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Physiol. Genomics 25: 387-392, 2006; doi:10.1152/physiolgenomics.00010.2006
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Received 23 January 2006; accepted in final form 14 February 2006.
Physiological Genomics 25:387-392 (2006)
1094-8341/06 $8.00 © 2006 American Physiological Society

Fine mapping of Dyscalc1, the major genetic determinant of dystrophic cardiac calcification in mice

Susanne Korff *, Frank Schoensiegel *, Nora Riechert , Dieter Weichenhan , Hugo A. Katus and Boris T. Ivandic

Department of Medicine III, Division of Cardiology, University of Heidelberg, Heidelberg, Germany


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Calcification of severely dystrophic muscle is occasionally observed in targeted mouse models of muscular dystrophy and cardiomyopathy. Intracellular calcium deposition occurs in necrotic myocytes in the absence of plasma calcium and phosphate imbalances. In the heart, this recessive trait is referred to as dystrophic cardiac calcinosis (DCC). We identified previously Dyscalc1, a major genetic determinant of DCC, in a 15.2-Mbp region on proximal chromosome 7. We report now further steps toward the identification of the Dyscalc1 gene by reverse genetics. Transferring the Dyscalc1 locus from susceptible mouse strain C3H/He onto a resistant C57BL/6 strain background, we generated congenic inbred strains B6.C3-(D7Mit56-D7Mit230) and B6.C3-(D7Nds5-D7Mit230). Three days after myocardial freeze-thaw injury, both strains exhibited calcification of necrotic lesions, confirming the pathogenetic relevance of Dyscalc1. Analysis of two (129S1 x C57BL/6) x 129S1 backcrosses allowed mapping of Dyscalc1 more precisely to a region spanning 0.76 Mbp between genes Fgf21 (39.70 Mbp) and Myod1 (40.46 Mbp). This interval contains 31 known and putative genes in three large, ancestral haplotypes shared by susceptible strains C3H/He, 129S1, and DBA/2. Thus we were able to exclude previously proposed candidate genes Bax and Hrc. Instead, a potential candidate may be the gene encoding the ATP-binding cassette C6. Mutations in the orthologous human ABCC6 gene cause pseudoxanthoma elasticum, or Gronblad-Strandberg syndrome, an elastic tissue disorder with cardiovascular calcifications.

Abcc6; congenic strains; cardiomyopathy; pseudoxanthoma elasticum


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
TARGETED DELETION of intermediate filaments, members of the sarcomere, or the dystroglycan complex may lead to muscular dystrophy and/or cardiomyopathy in the mouse. Calcification of severely dystrophic muscle, which occurred in the presence of physiological serum calcium and phosphate levels, was occasionally reported in these mouse models (11, 13, 18, 19). Histological examination revealed intracellular mineralization, which may be initiated by calcified mitochondria (16). In the heart, this phenotype is referred to as dystrophic cardiac calcinosis (DCC) (9). Certain diets and hormones, viral infection, and also direct freeze-thaw injury lead to myocardial calcifications in susceptible mouse strains (4, 10, 12, 17, 21). The susceptibility to DCC displays a recessive mode of inheritance and may be considered as a modifier of the cardiomyopathy phenotype in mice. To dissect the genetics of DCC, we performed quantitative trait locus (QTL) analysis of an F2 intercross between susceptible strain C3H and resistant strain C57BL/6 (14). At least four genetic loci, designated Dyscalc1–4, were identified on mouse chromosomes 7, 4, 12, and 14, respectively (15). Together, these loci accounted for 50% of the phenotypic variance of DCC induced by a high-fat diet. The major determinant, Dyscalc1, was mapped to a relatively large interval spanning ~15.2 Mbp between the genetic markers D7Mit224 (28.46 Mbp) and D7Mit230 (43.62 Mbp) on proximal chromosome 7 (14, 15). Later, other authors (5, 16, 24) confirmed the major role of Dyscalc1 for DCC in C3H and 129S1 and also in DBA/2.

