| RRC ID |
83869
|
| 著者 |
Mutai H, Kuroda Y, Noji S, Ichikawa S, Matsuo K, Tanaka S, Kataoka N, Fujioka M, Matsunaga T.
|
| タイトル |
Complete omission of exon 21 from Slc12a2 transcripts in mice results in hearing loss.
|
| ジャーナル |
Sci Rep
|
| Abstract |
Hereditary hearing loss is highly heterogeneous. SLC12A2 is linked to autosomal dominant nonsyndromic hearing loss, DFNA78, with all the pathogenic variants affecting the exon 21. The gene encodes a cotransporter NKCC1 crucial for regulating intracellular osmotic pressure and producing endolymph in the cochlea. We generated two mouse strains with heterologous Slc12a2 variants in the splice site of the exon 21 (Em1: NM_009194.3:c.2912-2 A > G and Em2: c.2912-4_2913del). Slc12a2Em2/Em2 mice with complete skip of the exon 21 showed reduced endolymph on postnatal day 1 (P1), reduced stria vascularis (StV) and no auditory brainstem responses at 4 weeks. Reduced StV size was considered to be due to rebalance osmotic pressure, and upregulation of Cldn9 revealed by RNA-seq was considered as tissue response to repair the gaps from reduced cell sizes in the Slc12a2Em2/Em2 cochlea. Female Slc12a2Em2/+ mice also exhibited mild elevation of ABR thresholds in several sound frequencies. Slc12a2Em1/Em1 mice showed normal hearing, presumably due to sufficient cotransporter activity from the 9 bases shorter transcript by cryptic splicing. Minigene assays indicated that a single nucleotide difference between humans and mice at the 5' end of the exon 21 affects exon 21 splicing. Slc12a2Em2 mouse is proposed as a model for studying DFNA78 pathology.
|
| 巻・号 |
15(1)
|
| ページ |
14790
|
| 公開日 |
2025-4-28
|
| DOI |
10.1038/s41598-025-99827-7
|
| PII |
10.1038/s41598-025-99827-7
|
| PMID |
40295800
|
| PMC |
PMC12038040
|
| MeSH |
Animals
Cochlea / metabolism
Cochlea / pathology
Disease Models, Animal
Endolymph / metabolism
Evoked Potentials, Auditory, Brain Stem
Exons* / genetics
Female
Hearing Loss* / genetics
Male
Mice
Solute Carrier Family 12, Member 2* / genetics
Solute Carrier Family 12, Member 2* / metabolism
Stria Vascularis / metabolism
Stria Vascularis / pathology
|
| IF |
3.998
|
| リソース情報 |
| ヒト・動物細胞 |
293T(RCB2202) |
