetic Analyzer was used for genotyping, and allele sizes were determined with Genescan Analysis 3.7 and Genotyper 3.7 software (Applied Biosystems).
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Single Nucleotide Polymorphisms
Single nucleotide polymorphisms (SNPs) were known for the genes CAV1, DES, TCAP, and TNNT2 (Table 3). Genomic DNA fragments of the Newfoundland dogs were PCR amplified (the thermal cycling program, Ta and primer sequences are listed in Table 3). The program was either Touchdown PCR at 95 °C for 5 min, 14x (95 °C for 30 s, Ta + 7 °C for 30 s, and 72 °C for 20 s) with Ta decreasing 0.5 °C per cycle, then 25x (94 °C for 30 s, Ta °C for 30 s, and 72 °C for 30 s), and 72 °C for 2 min; or regular PCR at 94 °C for 10 min, 35x (94 °C for 30 s, Ta °C for 30 s, and 72 °C for 30 s), and 72 °C for 10 min. Products were used in a Tercycle reaction, purified and analyzed as described above. DNA sequences were aligned using the Staden Package (Staden et al. 1998) and homo- and heterozygotes were scored by visual inspection.
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Linkage Analysis
Linkage analysis of DCM in the Newfoundland dogs and each of the candidate genes was conducted on 4 families segregating this disease. Dogs without signs of DCM were classified in one of 4 liability classes based on age at which the animal was examined last for DCM (Dukes-McEwan and Jackson 2002). Dogs examined at an age of <4 years were classified in group 1, dogs examined between 4 and 7 years of age were classified in group 2, between 7 and 10 years in group 3, and dogs older than 10 years in group 4. The penetrance of the genotype at risk was set at 0.10, 0.25, 0.80, and 1.0 for the liability classes 1–4, respectively, and a gene frequency of 0.01 was used. The Newfoundland dogs were genotyped for the microsatellites and SNPs closely situated by or within the respective candidate genes (Table 4). The allele frequencies were calculated based on the genotypes observed in the unrelated parents of our 4 families. Haplotypes were deduced and used to calculate LOD scores. Two-point linkage analysis was performed using MLINK of the LINKAGE package (Terwilliger and Ott 1994), with the disease modeled as an autosomal dominant trait with age-dependent penetrance and no phenocopies. A gene was excluded at a LOD score < –2.0.
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Two different approaches were used to test the candidate genes for involvement in DCM in the Newfoundland dog. For 2 genes (PLN and TCAP), a direct mutation screening was used because of the small size and limited number of exons of these genes. For the remaining 13 genes, polymorphic microsatellites and SNPs were used in a linkage analysis approach.
Mutation Detection
DNA sequence analysis was performed of the 2 exons and 6 putative promoter elements of the PLN gene (Stabej, Leegwater, Stokhof, et al. 2005). No differences were detected between 4 DCM-affected and 4 unaffected Newfoundland dogs. Alignment of the DNA sequence of the gene of Newfoundland dogs with published PLN DNA sequences (Uyeda et al. 1987; Stabej, Leegwater, Stokhof, et al. 2005) showed these to be identical.
Likewise, DNA sequence analysis was performed of the 2 exons of the TCAP gene in 4 DCM-affected and 4 unaffected Newfoundland dogs. Blast analysis showed the Newfoundland consensus sequence of exon 1 to be identical to TCAP exon 1 in the reference dog genome sequence. In TCAP exon 2, a SNP (T/C, position 29957 of AAEX01022011) was detected. This SNP was silent at the amino acid level. Both homozygous TT and heterozygous TC dogs were seen in the DCM-affected and the DCM-unaffected group. Except for this SNP, Blast analysis showed no DNA sequence differences between TCAP exon 2 of the Newfoundland dogs and the available DNA sequence in GenBank. An additional SNP (TCAP SNP 28.606, located 0.8 kb upstream of the gene's start codon) was typed to enable linkage analysis (see Tables 3 and 4).
Linkage Analysis of DCM
For some genes in this study, a single microsatellite or SNP was used for linkage analysis in the families of Newfoundland dogs. This was the case for the genes CSRP3, LMNA, MYH7, TNNT2, TPM1, TTN, and VCL (Table 4). For other genes, more than one polymorphic marker was analyzed to improve the informativeness. We did not observe recombination events between these markers, and deduced haplotypes were used in 2-point linkage calculations. Haplotypes were based on the genotypes of 2 microsatellites for ACTC and SGCD, 3 microsatellites in the case of TTNI3, and 3 SNPs in the case of LDB3. Data from both microsatellites and SNPs were used in haplotype construction for the genes CAV1 and DES. The markers used for each gene and the number of haplotypes formed are shown in Table 4. As an example, combination of microsatellite data and SNP data resulted in increased informativeness for DES: a CA repeat with 4 alleles in our families was combined with the information of 4 SNPs, resulting in 9 haplotypes that were used for linkage analysis (Table 4, Figure 1). The LOD scores obtained for each gene in 2-point linkage calculations are listed in Table 4.
