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Destabilization and Mislocalization of POU3F4 by C-Terminal Frameshift Truncation and Extension Mutation

 Byung Yoon Choi ; Do-Hwan Kim ; Woong-Yang Park ; Seung-Ha Oh ; Dongsup Kim ; Jinwoong Bok ; Sun O Chang ; Jungirl Seok ; Ah Reum Kim ; Eun-Hye Kim ; Mi Chang ; Taesu Chung 
 Human Mutation, Vol.34(2) : 309~316, 2013 
Journal Title
 Human Mutation 
Issue Date
Most X-linked nonsyndromic hearing loss is caused by various types of mutations of the POU domain class 3 transcription factor 4 gene (POU3F4). We found five unique missense and frameshift truncation and extension mutations in Korean patients. Two missense mutations (p.Thr211Met and p.Gln229Arg) disturbed transcriptional activity. Two frameshift extension mutations (p.Thr354GlnfsX115 and p.X362ArgextX113) were located outside of POU domain and nuclear localization signal (NLS) at the C-terminus. POU3F4 protein levels were low and could be restored by MG132, a proteasome inhibitor, in vitro. These mutant POU3F4 proteins were exclusively localized to the cytoplasm and did not have transcriptional activity. Frameshift mutation (p.Leu317PhefsX12) in POU3F4 leads to the truncation of the C-terminal 44 amino acids spanning the POU domain and NLS. This frameshift truncation mutant protein was located in both the nucleus and cytoplasm and was present at low protein levels. This mutant was also transcriptionally inactive, even in the presence of MG132. From these results, we conclude that frameshift truncation and extension mutations in the C-terminus of POU3F4 lead to cytoplasmic localization and subsequent proteosomal degradation due to structural aberrations, which cause transcriptional inactivity and thus nonsyndromic hearing loss.
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1. 연구논문 > 1. College of Medicine > Dept. of Anatomy
Yonsei Authors
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