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Sci Rep. 2017 Aug 8;7(1):7551. doi: 10.1038/s41598-017-08236-y.

A novel missense variant in the nuclear localization signal of POU4F3 causes autosomal dominant non-syndromic hearing loss.

Lin YH1,2, Lin YH1,3, Lu YC1, Liu TC1, Chen CY4, Hsu CJ5,6, Chen PL7,8,9,10,11, Wu CC12,13.

Author information

1
Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan.
2
Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan.
3
Graduate Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
4
Department of Bio-Industrial Mechatronics Engineering, National Taiwan University, Taipei, Taiwan.
5
Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan. cjhsu@ntu.edu.tw.
6
Department of Otolaryngology, Taichung Tzu-Chi Hospital, Taichung, Taiwan. cjhsu@ntu.edu.tw.
7
Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan. paylong@ntu.edu.tw.
8
Graduate Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei, Taiwan. paylong@ntu.edu.tw.
9
Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan. paylong@ntu.edu.tw.
10
Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan. paylong@ntu.edu.tw.
11
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. paylong@ntu.edu.tw.
12
Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan. chenchiwu@ntuh.gov.tw.
13
Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan. chenchiwu@ntuh.gov.tw.

Abstract

Autosomal dominant non-syndromic hearing loss (ADNSHL) is genetically heterogeneous with more than 35 genes identified to date. Using a massively parallel sequencing panel targeting 159 deafness genes, we identified a novel missense variant of POU4F3 (c.982A>G, p.Lys328Glu) which co-segregated with the deafness phenotype in a three-generation Taiwanese family with ADNSHL. This variant could be classified as a "pathogenic variant" according to the American College of Medical Genetics and Genomics guidelines. We then performed subcellular localization experiments and confirmed that p.Lys328Glu compromised transportation of POU4F3 from the cytoplasm to the nucleus. POU3F4 p.Lys328Glu was located within a bipartite nuclear localization signal (NLS), and was the first missense variant in bipartite NLS of POU4F3 validated in functional studies. These findings expanded the mutation spectrum of POU4F3 and provided insight into the pathogenesis associated with aberrant POU4F3 localization.

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