The Newfoundland dog families that segregate DCM, and in which all the candidate genes were examined, are shown in Figure 1. Initially, only families A and B were available for linkage analysis, but during the study, the pedigrees were extended. All typed markers were informative in this family, and no recombination was observed between the markers tested for each gene. The results of the 2-point linkage analysis of each candidate gene and the LOD score obtained for each gene (at 
= 0.00 and 0.01) are shown in Table 4.
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Discussion |
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Pedigree and linkage analysis may be confounded in a late onset disease when screening of young animals is not informative. Furthermore, in this population of Newfoundlands, we identified many individuals with equivocal echocardiographic abnormalities such as depressed contractility or left ventricular enlargement, some of which progressed over time to an unequivocal phenotype of DCM. We selected families of dogs where animals had received serial echocardiographic examinations every 12–24 months in order to avoid wrong assignment of the phenotype. Dogs were included in the analysis if they had the early, equivocal echocardiographic abnormalities but were labeled as "unknown" in any linkage analysis. Of equal importance, dogs were only assigned as healthy when they were older than 8 years without any significant echocardiographic abnormalities, with left ventricular dimensions within reference ranges, and normal systolic function.
The linkage analysis of ACTC, CAV1, LDB3, LMNA, MYH7, SGCD, TCAP, TNNI3, TNNT2, TPM1, TTN, and VCL resulted in an LOD score less than –2.0 at = 0.00. Therefore, these genes can be excluded as the cause of DCM in the Newfoundland. For CSRP3, a LOD of –1.525 was obtained based on a CA repeat, which displayed 3 alleles. Analysis of 5 intragenic SNPs (data not shown) did not lead to additional CSRP3 haplotypes. For DES, a LOD of –1.828 was obtained based on a CA repeat combined with 4 intragenic SNPs. Both LOD scores make it highly unlikely that either of these genes is responsible for DCM in the Newfoundland dog.
The polymorphic microsatellites used in this linkage study were located between 0 (intragenic marker) and 179.8 kb away from the corresponding gene (Wiersma AC, Leegwater PAJ, Van Oost BA, Ollier WE, Dukes-McEwan J, forthcoming). The TNNI3 microsatellites 20CAa, 20CAb, and 17GA were located at a relatively large distance to the gene (Table 4) compared with the situation of the other microsatellites of this study. Together, these 3 microsatellites span a distance of approximately 293 kb. Because no recombination was observed between these markers in our families, the 3 microsatellites were analyzed in combination without genetic distance between them. Haplotypes were constructed for the 3 markers, and these were used in 2-point linkage analysis. The distance of the remaining 12 microsatellites used here, from their respective genes, was on average 20.3 kb (0–88.6 kb). Although there was virtually no genetic distance between each gene and its corresponding markers, LOD scores were calculated at both = 0.00 and = 0.01 (Table 4) to allow for unobserved crossover events and/or unlikely double recombinants. As a bi-allelic marker, a SNP is in general less informative than most microsatellites. However, by using haplotypes consisting of several SNPs and/or microsatellites, the informativeness could be increased.
For PLN and TCAP, a mutation screening approach was used. For PLN, the mutation detection of the 2 exons and promoter elements displayed no differences between DCM-affected and unaffected Newfoundland dogs. Although these results suggest that PLN is not involved in DCM in this breed, we cannot exclude mutations in other regions of the gene or as yet unknown regulatory sequences. For TCAP, a mutation detection screening of the gene's 2 exons and linkage analysis of a SNP (LOD score obtained = –4.231) were combined and indicated exclusion of TCAP as cause of DCM in the Newfoundland dog.
According to Aguirre-Hernández and Sargan (2005), whole-genome linkage studies are more effective than candidate gene studies in the search for genes involved in hereditary canine diseases. However, a low-resolution genome scan (Dukes-McEwan and Jackson 2002) performed in families A and B (Figure 1) did not identify the position of the disease locus. An SLINK power calculation based on this initial sample set had shown a minimum expected LOD score of 2.7 (for = 0.01) (Dukes-McEwan 1999), indicating that detection of the gene should be possible with markers at a short distance. Our sample set has been extended with 2 families (C and D) since. The present candidate gene approach allowed exclusion of 15 available candidate genes as a cause of DCM in Newfoundland dogs. This warrants a genome scan with a marker set of high resolution and a larger set of samples.
Our study concludes that the genetic cause of Newfoundland DCM may be different from the currently known gene mutations implicated in naturally occurring disease in man and experimental models of the disease. Identification of the cause of Newfoundland DCM may therefore be important for other breeds of dogs as well as other species, including humans.
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The Kennel Club Charitable Trust Canine Health Foundation Fund; Faculty of Veterinary Science, University of Liverpool (A.C.W.).
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Acknowledgments |
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We are grateful to Sandra Imholz and Francine Jury for technical assistance.
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Footnotes |
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Corresponding Editor: Ernest Bailey
Received February 22, 2007
Accepted September 25, 2007
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