听神经病患者OTOF基因突变的遗传特征及其相关功能机制研究进展
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摘要
听神经病是遗传性耳聋中重要的一种疾病类型,OTOF基因是在能够导致听神经病的多个致病基因中重要基因之一,OTOF变异可导致听神经病。OTOF基因转录翻译otoferlin蛋白,蛋白结构中有6个重要的C2结构域,可与Ca2+结合。多个小鼠模型和斑马鱼模型被构建以探究OTOF基因的功能,目前认为otoferlin蛋白参与内毛细胞带状突触的神经递质释放过程。在听力学方面,相较于其他听神经病患者,OTOF变异致听神经病患者有特殊的耳蜗电图波形。OTOF基因变异还可导致温度敏感性听神经病。本文将从多个方面对OTOF基因进行阐述和概括。
Auditory neuropathy is an important category in hereditary deafness, which can be caused by OTOF?gene variations. The OTOF gene transfers and translates the otoferlin protein, which has six important C2 domains that can bine with Ca2 +. Multiple mice and zebrafish models have been built to explore OTOF gene functions. At present,otoferlin is thought to be involved in the release of neurotransmitters across ribbon synapses in inner hair cells. In audiology, compared with other types of auditory neuropathy, auditory neuropathy caused by OTOF variations shows specific waveforms on ECochG. In addition, OTOF gene variants can also lead to temperature sensitive auditory neuropathy.This article will elaborate on the OTOF gene from several aspects.
Auditory neuropathy is an important category in hereditary deafness, which can be caused by OTOF?gene variations. The OTOF gene transfers and translates the otoferlin protein, which has six important C2 domains that can bine with Ca2 +. Multiple mice and zebrafish models have been built to explore OTOF gene functions. At present,otoferlin is thought to be involved in the release of neurotransmitters across ribbon synapses in inner hair cells. In audiology, compared with other types of auditory neuropathy, auditory neuropathy caused by OTOF variations shows specific waveforms on ECochG. In addition, OTOF gene variants can also lead to temperature sensitive auditory neuropathy.This article will elaborate on the OTOF gene from several aspects.
引文
1张秋静,王秋菊.听神经病谱系障碍的分子遗传学研究进展[J].中华耳鼻咽喉头颈外科杂志.2014;49(12):1040-1045.Zhang QJ,Wang QJ.Advances in molecular genetics of pedigree disorders of auditory neuropathy[J],Chin J Otorhinolaryngol Head Neck Surg.2014,49(12):1040-1045.
2 Del Castillo FJ and Del Castillo I:Genetics of isolated auditory neuropathies[J].Front Biosci(Landmark Ed).2012,17:1251-1265.
3 Cha?b H,Place C,Salem N,et al.A gene responsible for a sensorineural nonsyndromic recessive deafness maps to chromosome2p22-23[J].Hum Mol Genet.1996,5:155-158.
4 Rodriguez-Ballesteros M,Reynoso R,etal.A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene(OTOF)in subjects with nonsyndromic hearing impairment and auditory neuropathy[J].Hum Mutat.2008,29:823-831.
5 Rodriguez-Ballesteros M,del Castillo FJ,Martin Y,et al.Auditory neuropathy in patients carrying mutations in the otoferlin gene(OTOF)[J].Hum Mutat.2003;22:451-456.
6 Chiu YH,Wu CC,Lu YC,et al.Mutations in the OTOF Gene in Taiwanese Patients with Auditory Neuropathy[J].Audiol Neurootol.2010,15:364-374.
7 Byung Yoon Choi.Refinement of Molecular Diagnostic Protocol of Auditory Neuropathy Spectrum Disorder[J].Medicine.2015.
8 Zhang Qiujing,Han Bing,Wang Qiuju,et al.High frequency of OTOF mutations in Chinese infants with congenital auditory neuropathy spectrum disorder[J].Clin Genet.2016,90:238-246.
9 Roux I,Safieddine S,Nouvian R,et al.Otoferlin defective in a human deafness form,is essential for exocytosis at the auditory ribbon synapse[J].Cell.2006,127:277-289.
10 Ok-Ho Shin.Exocytosis and Synaptic Vesicle Function[J].Comprehensive Physiology.2014,4:149-175.
11 Wilson,L.,Ching,Y.H.,Farias,M.,et al.Random mutagenesis of proximal mouse chromosome 5 uncovers predominantly embryonic lethal mutations[J].Genome Res.2005,15,1095-1105.
12 Chantal Longo-Guess,etal.A missense mutation in the conserved C2B domain of otoferlin causes deafness in a new mouse model of DFNB9[J].Hearing Research.2007,234:21-28
13 Martin Schwander,etal.A Forward Genetics Screen in Mice Identifies Recessive Deafness Traits and Reveals That Pejvakin Is Essential for Outer Hair Cell Function[J].The Journal of Neuroscience.2007:27(9):2163-2175.
14 Karen B Avraham.What’s hot about otoferlin[J].EMBO J.2016,35(23):2502-2504.
15 Strenzke N,Chakrabarti R,Al-Moyed H,et al.Hair cell synaptic dysfunction,auditory fatigue and thermal sensitivity in otoferlin Ile515Thr mutants[J].EMBO J.2016,35(23):2519-2535.
