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FEBS Lett. 2019 Jun 14. doi: 10.1002/1873-3468.13482. [Epub ahead of print]

Mutations in TOP2B cause autosomal-dominant hereditary hearing loss via inhibition of the PI3K-Akt signalling pathway.

Author information

1
Institutes of Biomedical Science, Fudan University, Shanghai, China.
2
Department of Otorhinolaryngology, Shanghai East Hospital, Tongji University, Shanghai, China.
3
Department of Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, ENT Institute and Otorhinolaryngology, Fudan University, Shanghai, China.
4
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, Collaborative Innovation Centre of Genetics and Development, School of Basic Medical Sciences, Fudan University, Shanghai, China.

Abstract

Hereditary hearing impairment is a clinically and genetically heterogeneous disease. Whole-exome sequencing was performed on seven affected and six unaffected members in a large Chinese family with autosomal-dominant nonsyndromic hearing loss. The pathogenic variant of the gene encoding human topoisomerase IIβ TOP2B (c.G4837C:p.D1613H) was cosegregated with hearing loss in this pedigree and another two variants of TOP2B were detected in 66 sporadic patients with hearing loss. top2b knockdown led to significant defects in zebrafish inner ears and caused downregulation of akt which resulted in inactivation of PI3K-Akt signalling. As a result, supporting cell and hair cell numbers were reduced through inhibition of the PI3K-Akt pathway. Therefore, we hypothesized that mutations in TOP2B can cause autosomal-dominant nonsyndromic hearing impairment through inhibition of the PI3K-Akt signalling pathway. DATABASE: The whole-exome sequence data in the study are available at the Sequence Read Archive database (NCBI) under the accession numbers SRR9050868, SRR9050867, SRR90508676, SRR90508675, SRR90508674, SRR90508673, SRR90508672, SRR90508671, SRR90508679, SRR90508670, SRR9050859. SRR9050858 and SRR9050857, respectively.

KEYWORDS:

PI3K-Akt signalling pathway; TOP2B; deafness genes; nonsyndromic hearing loss; zebrafish

PMID:
31198993
DOI:
10.1002/1873-3468.13482

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