Genomic structures of SCN2A and SCN3A - candidate genes for deafness at the DFNA16 locus

DFNA16 is a form of autosomal dominant non-syndromic hearing loss (ADNSHL) characterized by fluctuating progressive hearing impairment. Earlier, we ma pped the deafness-causing gene to chromosome 2q23-24.3. In this paper, we d escribe fine mapping results using additional markers tightly linked to the DFNA16 candidate region. Critical recombinants at markers D2S354 and D2S12 4 define a 3.5-cM interval that contains the DNA16 gene. Positional candida te genes include two members of the voltage-gated sodium channel family, th e type 2 alpha subunit (SCN2A) and the type 3 alpha subunit (SCN3A). After showing that SCN2A is expressed in human fetal cochlea, we determined its g enomic structure to facilitate mutation screening in our DFNA16 kindred. We also determined the genomic structure of SCN3A. These two genes are orient ed head-to-head, with their 5' ends separated by approximately 40 kb; their homology is 82% at the nucleotide level, and 85% for identities and 90% fo r positives at the amino acid level. They share similar genomic structures and have alternative splice isoforms that are developmentally regulated and highly conserved between species. Although no DFNA16-causing mutations wer e found in either gene, haplotype analysis with polymorphic markers in SCN2 A introns further narrowed the candidate gene interval to the region flanke d by D2S354 and STS SHGC-82894. (C) 2001 Elsevier Science B.V. All rights r eserved.