Functional Correlation of Two Novel Nonsense POU4F3 Mutations Causing Late-Onset Progressive Nonsyndromic Hearing Loss in DFNA15 Families.

Abstract

Background: POU4F3 mutations cause DFNA15, an autosomal dominant nonsyndromic hearing loss. POU4F3 encodes a transcription factor crucial for inner ear hair cell development and maintenance.

Objective: To identify and functionally characterize novel POU4F3 mutations in two Chinese families with late-onset progressive hearing loss.

Methods: Massively parallel DNA sequencing (MPS) was performed on affected individuals from two unrelated Chinese families. Sanger sequencing validated mutations and confirmed co-segregation. Functional analyses included protein expression analysis by Western blots and subcellular localization studies by immunofluorescence.

Results: We identified two novel nonsense mutations in POU4F3: c.863C > A (p.Ser288Ter) and c.172G > T (p.Glu58Ter), both co-segregating with the hearing loss phenotype. Functional studies showed p.Ser288Ter produced a stable but mislocalized protein with impaired nuclear transport, while p.Glu58Ter resulted in a severely truncated, rapidly degraded protein.

Conclusion: This study expands the DFNA15 mutation spectrum and provides new insights into POU4F3-related hearing loss pathogenesis. Our findings demonstrate that different molecular mechanisms can lead to similar DFNA15 phenotypes, supporting POU4F3 haploinsufficiency as the primary pathogenic mechanism.