Hypertrophic cardiomyopathy mutation R723G alters mRNA secondary structure.

Point mutation R723G in the gene causes hypertrophic cardiomyopathy (HCM). Heterozygous patients with this mutation exhibit a comparable allelic imbalance of the gene. On average 67% of the total mRNA are derived from the -allele and 33% from the allele. Mechanisms underlying mRNA allelic imbalance are largely unknown. We suggest that a different mRNA lifetime of the alleles may cause the allelic drift in R723G patients. A potent regulator of mRNA lifetime is its secondary structure. To test for alterations in the mRNA structure we used selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) analysis. We show significantly different SHAPE reactivity of wild-type and RNA, which is in accordance with bioinformatically predicted structures. Thus, we provide the first experimental evidence for mRNA secondary structure alterations by the HCM point mutation. We assume that this may result in a prolonged lifetime of mRNA in vivo and subsequently in the determined allelic imbalance.