Determination of the mutation responsible for tachycardia in ENU mutant strain HLB468.

Emma Anderson

Document Type

Article

Publication Date

Summer 2016

JAX Location

In: Student Reports, Summer 2016, Jackson Laboratory

Abstract

Tachycardia, or a fast heart rate, is a cardiac condition with a number of unpleasant symptoms that is not well understood. Tachycardia in humans is characterized by a resting heart rate of over 100 bpm and is associated with symptoms such as palpitations, tiredness, chest pain, and exercise intolerance, as well as psychiatric problems such as anxiety and depression. Therapeutic options for reducing heart rate and diminishing the symptoms are not well-developed due to the fact that we have not yet achieved an understanding of the syndrome’s underlying mechanisms. Mouse models are useful in advancing our knowledge of human disease, and to develop new research models, chemical mutagenesis followed by phenotypic assessment can be performed. ENU mutagenesis of mouse strain C57 BL/6J (B6) generated a mutant strain, C57BL/6J-Hlb468/J (HLB468), with a robust phenotype of tachycardia, discovered by analysis of electrocardiogram (EKG) data. The mutation was mapped to chromosome 9, and the HLB468 exome was sequenced and compared to a reference sequence obtained from B6. Single nucleotide polymorphisms (SNPs) within candidate genes in the confidence interval were evaluated utilizing PCR to test for the presence of the mutation in HLB468 colony animals. A SNP in the Hcn4 gene was a top candidate due to the fact that the HCN4 channels of the sinoatrial node (SAN) are an essential component of the cardiac conduction process. We have identified a SNP in the Hcn4 gene that results in a robust tachycardiac phenotype in the strain HLB468. This is a novel mouse mutation that adds a new mouse model to the study of cardiac conductance and tachycardia.

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