We report here further progress toward the discovery of the still unknown Dyscalc1 gene including the analysis of novel congenic strains and high-resolution mapping to provide the basis for positional cloning or direct candidate gene tests. We were able to map the Dyscalc1 locus to an interval <1 million base pairs (Mbp) and propose a new candidate gene, Abcc6. Mutations in the orthologous human gene cause pseudoxanthoma elasticum [Online Mendelian Inheritance in Man (OMIM) entry no. 264800], a multisystem disorder that is associated with calcium deposition in the cardiovascular system.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals.
Inbred strains C57BL/6NCrlBr (C57BL/6), C3H/HeNCrlBr (C3H/He), CBA/JNCrljCrlg (CBA), and 129S1/SvImJ (129S1) were purchased from Charles River (Sulzbach-Rosenberg, Germany). Mice were maintained in specific pathogen-free facilities, with 15 air changes/h and a 12:12-h light-dark cycle. Room temperature was 22 ± 2°C, and relative humidity was 55 ± 10%. Up to five mice were maintained in Macrolon Type II cages on hardwood bedding. They had free access to standard rodent chow and tap water.

Animal procedures were conducted in accordance with the German Animal Welfare Act; the experimental plan was approved by the government. At the age of 6–8 wk, female mice were subjected to transdiaphragmal freeze-thaw injury as described previously (1, 3, 25). Three days after freeze-thaw injury, mice were killed by cervical dislocation. Then, hearts were quickly excised, rinsed with phosphate-buffered saline, immersed in tissue freeze medium (Leica Instruments, Leimen, Germany), frozen in liquid nitrogen, and stored at –20°C until histological examination. Calcium deposits were detected using Alizarin red S staining (Sigma) as described previously (1, 7, 15).

Analysis of DNA.
DNA was isolated from small tail biopsies by use of standard protocols. Simple sequence length polymorphism (SSLP) markers were selected from the Mouse Phenome Database (http://aretha.jax.org/pub-cgi/phenome/mpdcgi?rtn=projects/details&id=148) and amplified by PCR. Primer sequences were obtained from a database at the Broad Institute (http://www.broad.mit.edu/cgi-bin/mouse/sts_info?database=mouserelease). Marker genotypes were determined by electrophoretic separation of allelic size differences of the PCR fragments on a 4% Metaphor agarose gel (Cambrex Bioproducts, Verviers, Belgium) if they were expected to differ by >5%. Smaller allelic differences were resolved by polyacrylamide gel electrophoresis by use of Cy5-labeled forward primers and a fluorescence-assisted sequencer (ALF Express, Pharmacia). Single nucleotide polymorphisms (SNPs) were genotyped by direct sequencing. Primers were designed with sequence context obtained from the Ensembl Mouse Genome Server, querying "rs"-accession numbers (http://www.ensembl.org/Mus_musculus/). Additional SNPs were identified newly by alignment of genomic sequences from different strains.

Positions of SSLPs, SNPs, and genes were obtained by querying [basic local alignment search tool (Blast)N algorithm] their sequence context against the mouse genome assembly available on the Ensembl Mouse Genome Server (Build 34, released May 17, 2005).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Novel congenic strains for DCC.
Congenic strains are inbred, allowing us to study the effects of a locus of interest in multiple animals with a defined, identical genetic background. Phenotypic differences between congenic and background strain are caused by allelic differences at this locus. To obtain proof of the pathogenetic relevance, we transferred Dyscalc1 by breeding from the susceptible donor strain C3H/He onto the genetic background of the resistant acceptor strain C57BL/6. At the outset, male (C57BL/6 x C3H/He)F1 mice were crossed back to C57BL/6 females. Male offspring was genotyped by use of SSLP markers D7Mit56, D7Mit247, D7Mit229, D7Mit230, D7Mit82, D7Mit31, and D7Mit332. Only mice that retained heterozygous alleles at all these marker loci were further backcrossed to C57BL/6 females. Marker-assisted selection and backcrossing was repeated for nine generations to reduce residual nontarget donor background by ~50% in each round. Then, offspring (generation N10) was intercrossed, and recombinant progeny were selected for further brother x sister mating to obtain different congenic inbred strains with homozygous C3H/He donor regions of various extent on proximal chromosome 7. We obtained congenic strain B6.C3-(D7Mit56-D7Mit230), which exhibited a donor segment of ~37 Mbp starting at the acrocentric centromere (Table 1). This strain was then backcrossed to C57BL/6 to reduce the size of the donor segment further. This resulted in another congenic strain, designated B6.C3-(D7Nds5-D7Mit230), that exhibited susceptible C3H alleles in a donor segment of at least 5.35 Mbp (Table 1) located between SSLP markers D7Nds5 (38.28 Mbp) and D7Mit230 (43.62 Mbp). Both congenic strains were susceptible to DCC (Fig. 1, A and B), suggesting that Dyscalc1 resides in the smaller donor segment of B6.C3-(D7Nds5-D7Mit230). DCC was confirmed in all mice tested (n = 5). Resistant strains such as C57BL/6 (data not shown) and CBA (Fig. 1C) exhibited no calcium deposition in necrotic lesions.


