4 255

Cited 12 times in

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

Authors
 Byung Yoon Choi  ;  Do-Hwan Kim  ;  Taesu Chung  ;  Mi Chang  ;  Eun-Hye Kim  ;  Ah Reum Kim  ;  Jungirl Seok  ;  Sun O Chang  ;  Jinwoong Bok  ;  Dongsup Kim  ;  Seung-Ha Oh  ;  Woong-Yang Park 
Citation
 HUMAN MUTATION, Vol.34(2) : 309-316, 2013 
Journal Title
 HUMAN MUTATION 
ISSN
 1059-7794 
Issue Date
2013
MeSH
Adolescent ; Amino Acid Sequence ; Asian Continental Ancestry Group/genetics ; Blotting, Western ; Child ; Child, Preschool ; Fluorescent Antibody Technique ; Frameshift Mutation* ; Gene Frequency ; HEK293 Cells ; Hearing Loss, Sensorineural/genetics* ; Humans ; Leupeptins/pharmacology ; Magnetic Resonance Imaging ; Male ; Molecular Sequence Data ; Mutation, Missense ; Nuclear Localization Signals ; POU Domain Factors/genetics* ; POU Domain Factors/metabolism ; Pedigree ; Phenotype ; Proteasome Inhibitors/pharmacology ; Protein Conformation ; Transcriptional Activation/genetics
Keywords
Adolescent ; Amino Acid Sequence ; Asian Continental Ancestry Group/genetics ; Blotting, Western ; Child ; Child, Preschool ; Fluorescent Antibody Technique ; Frameshift Mutation* ; Gene Frequency ; HEK293 Cells ; Hearing Loss, Sensorineural/genetics* ; Humans ; Leupeptins/pharmacology ; Magnetic Resonance Imaging ; Male ; Molecular Sequence Data ; Mutation, Missense ; Nuclear Localization Signals ; POU Domain Factors/genetics* ; POU Domain Factors/metabolism ; Pedigree ; Phenotype ; Proteasome Inhibitors/pharmacology ; Protein Conformation ; Transcriptional Activation/genetics
Abstract
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.
Full Text
http://onlinelibrary.wiley.com/doi/10.1002/humu.22232/abstract
DOI
10.1002/humu.22232
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Anatomy (해부학교실) > 1. Journal Papers
Yonsei Authors
Bok, Jin Woong(복진웅) ORCID logo https://orcid.org/0000-0003-1958-1872
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/87468
사서에게 알리기
  feedback

qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse

Links