Inner ear manifestations in CHARGE: Abnormalities, treatments, animal models, and progress toward treatments in auditory and vestibular structures.
Inner ear manifestations in CHARGE: Abnormalities, treatments, animal models, and progress toward treatments in auditory and vestibular structures.
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DOI：
10.1002/ajmg.c.31587
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发表时间：
2017-12
期刊：
影响因子：
--
通讯作者：
Raphael Y
中科院分区：
文献类型：
--
作者：
Choo DI;Tawfik KO;Martin DM;Raphael Y
内耳包含听觉和平衡的感觉器官。患有电荷综合征(CS)的人通常会影响听力和平衡，这是一种常染色体显性疾病，由CHD7基因的杂合致病变异引起。半规管发育不良或发育不全是充血性疾病患者最常见的特征，导致缺乏粗大的运动技能和行走能力。CHD7作为主要致病基因的发现，加速了这一领域的研究。CHD7在内耳发育和功能以及中耳、听觉和前庭神经通路等相关器官中的作用已有很大进展。目前对CHD7和CS的研究目的是：(A)提高我们对CHD7致病变异体引起的病理的认识；(B)为预后和治疗提供更好的工具。目前的研究利用了细胞和整个动物，从苍蝇到哺乳动物。小鼠是探索CHD7在耳朵中功能机制的优秀模型，因为小鼠和人类的耳朵结构、功能、CHD7表达和突变表型的相似性在进化上是保守的。新发现的小鼠CHD7的发育功能揭示了CHD7的异常如何导致人类的CS症状。在这里，我们回顾已知的与CHD7致病变异体和CS相关的人类内耳表型，总结内耳相关病理的诊断和治疗进展，并根据基础科学发现探索治疗的新途径。
The inner ear contains the sensory organs for hearing and balance. Both hearing and balance are commonly affected in individuals with CHARGE syndrome (CS), an autosomal dominant condition caused by heterozygous pathogenic variants in the CHD7 gene. Semicircular canal dysplasia or aplasia is the single most prevalent feature in individuals with CHARGE leading to deficient gross motor skills and ambulation. Identification of CHD7 as the major gene affected in CHARGE has enabled acceleration of research in this field. Great progress has been made in understanding the role of CHD7 in the development and function of the inner ear, as well as in related organs such as the middle ear and auditory and vestibular neural pathways. The goals of current research on CHD7 and CS are to (a) improve our understanding of the pathology caused by CHD7 pathogenic variants and (b) to provide better tools for prognosis and treatment. Current studies utilize cells and whole animals, from flies to mammals. The mouse is an excellent model for exploring mechanisms of Chd7 function in the ear, given the evolutionary conservation of ear structure, function, Chd7 expression, and similarity of mutant phenotypes between mice and humans. Newly recognized developmental functions for mouse Chd7 are shedding light on how abnormalities in CHD7 might lead to CS symptoms in humans. Here we review known human inner ear phenotypes associated with CHD7 pathogenic variants and CS, summarize progress toward diagnosis and treatment of inner ear-related pathologies, and explore new avenues for treatment based on basic science discoveries.
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