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Identification of candidate genes for histiocytoid cardiomyopathy (HC) using whole genome expression analysis:
Bahig M Shehata1, Mark Bouzyk, Sarah C Shulman
1Department of Pathology, Children's Healthcare of Atlanta, Atlanta, GA 30322, USA. bshehat@emory.edu
Insights
Histiocytoid cardiomyopathy (HC) involves genetic defects leading to heart failure and sudden death in infants. This study identifies downregulated gene pathways, including S100A and interleukin 33 signaling, as potential causes of HC.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Pediatric Cardiology
Background:
- Histiocytoid cardiomyopathy (HC) is a rare, fatal arrhythmogenic disorder in infants.
- The genetic underpinnings of HC have remained largely unknown for decades.
- Early identification of genetic factors is crucial for understanding HC pathogenesis.
Purpose of the Study:
- To identify the molecular-genetic basis of histiocytoid cardiomyopathy.
- To investigate differential gene expression and copy number variations in HC cardiac tissue.
- To propose a molecular pathway implicated in HC development.
Main Methods:
- Analysis of RNA and DNA from cardiac tissue of HC cases and controls.
- Whole genome cDNA profiling to identify differentially expressed genes.
- TaqMan quantitative PCR and copy number variant assays for validation.
Main Results:
- Two gene clusters, S100A8/S100A9/S100A12 and IL1RL1/IL18R1/IL18RAP, were significantly downregulated in HC hearts.
- Decreased expression of interleukin 33 was observed.
- Reduced copy number of S100A genes was confirmed, suggesting a link to the IL-33/p38-MAPK/S100A axis.
Conclusions:
- A downregulated interleukin 33-IL1RL1/p38-MAPK/S100A8-S100A9 signaling axis is implicated in HC.
- Candidate genes on chromosomes 1q21.3c and 2q12.1a may harbor mutations predisposing to HC.
- Further research into these genetic pathways could reveal novel diagnostic and therapeutic targets for HC.
Abstract:
Histiocytoid cardiomyopathy (HC) is a rare but distinctive arrhythmogenic disorder characterized by incessant ventricular tachycardia, cardiomegaly, and often sudden death by age 2 years. The underlying genetic mechanism of HC has eluded researchers for decades. To further identify the potential molecular-genetic bases of HC, molecular analyses of HC hearts and hearts of age-matched controls were performed. Total RNA and genomic DNA were prepared from formalin-fixed, paraffin-embedded cardiac tissue from 12 cases of HC and 12 age-matched controls. To identify genes differentially expressed in HC, whole genome cDNA-mediated annealing, selection, extension, and ligation profiling was performed. TaqMan quantitative polymerase chain reaction confirmed changes in RNA expression. DNA copy number changes were measured by TaqMan copy number variant analysis. Analysis of differential gene expression in HC cases identified 2 significantly downregulated gene sets aligned sequentially along the genome. The 1st gene cluster consisted of genes S100A8 , S100A9 , and S100A12 at 1q21.3c, and the 2nd cluster consisted of genes IL1RL1 ( ST2 ), IL18R1 , and IL18RAP at 2q12.1a. Strong decreases in interleukin 33 expression were also observed. Decreases in copy number of the S100A genes were confirmed by TaqMan copy number variant assays. S100A genes are downstream of the p38-MAPK pathway that can be activated by interleukin 33 signaling. These data suggest a model in which the interleukin 33-IL1RL1/p38-MAPK/ S100A8-S100A9 axis is downregulated in HC cardiac tissue and provide several candidate genes on 1q21.3c and 2q12.1a for inherited mutations that may predispose individuals to HC.
