br Genetic basis for atrial standstill br Genetic basis
Genetic basis for atrial standstill
Genetic basis of conduction block
Genes involved in cardiac development and bradycardia Development of the CCS is a complex biological process with the potential to be wrought with problems. Several transcription factors, including homeodomain proteins and T-box proteins, are essential for CCS morphogenesis and the activation or repression of key regulatory genes . Of the cardiogenic transcription factor genes; GATA4, NKX2-5, TBX3, and TBX5 play key roles in the development of the primary and second heart fields, while mutation results in congenital heart diseases such as patent foramen ovale, itself often associated with conduction disorders . Holt–Oram syndrome is an inherited, multi-organ anomaly caused by TBX5 mutation . As TBX5 promotes the Apoptosis Compound Library of several genes involved in the development of the upper limbs, varying degrees of upper limb abnormalities have been recognized in Holt–Oram syndrome cases. Approximately 75% of probands have cardiac anomalies, whereas about 40% of affected family members present only with ECG abnormalities and without heart malformations . Common ECG abnormalities include first degree AVB and bradycardia , which is in line with the preferential expression of TBX5 in the endocardial cushion region during the developmental stage. The vast majority of TBX5 mutations in Holt–Oram syndrome are truncation mutations that often delete the T-box domain and result in haplo-insufficiency of T-box activity. In contrast, most missense mutations result in less severe anomalies as the full protein structure is well preserved. A missense mutation, G125R, has been identified in a family suffering from faint digit abnormalities and a higher prevalence of AF without heart malformation . AF is believed to be associated with the increased expression of NPPA, GJA5, KCNJ2, and TBX3.
Advanced genetic and genomic technologies Many of the causative genes described here were identified using a candidate gene approach, in which genes are selected based on findings of preceding genetic linkage analysis or molecular pathway information . Considering that the human genome encodes at least 20,000 protein-coding genes, the candidate gene approach focuses only on a small fraction of the genome with the remainder unanalyzed. Genome-wide association studies (GWAS) using single nucleotide polymorphisms (SNPs) can significantly expedite linkage analysis by narrowing the regions of interest for further directed sequencing. GWAS has been used in the cardiac electrophysiological field and has resulted in the identification of several new loci involved in long QT syndrome, a key role for calcium signaling pathways in myocardial repolarization , and many other ECG parameters [41,65]. GWAS on heart rate revealed the genetic heterogeneity of heart rate regulation and 21 loci were identified; including HCN4, gap junction gene GJA1, and the atrial α-myosin heavy chain (α-MHC) gene MYH6. A rare MYH6 variant, R721W, that predisposes individuals to SSS susceptibility has been previously identified ; however, the disease-causing MYH6 mutations for familial SSS and their underlying mechanisms remain unknown. We screened nine genotype-negative probands with SSS families for mutations in MYH6 and identified an in-frame 3-bp deletion that was predicted to delete one residue (delE933) at the highly conserved coiled-coil structure within the binding motif of myosin-binding protein C in one patient . Irregular fluorescent speckles retained in the cytoplasm with substantially disrupted sarcomere striation have been observed in neonatal rat cardiomyocytes transfected with α-MHC mutants carrying delE933 or R721W. In addition to sarcomere impairments, delE933 α-MHC exhibited electrophysiological abnormalities both in vitro and in vivo. The atrial cardiomyocyte cell line HL-1 stably expressing delE933 α-MHC showed a significantly slower conduction velocity on multielectrode array when compared with those of wild-type α-MHC or control plasmid transfected cells. Furthermore, targeted morpholino knockdown of MYH6 in zebrafish resulted in significantly reduced heart rate that could be rescued by co-expressed wild-type human α-MHC and not by delE933 α-MHC. These data reinforces the relevance of MYH6 in sinus node function and suggests that structural damage to the sarcomere and functional impairment of atrial action potential propagation may underlie familial SSS with MYH6 mutations .