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

• Published in: Gene Vol. 264; no. 1; pp. 113 - 122
• Main Authors: Kasai, Norio, Fukushima, Kunihiro, Ueki, Yasuyoshi, Prasad, Sai, Nosakowski, Jennifer, Sugata, Ken-ichi, Sugata, Akemi, Nishizaki, Kazunori, Meyer, Nicole C, Smith, Richard J.H
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 07.02.2001
• Subjects: Alternative Splicing; Autosomal dominant non-syndromic hearing loss; Base Sequence; chromosome 2; Chromosomes, Human, Pair 2 - genetics; Contig Mapping; Deafness - genetics; DFNA16; DFNA16 gene; DNA - chemistry; DNA - genetics; DNA Mutational Analysis; DNA, Complementary - chemistry; DNA, Complementary - genetics; Exons; Family Health; Female; Genes - genetics; Humans; Introns; Male; Microsatellite Repeats; Mutation; NAV1.2 Voltage-Gated Sodium Channel; NAV1.3 Voltage-Gated Sodium Channel; Nerve Tissue Proteins - genetics; Pedigree; Physical Chromosome Mapping; Polymorphism, Single Nucleotide; Polymorphism, Single-Stranded Conformational; Protein Subunits; SCN2A; SCN2A gene; SCN3A; SCN3A gene; Sequence Analysis, DNA; Sodium Channels - genetics; ADNSHL, autosomal dominant non-syndromic hearing loss; SSCP, single strand confirmation polymorphism; PAC, P1-derived artificial chromosome; RT-PCR, reverse transcriptase polymerase chain reaction; MDE, mutation detection enhancement; UTR, untranslated region; EST, expressed sequence tag; DFNA16; GB4, GeneBridge 4; Autosomal dominant non-syndromic hearing loss; RACE, rapid amplification of cDNA ends; SCN2A; SCN3A
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/S0378-1119(00)00594-1

DFNA16 is a form of autosomal dominant non-syndromic hearing loss (ADNSHL) characterized by fluctuating progressive hearing impairment. Earlier, we mapped the deafness-causing gene to chromosome 2q23-24.3. In this paper, we describe fine mapping results using additional markers tightly linked to the DFNA16 candidate region. Critical recombinants at markers D2S354 and D2S124 define a 3.5-cM interval that contains the DFNA16 gene. Positional candidate genes include two members of the voltage-gated sodium channel family, the type 2 α subunit ( SCN2A) and the type 3 α subunit ( SCN3A). After showing that SCN2A is expressed in human fetal cochlea, we determined its genomic structure to facilitate mutation screening in our DFNA16 kindred. We also determined the genomic structure of SCN3A. These two genes are oriented 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% for 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 were found in either gene, haplotype analysis with polymorphic markers in SCN2A introns further narrowed the candidate gene interval to the region flanked by D2S354 and STS SHGC-82894.