人类有六种ferlin蛋白家族成员：dysferlin、myoferlin、otoferlin、fer1L4、fer1L5和fer1L6。这些蛋白共享共同的特征，如多个Ca2+结合的C2结构域、FerA结构域和通过它们的单个C-末端跨膜结构域在膜上锚定，被认为在钙触发的膜融合和囊泡运输中起关键作用。Otoferlin在听觉和前庭功能中发挥至关重要的作用。在本综述中，我们将讨论我们如何看待otoferlin作为一个依赖于Ca2+的机械传感器，在毛细胞丝带突触中调节突触囊泡融合的作用。尽管otoferlin也存在于中枢神经系统中，特别是皮层和杏仁核中，但其在脑组织中的作用仍然未知。OTOF基因突变导致先天性聋的最常见遗传形式DFNB9。这些突变导致由于内耳毛细胞与听神经纤维之间突触兴奋性谷氨酸传递的缺陷而产生严重至深度听力丧失。允许在毛细胞中正常恢复otoferlin表达的基因治疗方案刚刚开始，并且目前处于临床前阶段。同时，研究表明ferlin蛋白通过其对细胞信号传导和发育的影响与癌症有关，使肿瘤得以形成并使癌细胞适应恶劣环境。机械力和Ca2+信号调节是转移过程的关键决定因素。尽管ferlin在癌症中的重要性尚未得到广泛研究，但数据显示otoferlin的表达显著与特定癌症类型的生存相关，包括透明细胞和乳头状细胞肾癌以及尿路膀胱癌。这些发现表明otoferlin在这些肿瘤的癌发中起着作用，需要进一步研究以确认并理解其在不同肿瘤位置上的确切作用。定位这种蛋白可能会导致新的癌症治疗方法。版权所有 © 2023 Leclère and Dulon.

Humans have six members of the ferlin protein family: dysferlin, myoferlin, otoferlin, fer1L4, fer1L5, and fer1L6. These proteins share common features such as multiple Ca2+-binding C2 domains, FerA domains, and membrane anchoring through their single C-terminal transmembrane domain, and are believed to play a key role in calcium-triggered membrane fusion and vesicle trafficking. Otoferlin plays a crucial role in hearing and vestibular function. In this review, we will discuss how we see otoferlin working as a Ca2+-dependent mechanical sensor regulating synaptic vesicle fusion at the hair cell ribbon synapses. Although otoferlin is also present in the central nervous system, particularly in the cortex and amygdala, its role in brain tissues remains unknown. Mutations in the OTOF gene cause one of the most frequent genetic forms of congenital deafness, DFNB9. These mutations produce severe to profound hearing loss due to a defect in synaptic excitatory glutamatergic transmission between the inner hair cells and the nerve fibers of the auditory nerve. Gene therapy protocols that allow normal rescue expression of otoferlin in hair cells have just started and are currently in pre-clinical phase. In parallel, studies have linked ferlins to cancer through their effect on cell signaling and development, allowing tumors to form and cancer cells to adapt to a hostile environment. Modulation by mechanical forces and Ca2+ signaling are key determinants of the metastatic process. Although ferlins importance in cancer has not been extensively studied, data show that otoferlin expression is significantly associated with survival in specific cancer types, including clear cell and papillary cell renal carcinoma, and urothelial bladder cancer. These findings indicate a role for otoferlin in the carcinogenesis of these tumors, which requires further investigation to confirm and understand its exact role, particularly as it varies by tumor site. Targeting this protein may lead to new cancer therapies.Copyright © 2023 Leclère and Dulon.