3 research outputs found
Gene duplications and evolution of vertebrate voltage-gated sodium channels
Author Posting. © The Author(s), 2006. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Journal of Molecular Evolution 63 (2006): 208-221, doi:10.1007/s00239-005-0287-9.Voltage-gated sodium channels underlie action potential generation in excitable tissue.
To establish the evolutionary mechanisms that shaped the vertebrate sodium channel
a-subunit (SCNA) gene family and their encoded Nav1 proteins, we identified all SCNA
genes in several teleost species. Molecular cloning revealed that teleosts have eight
SCNA genes, comparable to the number in another vertebrate lineage, mammals.
Prior phylogenetic analyses had indicated that teleosts and tetrapods share four
monophyletic groups of SCNA genes and that tandem duplications selectively
expanded the number of genes in two of the four mammalian groups. However, the
number of genes in each group varies between teleosts and tetrapods suggesting
different evolutionary histories in the two vertebrate lineages. Our findings from
phylogenetic analysis and chromosomal mapping of Danio rerio genes indicate that
tandem duplications are an unlikely mechanism for generation of the extant teleost
SCNA genes. Instead, analysis of other closely mapped genes in D. rerio supports the
hypothesis that a whole genome duplication was involved in expansion of the SCNA
gene family in teleosts. Interestingly, despite their different evolutionary histories,
mRNA analyses demonstrated a conservation of expression patterns for SCNA
orthologues in teleosts and tetrapods, suggesting functional conservation.The authors’ work was supported by NIH grants (NS 38937; AEN,
ADT and ABR, NS 25513; HHZ and YL and NSF IBN 0236147; MCJ)
Genetic variation in SCN10A influences cardiac conduction
To identify genetic factors influencing cardiac conduction, we carried out a genome-wide association study of electrocardiographic time intervals in 6,543 Indian Asians. We identified association of a nonsynonymous SNP, rs6795970, in SCN10A (P = 2.8 x 10(-15)) with PR interval, a marker of cardiac atrioventricular conduction. Replication testing among 6,243 Indian Asians and 5,370 Europeans confirmed that rs6795970 (G>A) is associated with prolonged cardiac conduction (longer P-wave duration, PR interval and QRS duration, P = 10(-5) to 10(-20)). SCN10A encodes Na(V)1.8, a sodium channel. We show that SCN10A is expressed in mouse and human heart tissue and that PR interval is shorter in Scn10a(-/-) mice than in wild-type mice. We also find that rs6795970 is associated with a higher risk of heart block (P < 0.05) and a lower risk of ventricular fibrillation (P = 0.01). Our findings provide new insight into the pathogenesis of cardiac conduction, heart block and ventricular fibrillation