Structure of the Sodium Channel Gene SCN11A: Evidence for Intron-to-Exon Conversion Model and Implications for Gene Evolution

Abstract

Exon/intron boundaries in the regions encoding the trans-membrane segments of voltagegated Na channel genes are conserved, supporting their proposed evolution from a single domain channel, while the exons encoding the cytoplasmic loops are less conserved with their evolutionary heritage being less defined. SCN11A encodes the tetrodotoxin-resistant (TTX-R) sodium channel Na_v 1.9a/NaN, which is preferentially expressed in nociceptive primary sensory neurons of dorsal root ganglia (DRG) and trigeminal ganglia. SCN11A is localized to human chromosome 3 (3p21-24) close to the other TTX-R sodium channel genes SCN5A and SCN10A. An alternative transcript, Na_v1.9b, has been detected in rat DRG and trigeminal ganglion. Na_v1.9b is predicted to produce a truncated protein due to a frame-shift, which is introduced by the new sequence of exon 23c (E23c). In human and mouse SCN11A, divergent splicing signals prevent utilization of E23c. Unlike exons 5A/N in genes encoding TTX-sensitive sodium channels, which appear to have resulted from exon duplication, E23c might have evolved from the conversion of an intronic sequence. Although a functional role for Na_v1.9b has yet to be established, intron-to-exon conversion may represent a mechanism for ion channels to acquire novel features.