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Review
. 2023;28(6):407-419.
doi: 10.1159/000528766. Epub 2023 Jun 16.

Genotype-Phenotype Correlations in TMPRSS3 (DFNB10/DFNB8) with Emphasis on Natural History

Eric Nisenbaum  1 , Denise Yan  2 , A Eliot Shearer  3 , Evan de Joya  2   4 , Torin Thielhelm  2 , Nicole Russell  3 , Hinrich Staecker  5 , Zhengyi Chen  6 , Jeffrey R Holt  3 , Xuezhong Liu  2   4   6   7
Affiliations
Review

Genotype-Phenotype Correlations in TMPRSS3 (DFNB10/DFNB8) with Emphasis on Natural History

Eric Nisenbaum et al. Audiol Neurootol. 2023.

Abstract

Background: 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.

Summary: 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.

Key messages: 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.

Keywords: Autosomal recessive non-syndromic hearing loss; Gene therapy; Genetic disease; Genotype-phenotype correlation; Hearing loss.

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Conflict of interest statement

All authors declare no relevant conflicts of interest.

Figures

Fig. 1.
Fig. 1.
Schematic representation depicting the predicted functional domains and sequence motifs. The positions of the described TMPRSS3 mutations are shown at the top of the figure.
See this image and copyright information in PMC

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