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A Haplotype of Two Novel Polymorphisms in δ-Sarcoglycan Gene Increases Risk of Dilated Cardiomyopathy in Mongoloid Population.

Chen J, Jin Y, Wang H, Wei S, Chen D, Ying L, Zhou Q, Li G, Li J, Gao J, Kato N, Hu W, Li Y, Wang Y - PLoS ONE (2015)

Bottom Line: C.-100~-110 resulted in a decrease of δ-SG promoter activity to 64±3% of the control level (p<0.01).Both co-immunoprecipitation and in vitro protein pull-down assays demonstrated that δ-SG-283R interacts normally to β- and γ-SG, but significantly decreased localization of β/δ/γ-SG on the plasma membrane.In conclusion, haplotype -_G composed of c.-100~-110 and A848G confers higher susceptibility to DCM in the Mongoloid population.

View Article: PubMed Central - PubMed

Affiliation: Molecular Cardiology Research Laboratory, Department of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

ABSTRACT
The role of genetic abnormality of δ-sarcoglycan (δ-SG) gene in dilated (DCM) and hypertrophied (HCM) cardiomyopathy patients is still unfolding. In this study we first defined the promoter region and then searched for polymorphisms/mutations among the promoter, 5'-untranslated region, and the encoding exons in δ-SG gene in 104 Chinese patients with DCM, 145 with HCM, and 790 normal controls. Two novel polymorphisms were found, an 11 base-pair (bp) deletion (c.-100~-110; -) in the promoter region and a missense polymorphism of A848G resulting in p.Q283R in the highly conserved C-terminus. The prevalence of homozygous genotype -/- of c.-100~-110 was slightly higher in DCM (14.42%) and HCM patients (14.48%), as compared with normal controls (11.01%). The prevalence of genotype of 848A/G was significantly higher in DCM (6.73%; OR = 9.43; p = 0.0002), but not in HCM patients (1.38%; OR = 1.37; p = 0.62), as compared with controls (0.76%). Haplotype -_G consisting c.-100~-110 and A848G was associated with increased risk of DCM (OR = 17.27; 95%CI = 3.19-93.56; p = 0.001) but not associated with HCM (OR = 1.90; 95%CI = 0.38-9.55; p = 0.44). Co-occurrence of the genotypes -/- of c.-100~-110 and 848A/G was found in 5 patients with DCM (4.81%; OR = 39.85; p = 0.0001), none of HCM patients, and only 1 of the controls (0.13%). Both polymorphisms were also found in the Japanese population, but not in the Africans and Caucasians. C.-100~-110 resulted in a decrease of δ-SG promoter activity to 64±3% of the control level (p<0.01). Both co-immunoprecipitation and in vitro protein pull-down assays demonstrated that δ-SG-283R interacts normally to β- and γ-SG, but significantly decreased localization of β/δ/γ-SG on the plasma membrane. In conclusion, haplotype -_G composed of c.-100~-110 and A848G confers higher susceptibility to DCM in the Mongoloid population.

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Genotypic analysis of the Exon-8 of the human δ-SG gene.Fig 3A shows genomic sequences of a wild type sample (upper panel) and a sample with 848A/G (lower panel). Fig 3B illustrates that 848A/G results in Q283A in the highly conserved C-terminus of the δ-SG gene among different species. Fig 3C shows that 848A/G creates a neonate cutting site for Bsl I. Fig 3D demonstrates differential cutting patterns by Bsl I of normal samples (N; double bands of 94 and 240bp) and a sample with 848A/G (He; quadruple bands of 23, 71, 94 and 240bp). The cut samples were separated on 12.5% polyacrylamide gel and the gels were stained by SYBR-green.
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pone.0145602.g003: Genotypic analysis of the Exon-8 of the human δ-SG gene.Fig 3A shows genomic sequences of a wild type sample (upper panel) and a sample with 848A/G (lower panel). Fig 3B illustrates that 848A/G results in Q283A in the highly conserved C-terminus of the δ-SG gene among different species. Fig 3C shows that 848A/G creates a neonate cutting site for Bsl I. Fig 3D demonstrates differential cutting patterns by Bsl I of normal samples (N; double bands of 94 and 240bp) and a sample with 848A/G (He; quadruple bands of 23, 71, 94 and 240bp). The cut samples were separated on 12.5% polyacrylamide gel and the gels were stained by SYBR-green.

Mentions: Next, we searched for SNP/mutations in all 8 exons in CM patients by direct sequencing. No previously-reported mutations or SNPs were found in exon-1~7 [18, 21–25]. In exon-8, a novel nucleotide substitution of A848G (CAG→CGG), resulting in conversion of p.Q283R (Fig 3A), was discovered in the universally conserved extreme C-terminus (Fig 3B). This polymorphism creates a new restriction enzyme site for Bsl I (Fig 3C), which we used for genotyping (Fig 3D).


