Downregulation of GSTK1 Is a Common Mechanism Underlying Hypertrophic Cardiomyopathy

Nishimura Yuhei, Sasagawa Shota, Okabe Shiko, Murakami Soichiro, Ashikawa Yoshifumi, Yuge Mizuki, Kawaguchi Koki, Kawase Reiko, Okamoto Ryuji, Ito Masaaki, TANAKA TOSHIO; Front. Pharmacol., 14 June 2016, doi:10.3389/fphar.2016.00162

Open-access (article distributed under the terms of the Creative Commons Attribution License).

 HCM has multiple etiologies, including mutation in sarcomeric genes such as myosin heavy chain 7 (MYH7) and tropomyosin 1 (TPM1) and in non-sarcomeric genes such as PLN and FXN.Haploinsufficiency of FXN is a major cause of FA. FA is associated with progressive HCM, and this is a common cause of death in FA patients. FXN is an iron-binding protein targeted to the mitochondrial matrix, and consistent with this, mitochondrial function is impaired in FA.  Comparative transcriptomics could represent a new frontier in the search for novel biomarkers and/or therapeutic targets in diseases with multiple etiologies because it facilitates the identification of dysregulated genes common to all disease etiologie. We identified five genes dysregulated in all five HCM transcriptome datasets, among which glutathione S-transferase kappa 1 (Gstk1) was the only gene downregulated. We demonstrate here that knockout of gstk1 in zebrafish increased the expression of HCM marker genes and decreased the cardiac EDV and, to a lesser extent, the ESV, suggesting that downregulation of GSTK1 may be a common mechanism underlying HCM of various etiologies.