16 Hanan Al-Moyed,Andreia P Cepeda,Tobias Moser,et al.A dual-AAV approach restores fast exocytosis and partially rescues auditory function in deaf otoferlin knock-out mice[J].EMBOMolecular Medicine.2018;online.
17 Rosamaria Santarelli,Ignacio del Castillo,Arnold Starr,et al.Audibility,speech perception and processing of temporal cues in ribbon synaptic disorders due to OTOF mutations[J].Hearing Research.2015,330:200-212.
18张娇,张秋静,王秋菊等.听神经病谱系障碍患者的内科药物综合治疗及疗效分析[J].临床耳鼻咽喉头颈外科杂志.2014,28(8):544-547.Zhang J,Zhang QJ,Wang QJ,et al.The curative effect analysis of combined medical therapy for auditory neuropathy spectrum disorder[J].J Clin Otorhinolaryngol Head Neck Surg.2014,28(8):544-547.
19 Qiujing Zhang,Lan Lan,Qiuju Wang,et al.Temperature sensitive auditory neuropathy[J].Hearing Research.2016,335:53-63.
2 Del Castillo FJ and Del Castillo I:Genetics of isolated auditory neuropathies[J].Front Biosci(Landmark Ed).2012,17:1251-1265.
3 Cha?b H,Place C,Salem N,et al.A gene responsible for a sensorineural nonsyndromic recessive deafness maps to chromosome2p22-23[J].Hum Mol Genet.1996,5:155-158.
4 Rodriguez-Ballesteros M,Reynoso R,etal.A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene(OTOF)in subjects with nonsyndromic hearing impairment and auditory neuropathy[J].Hum Mutat.2008,29:823-831.
5 Rodriguez-Ballesteros M,del Castillo FJ,Martin Y,et al.Auditory neuropathy in patients carrying mutations in the otoferlin gene(OTOF)[J].Hum Mutat.2003;22:451-456.
6 Chiu YH,Wu CC,Lu YC,et al.Mutations in the OTOF Gene in Taiwanese Patients with Auditory Neuropathy[J].Audiol Neurootol.2010,15:364-374.
7 Byung Yoon Choi.Refinement of Molecular Diagnostic Protocol of Auditory Neuropathy Spectrum Disorder[J].Medicine.2015.
8 Zhang Qiujing,Han Bing,Wang Qiuju,et al.High frequency of OTOF mutations in Chinese infants with congenital auditory neuropathy spectrum disorder[J].Clin Genet.2016,90:238-246.
9 Roux I,Safieddine S,Nouvian R,et al.Otoferlin defective in a human deafness form,is essential for exocytosis at the auditory ribbon synapse[J].Cell.2006,127:277-289.
10 Ok-Ho Shin.Exocytosis and Synaptic Vesicle Function[J].Comprehensive Physiology.2014,4:149-175.
11 Wilson,L.,Ching,Y.H.,Farias,M.,et al.Random mutagenesis of proximal mouse chromosome 5 uncovers predominantly embryonic lethal mutations[J].Genome Res.2005,15,1095-1105.
12 Chantal Longo-Guess,etal.A missense mutation in the conserved C2B domain of otoferlin causes deafness in a new mouse model of DFNB9[J].Hearing Research.2007,234:21-28
13 Martin Schwander,etal.A Forward Genetics Screen in Mice Identifies Recessive Deafness Traits and Reveals That Pejvakin Is Essential for Outer Hair Cell Function[J].The Journal of Neuroscience.2007:27(9):2163-2175.
14 Karen B Avraham.What’s hot about otoferlin[J].EMBO J.2016,35(23):2502-2504.
15 Strenzke N,Chakrabarti R,Al-Moyed H,et al.Hair cell synaptic dysfunction,auditory fatigue and thermal sensitivity in otoferlin Ile515Thr mutants[J].EMBO J.2016,35(23):2519-2535.
16 Hanan Al-Moyed,Andreia P Cepeda,Tobias Moser,et al.A dual-AAV approach restores fast exocytosis and partially rescues auditory function in deaf otoferlin knock-out mice[J].EMBOMolecular Medicine.2018;online.
17 Rosamaria Santarelli,Ignacio del Castillo,Arnold Starr,et al.Audibility,speech perception and processing of temporal cues in ribbon synaptic disorders due to OTOF mutations[J].Hearing Research.2015,330:200-212.
18张娇,张秋静,王秋菊等.听神经病谱系障碍患者的内科药物综合治疗及疗效分析[J].临床耳鼻咽喉头颈外科杂志.2014,28(8):544-547.Zhang J,Zhang QJ,Wang QJ,et al.The curative effect analysis of combined medical therapy for auditory neuropathy spectrum disorder[J].J Clin Otorhinolaryngol Head Neck Surg.2014,28(8):544-547.
19 Qiujing Zhang,Lan Lan,Qiuju Wang,et al.Temperature sensitive auditory neuropathy[J].Hearing Research.2016,335:53-63.