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Genetic analysis of Down syndrome-associated heart defects in mice.

ABSTRACT: Human trisomy 21, the chromosomal basis of Down syndrome (DS), is the most common genetic cause of heart defects. Regions on human chromosome 21 (Hsa21) are syntenically conserved with three regions located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. In this study, we have analyzed the impact of duplications of each syntenic region on cardiovascular development in mice and have found that only the duplication on Mmu16, i.e., Dp(16)1Yey, is associated with heart defects. Furthermore, we generated two novel mouse models carrying a 5.43-Mb duplication and a reciprocal deletion between Tiam1 and Kcnj6 using chromosome engineering, Dp(16Tiam1-Kcnj6)Yey/+ and Df(16Tiam1-Kcnj6)Yey/+, respectively, within the 22.9-Mb syntenic region on Mmu16. We found that Dp(16Tiam1-Kcnj6)Yey/+, but not Dp(16)1Yey/Df(16Tiam1-Kcnj6)Yey, resulted in heart defects, indicating that triplication of the Tiam1-Knj6 region is necessary and sufficient to cause DS-associated heart defects. Our transcriptional analysis of Dp(16Tiam1-Kcnj6)Yey/+ embryos confirmed elevated expression levels for the genes located in the Tiam-Kcnj6 region. Therefore, we established the smallest critical genomic region for DS-associated heart defects to lay the foundation for identifying the causative gene(s) for this phenotype.

SUBMITTER: Liu C

PROVIDER: S-EPMC3257027 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Genetic analysis of Down syndrome-associated heart defects in mice.

Liu Chunhong C Morishima Masae M Yu Tao T Matsui Sei-Ichi S Zhang Li L Fu Dawei D Pao Annie A Costa Alberto C AC Gardiner Katheleen J KJ Cowell John K JK Nowak Norma J NJ Parmacek Michael S MS Liang Ping P Baldini Antonio A Yu Y Eugene YE

Human genetics 20110326 5

Human trisomy 21, the chromosomal basis of Down syndrome (DS), is the most common genetic cause of heart defects. Regions on human chromosome 21 (Hsa21) are syntenically conserved with three regions located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. In this study, we have analyzed the impact of duplications of each syntenic region on cardiovascular development in mice and have found that only the duplication on Mmu16, i.e., Dp(16)1Yey, is associated with heart defects. Furthermore, we gene ...[more]

PMID: 21442329

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Project description:Background: Down syndrome (DS) is one of the most common chromosomal abnormalities associated with congenital heart defects (CHD), with approximately 40 to 60% of cases showing cardiac defects. This study assessed (i) the association between maternal LINE-1 methylation and the occurrence of CHDs in children with DS and (ii) the impact of endogenous maternal factors (MTHFR C677T polymorphism and maternal age) and exogenous maternal factors (cigarette smoking, alcohol intake, medication use, body mass index and dietary habits such as folate intake) on maternal LINE-1 methylation and on the occurrence of CHD in children with DS. Patients and Methods: The study included 90 mothers of children with DS of maternal origin (49% DS-CHD+ mothers/51% DS-CHD- mothers). LINE-1 DNA methylation was analyzed in peripheral blood lymphocytes by quantification of LINE-1 methylation using the MethyLight method. MTHFR C677T polymorphism genotyping was performed using PCR-RFLP. Results: LINE-1 methylation was not significantly different between DS-CHD+ and DS-CHD- mothers (P = 0.997). Combination of MTHFR C677T genotype/diet and BMI were significant independent predictors of LINE-1 DNA methylation in DS-CHD+ mothers (β -0.40, P = 0.01 and β -0.32, P = 0.03, respectively). In the analyzed multivariate model (model P = 0.028), these two factors explained around 72% of the variance in LINE-1 DNA methylation in mothers of children with DS and CHD. The group with the highest BMI (≥30 kg/m2) had significantly lower LINE-1 methylation than the group with normal BMI (Bonferroni post hoc P = 0.03) and the overweight group (Bonferroni post hoc P = 0.04). The lowest LINE-1 DNA methylation values were found in DS-CHD+ mothers with the CT+TT genotype and a low-folate diet; the values were significantly lower than the values in mothers with the CC genotype and a folate-rich diet (Bonferroni post hoc P = 0.04). Conclusion: Association between maternal LINE-1 methylation and CHD in children with DS was not found. Study showed that the MTHFR genotype/diet combination and BMI were significantly associated with LINE-1 methylation in mothers of children with DS-CHD+. These results highlight the need for a multifactorial approach to assess the roles of endogenous and exogenous maternal factors in maternal LINE-1 DNA methylation and the consequent pathologies in children. More extensive studies in a larger sample may help elucidate these relationships.

Project description:BackgroundCongenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS), but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots (NDBS) of DS individuals with major CHDs compared to DS individuals without CHDs.MethodsWe used the Illumina EPIC array and whole-genome bisulfite sequencing (WGBS) to quantitate DNA methylation for 86 NDBS samples from the California Biobank Program: (1) 45 DS-CHD (27 female, 18 male) and (2) 41 DS non-CHD (27 female, 14 male). We analyzed global CpG methylation and identified differentially methylated regions (DMRs) in DS-CHD versus DS non-CHD comparisons (both sex-combined and sex-stratified) corrected for sex, age of blood collection, and cell-type proportions. CHD DMRs were analyzed for enrichment in CpG and genic contexts, chromatin states, and histone modifications by genomic coordinates and for gene ontology enrichment by gene mapping. DMRs were also tested in a replication dataset and compared to methylation levels in DS versus typical development (TD) WGBS NDBS samples.ResultsWe found global CpG hypomethylation in DS-CHD males compared to DS non-CHD males, which was attributable to elevated levels of nucleated red blood cells and not seen in females. At a regional level, we identified 58, 341, and 3938 CHD-associated DMRs in the Sex Combined, Females Only, and Males Only groups, respectively, and used machine learning algorithms to select 19 Males Only loci that could distinguish CHD from non-CHD. DMRs in all comparisons were enriched for gene exons, CpG islands, and bivalent chromatin and mapped to genes enriched for terms related to cardiac and immune functions. Lastly, a greater percentage of CHD-associated DMRs than background regions were differentially methylated in DS versus TD samples.ConclusionsA sex-specific signature of DNA methylation was detected in NDBS of DS-CHD compared to DS non-CHD individuals. This supports the hypothesis that epigenetics can reflect the variability of phenotypes in DS, particularly CHDs.

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Genetic analysis of Down syndrome-associated heart defects in mice.

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Genetic analysis of Down syndrome-associated heart defects in mice.

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