Abstract 16081: A Familial Hypertrophic Cardiomyopathy is Caused by a Mutation in Elp2, Encoding One of Subunits of Elongator Acetyltransferase Complex
Introduction: Elongator protein 2 (ELP2) is known as a STAT3-interacting protein and one of subunits of elongator, which can regulate RNA elongation via its histone acetyltransferase activity. It remains unknown whether ELP2 plays an important role in cardiac hypertrophy.
Aim: Our aim is to identify new gene mutations that cause familial HCM, which can progresses into dilated-phase HCM (d-HCM).
Methods: We examined a patient and her elder brother who both presented with complicated severe HCM and whose parents are married cousins. The elder brother had died suddenly as a child; the autopsy revealed that he had developed HCM. The patient was diagnosed with HCM, and HCM progressed to d-HCM during the 20-year follow-up. The patient received a left ventricular-assist device implant, and the patient is currently on a waiting list for cardiac transplantation. The parents are healthy. We hypothesized that a causative allele was transmitted to both the patient and the elder brother as an autosomal recessive mutation that caused familial HCM. The genome analysis and whole-exome sequencing was performed with samples from each of the three participants. Sarcomere organization in H9C2 cells overexpressed with ELP2 and localization of ELP2 in biopsy samples were examined.
Results: The gene exome analysis showed 340 single nucleotide polymorphisms (SNPs) that caused amino acid change for which the patient was homozygous and both parents were heterozygous. After excluding all known common (>10%) SNP gene mutations in the SNP Database (dbSNP), ELP2 was the only identified gene that is possibly associated with cardiac muscle. The identified missense mutation was a 2385 G>A nucleotide transition in ELP2 isoform 2. The resultant E795G substitution replaces a polar carboxylic glutamate with a nonpolar glycine. The H9C2 overexpressed with mutant ELP2 showed a distinct sarcomere organization compared with cells overexpressed with intact ELP2. Immunohistochemistry studies showed the localization of ELP2 in the patient’s endomyocardial biopsy sample was different from in control samples.
Conclusions: These results indicate both that mutations in ELP2 can cause a familial form of HCM and that ELP2 may be a new target for treatment of cardiac hypertrophy.
Author Disclosures: R. Okamoto: None. I. Goto: None. I. Kobayashi: None. R. Hashizume: None. N. Shimojo: None. K. Dohi: None. M. Nakamura: None. M. Ito: None.
- © 2014 by American Heart Association, Inc.