POU4F3基因与非综合征型听力损失的分子机制及临床特征研究进展

Research Progress on Molecular Mechanisms and Clinical Characteristics of POU4F3 Gene in Non-Syndromic Hearing Loss

摘要: POU4F3基因是耳蜗毛细胞生长发育和维持存活至关重要的转录因子，位于人类5号染色体长臂(5q31)，编码388个氨基酸残基构成的蛋白质，核心功能依赖于高度保守的POU结构域。此结构域由两部分构成：位于179-256位氨基酸区段的POU特异结构域(POU-specific domain)和位于274-333位氨基酸区段的POU同源结构域(POU homeodomain)，二者共同介导与DNA的结合。POU4F3基因对应的遗传学定位是DFNA15，于1998年被首次确认是导致常染色体显性非综合征型听力损失(autosomal dominant non-syndromic hearing loss, ADNSHL)的致病原因。目前报道的POU4F3致病突变涵盖多种类型，其后果可归纳为两类：一是导致蛋白产物被“截短”的突变(如无义、移码及部分缺失突变)，二是改变氨基酸序列从而“损坏”关键功能域的错义突变。无论何种形式，最终都破坏了POU4F3的正常功能，表现为转录活性丧失或亚细胞定位错误。从遗传机制上看，这通常源于单倍剂量不足或显性负效应，并引发进行性的毛细胞损伤与听力损失。临床研究表明，POU4F3相关听力损失多表现为迟发性、双侧对称性、进行性感音神经性聋，听力曲线以高频下降型为主，但中频下降型及平坦型亦见报道，表型异质性显著。除典型听力损失外，部分患者可伴有前庭功能障碍，但一般不伴其他系统异常，符合非综合征性特征。基因筛查显示，POU4F3突变在家族性ADNSHL中占一定比例，尤其在具有特定听力表型的大家系中贡献突出。鉴于其分子机制复杂、表型多样，深入研究POU4F3的病理生理途径对于开发靶向治疗及改善遗传性耳聋的临床管理具有重要意义。

Abstract: The POU4F3 gene is a transcription factor crucial for the growth, development and survival of cochlear hair cells. It is located on the long arm of human chromosome 5 (5q31) and encodes a protein composed of 388 amino acid residues. Its core function depends on the highly conserved POU domain. This domain consists of two parts: the POU-specific domain located in the amino acid region 179-256 and the POU homedomain located in the amino acid region 274-333, which together mediate binding to DNA. The genetic location corresponding to the POU4F3 gene is DFNA15, which was first confirmed in 1998 as the cause of autosomal dominant non-syndromic hearing loss (ADNSHL). The currently reported pathogenic mutations in POU4F3 cover many types, and their consequences can be summarized into two categories: one is mutations that lead to “truncation” of protein products (such as nonsense, frame-shift and partial deletion mutations), and the other is missense mutations that change amino acid sequences and thereby “damage” key functional domains. Regardless of the form, it ultimately disrupts the normal function of POU4F3, manifested by loss of transcriptional activity or erroneous subcellular positioning. From a genetic perspective, this usually results from a single dose deficiency or a dominant negative effect, and causes progressive hair cell damage and hearing loss. Clinical studies have shown that POU4F3-related hearing loss mostly manifests as delayed, bilateral symmetrical, and progressive sensorineural deafness. The hearing curve is mainly of the high-frequency decreasing type, but the intermediate-frequency decreasing type and flat type have also been reported. Phenotype heterogeneity is significant. In addition to typical hearing loss, some patients may have vestibular dysfunction, but generally not accompanied by other system abnormalities and are consistent with non-syndromic characteristics. Genetic screening showed that POU4F3 mutations accounted for a certain proportion of familial ADNSHL, especially in large families with specific hearing phenotypes. Given its complex molecular mechanisms and diverse phenotypes, in-depth research on the pathophysiological pathways of POU4F3 is of great significance for developing targeted therapies and improving the clinical management of hereditary deafness.