Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida, USA,
Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida, USA.
Audiol Neurootol. 2023;28(6):407-419. doi: 10.1159/000528766. Epub 2023 Jun 16.
Mutations in TMPRSS3 are an important cause of autosomal recessive non-syndromic hearing loss. The hearing loss associated with mutations in TMPRSS3 is characterized by phenotypic heterogeneity, ranging from mild to profound hearing loss, and is generally progressive. Clinical presentation and natural history of TMPRSS3 mutations vary significantly based on the location and type of mutation in the gene. Understanding these genotype-phenotype relationships and associated natural disease histories is necessary for the successful development and application of gene-based therapies and precision medicine approaches to DFNB8/10. The heterogeneous presentation of TMPRSS3-associated disease makes it difficult to identify patients clinically. As the body of literature on TMPRSS3-associated deafness grows, there is need for better categorization of the hearing phenotypes associated with specific mutations in the gene.
In this review, we summarize TMPRSS3 genotype-phenotype relationships including a thorough description of the natural history of patients with TMPRSS3-associated hearing loss to lay the groundwork for the future of TMPRSS3 treatment using molecular therapy.
TMPRSS3 mutation is a significant cause of genetic hearing loss. All patients with TMPRSS3 mutation display severe-to-profound prelingual (DFNB10) or a postlingual (DFNB8) progressive sensorineural hearing loss. Importantly, TMPRSS3 mutations have not been associated with middle ear or vestibular deficits. The c.916G>A (p.Ala306Thr) missense mutation is the most frequently reported mutation across populations and should be further explored as a target for molecular therapy.
TMPRSS3 突变是常染色体隐性非综合征性听力损失的一个重要原因。TMPRSS3 突变相关的听力损失表现为表型异质性，从轻度到重度听力损失不等，且通常呈进行性。基于基因突变在基因中的位置和类型，TMPRSS3 突变的临床表现和自然病史差异很大。了解这些基因型-表型关系以及相关的自然病史对于成功开发和应用基于基因的治疗方法和精准医学方法治疗 DFNB8/10 至关重要。TMPRSS3 相关疾病的异质性表现使得临床上很难识别患者。随着 TMPRSS3 相关性耳聋文献的不断增加，需要对与该基因特定突变相关的听力表型进行更好的分类。
本文综述了 TMPRSS3 基因型-表型关系，包括对 TMPRSS3 相关性听力损失患者自然病史的全面描述，为未来使用分子治疗 TMPRSS3 奠定基础。
TMPRSS3 突变是遗传性听力损失的一个重要原因。所有 TMPRSS3 突变患者均表现为重度至极重度语前（DFNB10）或语后（DFNB8）进行性感音神经性听力损失。重要的是，TMPRSS3 突变与中耳或前庭缺陷无关。c.916G>A（p.Ala306Thr）错义突变是最常见的人群突变，应进一步探索作为分子治疗的靶点。
