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Kommareddi P , Nair T , Kakaraparthi BN , Galano MM , Miller D , Laczkovich I , Thomas T , Lu L , Rule K , Kabara L , Kanicki A , Hughes ED , Jones JM , Hoenerhoff M , Fisher SG , Altschuler RA , Dolan D , Kohrman DC , Saunders TL , Carey TE
Hair Cell Loss, Spiral Ganglion Degeneration, and Progressive Sensorineural Hearing Loss in Mice with Targeted Deletion of Slc44a2/Ctl2
J Assoc Res Otolaryngol. 2015 Dec;16(6) :695-712
PMID: 26463873    PMCID: PMC4636594    URL: http://www.ncbi.nlm.nih.gov/pubmed/26463873
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SLC44A2 (solute carrier 44a2), also known as CTL2 (choline transporter-like protein 2), is expressed in many supporting cell types in the cochlea and is implicated in hair cell survival and antibody-induced hearing loss. In mice with the mixed C57BL/6-129 background, homozygous deletion of Slc44a2 exons 3-10 (Slc44a2 Delta/Delta) resulted in high-frequency hearing loss and hair cell death. To reduce effects associated with age-related hearing loss (ARHL) in these strains, mice carrying the Slc44a2 Delta allele were backcrossed to the ARHL-resistant FVB/NJ strain and evaluated after backcross seven (N7) (99 % FVB). Slc44a2 Delta/Delta mice produced abnormally spliced Slc44a2 transcripts that contain a frameshift and premature stop codons. Neither full-length SLC44A2 nor a putative truncated protein could be detected in Slc44a2 Delta/Delta mice, suggesting a likely null allele. Auditory brain stem responses (ABRs) of mice carrying the Slc44a2 Delta allele on an FVB/NJ genetic background were tested longitudinally between the ages of 2 and 10 months. By 6 months of age, Slc44a2 Delta/Delta mice exhibited hearing loss at 32 kHz, but at 12 and 24 kHz had sound thresholds similar to those of wild-type Slc44a2 +/+ and heterozygous +/Slc44a2 Delta mice. After 6 months of age, Slc44a2 Delta/Delta mutants exhibited progressive hearing loss at all frequencies and +/Slc44a2 Delta mice exhibited moderate threshold elevations at high frequency. Histologic evaluation of Slc44a2 Delta/Delta mice revealed extensive hair cell and spiral ganglion cell loss, especially in the basal turn of the cochlea. We conclude that Slc44a2 function is required for long-term hair cell survival and maintenance of hearing.
Kommareddi, Pavan Nair, Thankam Kakaraparthi, Bala Naveen Galano, Maria M Miller, Danielle Laczkovich, Irina Thomas, Trey Lu, Lillian Rule, Kelli Kabara, Lisa Kanicki, Ariane Hughes, Elizabeth D Jones, Julie M Hoenerhoff, Mark Fisher, Susan G Altschuler, Richard A Dolan, David Kohrman, David C Saunders, Thomas L Carey, Thomas E P30 DC005188/DC/NIDCD NIH HHS/United States R01 DC003686/DC/NIDCD NIH HHS/United States T32 DC000011/DC/NIDCD NIH HHS/United States J Assoc Res Otolaryngol. 2015 Dec;16(6):695-712. doi: 10.1007/s10162-015-0547-3.