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SLC44A4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss

Zhaoxin Ma  Wenjun Xia  Fei Liu  Jing Ma  Shaoyang Sun  Jin Zhang  Nan Jiang  Xu Wang  Jiongjiong Hu  Duan Ma  
【摘要】:Hearing impairment is considered one of the most prevalent clinic disability worldwide. The variety of hearing impairment causative genes determines the diversity of pathogenic machanism. In our studies,, clinical and genetic investigation of of a novel Chinese family with postlingual non-syndromic mid-frequency sensorineural hearing loss(MFSNHL) was performed. The affected individuals in this family showed the stable onset of hearing loss(age 27–30 years) across generations. During all stages of the disease, the audiograms present typical "bo-swhlaped" audiometric profile, which displays distinction with the reported families segregating MFSNHL. Site mutations were not observed in several frequent candidate genes known to be causative of hearing loss(GJB2, GJB3, SLC26A4, and mitochondrial genes), and genes reported to be causative of MFSNHL, such as DFNA10(EYA4), DFNA8/12(TECTA), DFNA13(COL11A2), DFNA44(CCDC50) were also ruled out by gene sequencing. Using the second generation sequencing, we identified choline transport protein encoding gene, SLC44A4, as the deafness pathogenic candidate gene in this family. On the zebra fish model, Q-RT PCR and in situ hybridization indicated that slc44a4 was widely expressed in inner ear and central nervous system. Morpholine down regulation of slc44a4 led to reduction and malformation of hair cells in cochlea. SLC44A4 transfected SH-SY5 Y cells showed increased choline uptake, while mutant ones didn't. We conclude that mutation o SLC44A4 mafy cause defect of Choline-Ach system, which is crucial to the efferent innervation of the hair cells from the olivocochlear(OC) bundle in the maintenance of physiological function of outer hair cells and the protection to hair cells from acoustic injury, leading to hearing loss.

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