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  		Table 1. Genotyping of DCC-susceptible congenic inbred strains on chromosome 7

 

Figure 1
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  		Fig. 1. Photomicrographs (12.5x) illustrate necrotic lesions 3 days after myocardial freeze-thaw injury in congenic strains B6.C3-(D7Mit56-D7Mit230) (A) and B6.C3-(D7Hd1-D7Mit69) (B) as well as inbred strain CBA (C). The extent of the necrotic lesion is delineated by arrowheads. Focal calcium deposits stained red with Alizarin red S and were observed in the right ventricular wall and the septum.

 
Dyscalc1 mapped to a 0.76-Mbp interval on chromosome 7.
Recently, we reported linkage of DCC to Dyscalc1 in inbred strain 129S1, analyzing segregation of SSLP marker D7Mit229 in 131 female progeny of a (129S1 x C57BL/6)F1 x 129S1 backcross (16). Here, we extended these studies to map Dyscalc1 more precisely and genotyped SSLPs D7Mit228, D7Mit364, D7Mit229, D7Mit69, and D7Mit230 covering the Dyscalc1 interval, which was defined by analysis of congenic strain B6.C3-(D7Nds5-D7Mit230). SNP rs3659049 and a SNP identified in the gene encoding the fibroblast growth factor-21, Fgf21, were included to improve the resolution of mapping (Tables 2 and 3). In DCC-resistant animals, recombinations occurred between Fgf21 and D7Mit229 and between SNP rs3659049 and D7Mit69, respectively (Table 2). Thus the size of the Dyscalc1 interval was reduced to 3.48 Mbp between Fgf21 (39.70 Mbp) and D7Mit69 (43.18 Mbp). However, this interval still encompassed 69 entries of known and predicted genes in the Ensembl database.


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  		Table 2. Genotypes and DCC phenotypes of 131 female (129S1 x C57BL/6) x 129S1 backcross progeny

 

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  		Table 3. Gene SNPs identified by sequencing and alignment of sequence information from different strains

 
To achieve further reduction, we bred and analyzed more (129S1 x C57BL/6)F1 x 129S1 backcross progeny (see above). This time, we genotyped SSLP markers D7Mit364 (39.31 Mbp) and D7Mit230 (43.62 Mbp) in 253 male and female mice. Two of five mice exhibiting a recombination between these flanking markers were genotyped by use of additional SSLPs (D7Mit229, D7Mit158, and D7Mit69) and SNPs (rs3680130, rs4226582, rs3659049, Fgf21, Fut2, Sec1, Myod1). SNPs in Fut2, Sec1, and Myod1 were identified newly by sequencing and alignment of sequence information from various strains (Table 3). We identified one female mouse with a recombination between D7Mit158 and Myod1 and crossed it back to 129S1 to confirm its phenotype by analysis of its offspring. Four of nine female progeny exhibited the heterozygous genotype of the recombination seen in the mother. As confirmed by histological examination, all four mice were completely resistant to DCC. These results suggested that the Dyscalc1 locus was flanked by Fgf21 (39.70 Mbp) and Myod1 (40.46 Mbp) at the proximal and the distal ends, respectively. This 0.76-Mb segment contains 31 known and predicted genes according to the Ensembl database.

