Ultrafine mapping of <i>Dyscalc1</i> to an 80-kb chromosomal segment on chromosome 7 in mice susceptible for dystrophic calcification

Aherrahrou, Zouhair; Doehring, Lars C.; Kaczmarek, Piotr; Liptau, Henrike; Ehlers, Eva-Maria; Pomarino, Andrea; Wróbel, Sandra; Götz, Anika; Mayer, Björn; Erdmann, Jeanette; Schunkert, Heribert

doi:10.1152/physiolgenomics.00133.2006

Cited by 24 publications

(20 citation statements)

References 19 publications

(34 reference statements)

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“…Tissues were prepared as previously described (13). Slides were stained using alizarin red S and calcein stains for analysis of calcium phosphate deposits (13,23).…”

Section: Methodsmentioning

confidence: 99%

“…Reverse Transcriptase PCR and mRNA Quantification-Total RNA was extracted from liver and reverse-transcribed into complementary DNA (cDNA) as previously described (13). Changes in mRNA levels were determined using the ⌬⌬Ct method as previously reported (11,13).…”

Section: Methodsmentioning

confidence: 99%

“…As shown in Table 3 we tested for genotype-phenotype association (Table 4) C3H, DBA, and 129S1 mice as well as B6.C3H Dyscalc1 congenic mice were found to carry the Thr allele at the 3Ј-border of exon 14 (at codon 619). All these mice were found to display DCC after freeze-thaw injury (13). In contrast, mice that carry the Cys allele were found either negative (C57, FVB, MRL, A, and CBA) or positive (NZB and Balb/c) for DCC.…”

Section: Volume 283 • Number 12 • March 21 2008mentioning

confidence: 98%

“…The genetic basis of DCC was initially facilitated by the identification of a major QTL locus named Dyscalc1 on mouse chromosome 7 that contributes to DCC (12). We ultrafine-mapped this locus to an 80-kb region on proximal mouse chromosome 7 that contains only two known genes, epithelial membrane protein-3 (EMP-3) and the ATP binding cassette C 6 (Abcc6), and one gene of unknown function (BC013491) using an in silico mapping strategy (13). In parallel, the locus for PXE was identified on human chromosome 16p13.1 to a 500-kb region that also includes Abcc6 (14,15).…”

Section: Dystrophic Cardiac Calcifications (Dcc)mentioning

confidence: 99%

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An Alternative Splice Variant in Abcc6, the Gene Causing Dystrophic Calcification, Leads to Protein Deficiency in C3H/He Mice

Aherrahrou

Doehring

Ehlers

et al. 2008

Journal of Biological Chemistry

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Dystrophic cardiac calcification (DCC) is an autosomal recessive trait characterized by calcium phosphate deposits in myocardial tissue. The Abcc6 gene locus was recently found to mediate DCC; however, at the molecular level the causative variants remain to be determined. Examining the sequences of Abcc6 cDNA in DCC-resistant C57BL/6 and DCC-susceptible C3H/He mice, we identified a missense mutation (Cys to Thr at codon 619, rs32756904) at the 3-border of exon 14 that creates an additional donor splice site (GT). Accordingly, an alternative transcript variant was detected, lacking the last 5 bp of exon 14 (-AGG(C/T)GCTgtga-) in DCC-susceptible C3H/He mice that carry the Thr allele. The 5-bp deletion was found to result in premature termination at codon 684, in turn leading to protein deficiency in DCC-susceptible mouse tissue as well as in cells transfected with Abcc6 cDNA lacking the last 5 bp of exon 14. All mouse strains that were found to carry the Thr allele, including C3H/He, DBA/2J, and 129S1/SvJ, were also found to be positive for DCC. In summary, we identified a splice variant leading to a 5-bp deletion in the Abcc6 transcript that gives rise to protein deficiency both in vivo and in vitro. The fact that all mouse strains that carry the deletion also develop dystrophic calcifications further suggests that the underlying splice variant affects the biological function of MRP6 protein and is a cause of DCC in mice.

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“…Tissues were prepared as previously described (13). Slides were stained using alizarin red S and calcein stains for analysis of calcium phosphate deposits (13,23).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Volume 283 • Number 12 • March 21 2008mentioning

confidence: 98%

Section: Dystrophic Cardiac Calcifications (Dcc)mentioning

confidence: 99%

See 2 more Smart Citations

An Alternative Splice Variant in Abcc6, the Gene Causing Dystrophic Calcification, Leads to Protein Deficiency in C3H/He Mice

Aherrahrou

Doehring

Ehlers

et al. 2008

Journal of Biological Chemistry

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“…Dyscalc1 is a major contributor to dystrophic cardiovascular calcification in susceptible strains, affecting both the vessels and myocardium (8). Two genes have been independently implicated in Dyscalc, Abcc6 and Emp3 (9,10). Both genes were excluded as accounting for dMOD1 gene using known disease-associated polymorphisms and finding that both parental strains had the susceptible alleles of each gene (data not shown).…”

Section: F 2 Mice Display An Intermediate Phenotype Between the Two Pmentioning

confidence: 99%

Latent TGF-β–binding protein 4 modifies muscular dystrophy in mice

Heydemann¹,

Ceco²,

Lim³

et al. 2009

J. Clin. Invest.

181

240

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Most single-gene diseases, including muscular dystrophy, display a nonuniform phenotype. Phenotypic variability arises, in part, due to the presence of genetic modifiers that enhance or suppress the disease process. We employed an unbiased mapping approach to search for genes that modify muscular dystrophy in mice. In a genome-wide scan, we identified a single strong locus on chromosome 7 that influenced two pathological features of muscular dystrophy, muscle membrane permeability and muscle fibrosis. Within this genomic interval, an insertion/deletion polymorphism of 36 bp in the coding region of the latent TGF-β-binding protein 4 gene (Ltbp4) was found. Ltbp4 encodes a latent TGF-β-binding protein that sequesters TGF-β and regulates its availability for binding to the TGF-β receptor. Insertion of 12 amino acids into the proline-rich region of LTBP4 reduced proteolytic cleavage and was associated with reduced TGF-β signaling, decreased fibrosis, and improved muscle pathology in a mouse model of muscular dystrophy. In contrast, a 12-amino-acid deletion in LTBP4 was associated with increased proteolysis, SMAD signaling, and fibrosis. These data identify Ltbp4 as a target gene to regulate TGF-β signaling and modify outcomes in muscular dystrophy.

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Modern Genome Annotation

Frishman¹,

Valencia²

2008

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Ultrafine mapping of Dyscalc1 to an 80-kb chromosomal segment on chromosome 7 in mice susceptible for dystrophic calcification

Abstract: mapping of Dyscalc1 to an 80-kb chromosomal segment on chromosome 7 in mice susceptible for dystrophic calcification.

Cited by 24 publications

References 19 publications

An Alternative Splice Variant in Abcc6, the Gene Causing Dystrophic Calcification, Leads to Protein Deficiency in C3H/He Mice

An Alternative Splice Variant in Abcc6, the Gene Causing Dystrophic Calcification, Leads to Protein Deficiency in C3H/He Mice

Latent TGF-β–binding protein 4 modifies muscular dystrophy in mice

Modern Genome Annotation

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