The identification of nearly a dozen ion channel genes involved in the genesis of human atrial and ventricular arrhythmias has been critical for the diagnosis and treatment of fatal cardiovascular diseases. In contrast, very little is known about the genetic and molecular mechanisms underlying human sinus node dysfunction (SND). Here, we report a genetic and molecular mechanism for human SND. We mapped two families with highly penetrant and severe SND to the human ANK2 (ankyrin-B/AnkB) locus. Mice heterozygous for AnkB phenocopy human SND displayed severe bradycardia and rate variability. AnkB is essential for normal membrane organization of sinoatrial node cell channels and transporters, and AnkB is required for physiological cardiac pacing. Finally, dysfunction in AnkB-based trafficking pathways causes abnormal sinoatrial node (SAN) electrical activity and SND. Together, our findings associate abnormal channel targeting with human SND and highlight the critical role of local membrane organization for sinoatrial node excitability.calcium ͉ trafficking ͉ arrhythmia ͉ cytoskeleton
Our study demonstrates that CNVs in KCNQ1 and KCNH2 explain around 3% of LQTS in patients with no point mutation in these genes. This percentage is likely higher than the frequency of point mutations in ANKB, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP9, and SNTA1 together. Thus, we propose that CNV screening in KCNQ1 and KCNH2 may be performed routinely in LQTS patients.
Introduction
We identified a large family of 53 members of whom 22 present a new cardiac syndrome characterized by electrical disorders and developmental defects following an autosomal dominant model. Among the affected family members 6 are implanted with a pacemaker, 2 experienced syncope and one a sudden death at 43yo. Linkage analysis points, with high confidence, to the chromosome 4q25 region. This region is associated with the Ankyrin syndrome (mutation in ANK2) sharing partly the electrical defects observed in the affected family members. No mutation was found in the coding region of the 4q25 region as well as in the coding and non-coding part of the ANK2.
Objective
Our aims are first to identity the responsible mutation present in this family and understand the molecular mechanisms leading to this new syndrome.
Method
Whole genome sequencing (WGS) has been employed to identify genetic variants responsible for this syndrome. ChIP-seq and ATAC-seq were used for functional annotation and genome editing (CRISPR-Cas9) to generate iPS cellular models.
Results
By WGS we uncovered a deleted region of 15kb in a gene desert area on 4q25, segregating in all affected relatives. Five other families (3 French and 2 Japanese) presenting the same phenotype show overlapping deletions. We generated human cardiac epigenetic data and identified among the 15kb deleted region a unique active enhancer region within the presence of a transcript factor CTCF binding site. Isogenic cell lines where the 15kb and the CTCF binding have been deleted are under investigation.
Conclusion
We identified a new cardiac syndrome and for the first time a mutation located within a gene desert area leading to severe and complex cardiac disorders. We demonstrated the presence of a likely gene regulatory element. Experiments are ongoing to characterize the molecular mechanisms and consequence of the deletion on gene expression.
Funding Acknowledgement
Type of funding source: Public Institution(s). Main funding source(s): Pays de la loire - Etoiles montantes
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