Because potential candidate genes were still numerous, we tried to exclude additional regions in the Dyscalc1 interval by haplotype analysis. We included 15 SNPs spanning the entire 0.76-Mbp interval with an average spacing of 60.850 bp (maximal spacing 123.903 bp). Three large haplotype blocks were shared by susceptible strains C3H/HeJ, 129S1/SvImJ, and DBA/2J and covered almost the entire Dyscalc1 interval (Table 4). In contrast, identical genotypes were found in these susceptible strains and resistant C57BL/6J and CBA in three very small regions around SNPs rs8258164 (39.81 Mbp), rs6302216 (40.19 Mbp), and rs6295036 (40.35 Mbp). These SNPs mapped at the loci of Sult2b1, Abcc8, and Otog, respectively.


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  		Table 4. SNP genotypes used for haplotype analysis

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Calcification of severely dystrophic muscle is a well-known phenomenon in mouse models of muscular dystrophy (13) and cardiomyopathy (11, 18, 19). The calcifying phenotype of cardiomyopathy is explained by a strain-dependent, genetic susceptibility to DCC. Interestingly, "subphenotypes" of DCC occur depending on the genetic background of the mouse strain: myocardial calcifications are found in DBA/2, C, C3H, and, with variable penetrance, also in BALB/c (9, 10, 12, 16). We reported previously that A/J is almost resistant and demonstrated here that CBA is completely resistant to myocardial DCC as well. Epi- and pericardial calcifications were seen in DBA/2 and BALB/c, but not in C3H (9, 10, 12, 16). Calcification of other striated muscles, such as the tongue, was observed in DBA/2 in response to a high-phosphorus diet (24). Calcification of the aortic root was found in DBA/2 and C3H on a high-fat, cholesterol-rich diet. Linkage analysis suggested that aortic and myocardial calcification shared Dyscalc1 as common genetic determinant (6). This raised the possibility that Dyscalc loci may also play a role in the pathogenesis of vascular calcifications, a hallmark of advanced atherosclerosis. The different subphenotypes of DCC may be explained by the close relationships among the strains that exhibit a high disease penetrance (2, 20, 26). DBA/2 was derived from one of the most ancestral progenitors of all strains in this group (Fig. 2) and was also the strain exhibiting all subphenotypes. Therefore, DBA/2 may harbor most, if not all, genetic contributors to DCC. Hypothetically, these susceptibility loci, however, were split and partially lost during the generation of related strains. Some strains may have retained loci for myocardial calcification (e.g., C3H), whereas others may have lost them (e.g., A/J and CBA). Admixture of other genetic modifiers may explain additional variability of DCC penetrance.


Figure 2
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  		Fig. 2. Genealogy of mouse inbred strains [simplified after Beck et al. (2)].

 
Congenic strains highlighted the relevance of Dyscalc1.
As a first step in the dissection of the complex genetics of myocardial calcifications, we identified previously several Dyscalc loci by use of QTL analysis. The existence of the major genetic determinant, Dyscalc1, was suggested by linkage of DCC to proximal chromosome 7 (maximal LOD score of 11.4) in a (C57BL/6 x C3H/He) F2 intercross (14, 15). Although very strong, this statistical association had to be confirmed in an in vivo model.

The next step, the confirmation of the pathogenetic relevance of Dyscalc1, was now achieved by generation of congenic strains. These strains were susceptible to DCC, because they had received a small chromosomal donor region from C3H/He that contained the susceptible Dyscalc1 alleles, while the remaining genetic background was derived from C57BL/6. Colinayo et al. (6) studied recombinant congenic strains that were previously constructed in the opposite way, i.e., with resistant strain C57BL/10 as the donor and susceptible C3H/DiSnA as the recipient strain (8). They analyzed segregation of DCC in an intercross between the resistant congenic strain HcB24 and the susceptible parental strain C3H/DiSnA and mapped Dyscalc1 to an interval spanning 11.57 Mbp between SSLP markers D7Mit270 (34.14 Mbp) and D7Mit82 (45.71 Mbp) (6). This chromosomal region contains 259 known and predicted genes and exhibits synteny with human chromosomes 19, 16, and 11. We reported recently that strain 129S1 is also susceptible to DCC and that myocardial calcifications are determined by Dyscalc1 in this strain as well. Interestingly, various 129-substrains are contaminated with genetic material from several other strains (22, 23). Genome analysis revealed that 129S1 received a segment from C3H extending from ~22 to 83 Mbp on chromosome 7 (20). Therefore, 129S1 may be considered as a "natural" congenic inbred strain for Dyscalc1. Consistently, the histological phenotype of DCC was comparable in 129S1 and C3H (16).