A Haplotype of Two Novel Polymorphisms in δ-Sarcoglycan Gene Increases Risk of Dilated Cardiomyopathy in Mongoloid Population.

Chen J, Jin Y, Wang H, Wei S, Chen D, Ying L, Zhou Q, Li G, Li J, Gao J, Kato N, Hu W, Li Y, Wang Y - PLoS ONE (2015)

Genotypic analysis of the Exon-8 of the human δ-SG gene.Fig 3A shows genomic sequences of a wild type sample (upper panel) and a sample with 848A/G (lower panel). Fig 3B illustrates that 848A/G results in Q283A in the highly conserved C-terminus of the δ-SG gene among different species. Fig 3C shows that 848A/G creates a neonate cutting site for Bsl I. Fig 3D demonstrates differential cutting patterns by Bsl I of normal samples (N; double bands of 94 and 240bp) and a sample with 848A/G (He; quadruple bands of 23, 71, 94 and 240bp). The cut samples were separated on 12.5% polyacrylamide gel and the gels were stained by SYBR-green.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4697846&req=5

pone.0145602.g003: Genotypic analysis of the Exon-8 of the human δ-SG gene.Fig 3A shows genomic sequences of a wild type sample (upper panel) and a sample with 848A/G (lower panel). Fig 3B illustrates that 848A/G results in Q283A in the highly conserved C-terminus of the δ-SG gene among different species. Fig 3C shows that 848A/G creates a neonate cutting site for Bsl I. Fig 3D demonstrates differential cutting patterns by Bsl I of normal samples (N; double bands of 94 and 240bp) and a sample with 848A/G (He; quadruple bands of 23, 71, 94 and 240bp). The cut samples were separated on 12.5% polyacrylamide gel and the gels were stained by SYBR-green.
Mentions: Next, we searched for SNP/mutations in all 8 exons in CM patients by direct sequencing. No previously-reported mutations or SNPs were found in exon-1~7 [18, 21–25]. In exon-8, a novel nucleotide substitution of A848G (CAG→CGG), resulting in conversion of p.Q283R (Fig 3A), was discovered in the universally conserved extreme C-terminus (Fig 3B). This polymorphism creates a new restriction enzyme site for Bsl I (Fig 3C), which we used for genotyping (Fig 3D).

Bottom Line: C.-100~-110 resulted in a decrease of δ-SG promoter activity to 64±3% of the control level (p<0.01).Both co-immunoprecipitation and in vitro protein pull-down assays demonstrated that δ-SG-283R interacts normally to β- and γ-SG, but significantly decreased localization of β/δ/γ-SG on the plasma membrane.In conclusion, haplotype -_G composed of c.-100~-110 and A848G confers higher susceptibility to DCM in the Mongoloid population.

View Article: PubMed Central - PubMed

Affiliation: Molecular Cardiology Research Laboratory, Department of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

ABSTRACT
The role of genetic abnormality of δ-sarcoglycan (δ-SG) gene in dilated (DCM) and hypertrophied (HCM) cardiomyopathy patients is still unfolding. In this study we first defined the promoter region and then searched for polymorphisms/mutations among the promoter, 5'-untranslated region, and the encoding exons in δ-SG gene in 104 Chinese patients with DCM, 145 with HCM, and 790 normal controls. Two novel polymorphisms were found, an 11 base-pair (bp) deletion (c.-100~-110; -) in the promoter region and a missense polymorphism of A848G resulting in p.Q283R in the highly conserved C-terminus. The prevalence of homozygous genotype -/- of c.-100~-110 was slightly higher in DCM (14.42%) and HCM patients (14.48%), as compared with normal controls (11.01%). The prevalence of genotype of 848A/G was significantly higher in DCM (6.73%; OR = 9.43; p = 0.0002), but not in HCM patients (1.38%; OR = 1.37; p = 0.62), as compared with controls (0.76%). Haplotype -_G consisting c.-100~-110 and A848G was associated with increased risk of DCM (OR = 17.27; 95%CI = 3.19-93.56; p = 0.001) but not associated with HCM (OR = 1.90; 95%CI = 0.38-9.55; p = 0.44). Co-occurrence of the genotypes -/- of c.-100~-110 and 848A/G was found in 5 patients with DCM (4.81%; OR = 39.85; p = 0.0001), none of HCM patients, and only 1 of the controls (0.13%). Both polymorphisms were also found in the Japanese population, but not in the Africans and Caucasians. C.-100~-110 resulted in a decrease of δ-SG promoter activity to 64±3% of the control level (p<0.01). Both co-immunoprecipitation and in vitro protein pull-down assays demonstrated that δ-SG-283R interacts normally to β- and γ-SG, but significantly decreased localization of β/δ/γ-SG on the plasma membrane. In conclusion, haplotype -_G composed of c.-100~-110 and A848G confers higher susceptibility to DCM in the Mongoloid population.

Show MeSH
Related in: MedlinePlus