In summary, present and previous studies of congenic strains established the pathogenetic relevance of Dyscalc1. However, systematic tests of potential candidate genes were not justified at this point, because the congenic donor segments were still very large. Further reduction of the size of the Dyscalc1 locus was therefore necessary.

High-resolution mapping pinpointed Dyscalc1.
We analyzed allelic recombinations in 384 mice of two (129S1 x C57BL/6) x 129S1 backcrosses and refined the location of Dyscalc1 to no more than 0.76 Mbp. Because this locus still contained 31 known or presumed candidate genes, we tried to exclude some of them by haplotype analysis. Three haplotypes were shared by resistant and susceptible strains but covered only a small fraction of the Dyscalc1 interval. They involved SNPs located in genes Sult2b1, Abcc8, and Otog. However, the size of these haplotypes must be determined more exactly to exclude reliably one of these genes. The remaining genomic interval of Dyscalc1 displayed three ancestral haplotypes shared only by susceptible strains C3H, 129S1, and DBA/2. Although closely related to C3H, strain CBA was resistant to DCC. Consistent with this novel finding, CBA and C57BL/6 had identical haplotypes. We did not exclude the existence of smaller, interspersed haplotypes. However, genotyping of more closely spaced SNPs may not resolve these haplotype blocks, because, at present, Dyscalc1 has been firmly established as the major genetic determinant of DCC in three strains only. Their close relationships limit their genomic diversity and, consequently, also the power of haplotype analysis.

Abcc6 is a potential candidate gene for Dyscalc1.
Until now, direct candidate gene testing was not practicable to identify the still unknown Dyscalc1 gene, because proximal chromosome 7 is particularly gene rich. Even the 0.76-Mbp interval contained 5 novel, putative and 26 known genes. None of these genes had an obvious role in apoptosis or calcium handling, both of which may be relevant for DCC. Thus the proapoptotic Bcl2-associated X-protein (Bax) and the histidine-rich calcium-binding protein (Hrc) of the sarcoplasmatic reticulum as well as the G protein-coupled receptor Gprc2-rs1, formerly known as calcium-sensing receptor-related sequence-1, can be excluded as potential candidate genes, because their loci did not map in the smaller Dyscalc1 interval reported here (6, 15). Because the pathophysiological mechanisms of DCC are unclear, alternative candidate genes and pathways were not identified at this stage, even if mapping information of the other Dyscalc loci was included for the search. Alternatively, candidate genes may be identified by comparative mapping of QTLs in different species that exhibit similar phenotypes or disorders. In humans, pseudoxanthoma elasticum (OMIM no. 246800), or Gronblad-Strandberg syndrome, is an elastic tissue disorder with cardiovascular calcifications. Histopathological findings in blood vessels demonstrated elastin fibers with granular calcium deposits, but the mechanisms of their development are still unclear. Pseudoxanthoma elasticum is caused by mutations in the ATP-binding cassette C6 (Abcc6), a plasma membrane transporter potentially involved in cellular detoxification. ABCC6 was mapped to human chromosome 16p13.1 and may be a potential candidate gene for DCC, because, in the mouse, it is located in the Dyscalc1 interval at 40.06 Mbp.


   GRANTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was mainly supported by Grant Iv 10/3-2 (to B. Ivandic) from the Deutsche Forschungsgemeinschaft. S. Korff received a research fellowship from the University of Heidelberg. Additional support came from Bundesministerium fuer Bildung und Forschung Grant NHK-S19T13 of the German National Genome Research Network (http://www.ngfn.de).


   ACKNOWLEDGMENTS
 
We thank Dr. Aherrahrou and Mr. Kaczmarek for assistance in the initial steps of the construction of the congenic strains. We thank also Ms. Menges-Wirth for excellent technical assistance.


   FOOTNOTES
 
Article published online before print. See web site for date of publication (http://physiolgenomics.physiology.org).

Address for reprint requests and other correspondence: B. Ivandic, Innere Medizin, Abt. III, Universitätsklinikum Heidelberg, Otto-Meyerhof-Zentrum, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany (e-mail: Boris.Ivandic{at}med.uni-heidelberg.de).

* S. Korff and F. Schoensiegel contributed equally to this study. Back


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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