Zebrafish Model for Nonsyndromic X-Linked Sensorineural Deafness, DFNX1

Alexandra A. DeSmidt, Bing Zou, M'hamed Grati, Denise Yan, Rahul Mittal, Qi Yao, Michael T. Richmond, Steven Denyer, Xue Z Liu, Zhongmin Lu

Research output: Contribution to journalArticle

Abstract

Hereditary deafness is often a neurosensory disorder and affects the quality of life of humans. Only three X-linked genes (POU class 3 homeobox 4 (POU3F4), phosphoribosyl pyrophosphate synthetase 1 (PRPS1), and small muscle protein X-linked (SMPX)) are known to be involved in nonsyndromic hearing loss. Four PRPS1 missense mutations have been found to associate with X-linked nonsyndromic sensorineural deafness (DFNX1/DFN2) in humans. However, a causative relationship between PRPS1 mutations and hearing loss in humans has not been well studied in any animal model. Phosphoribosyl pyrophosphate synthetase 1 (PRS-I) is highly conserved in vertebrate taxa. In this study, we used the zebrafish as a model to investigate the auditory role of zebrafish orthologs (prps1a and prps1b) of the human PRPS1 gene with whole mount in situ hybridization, reverse transcription polymerase chain reaction, phenotypic screening, confocal imaging, and electrophysiological methods. We found that both prps1a and prps1b genes were expressed in the inner ear of zebrafish. Splice-blocking antisense morpholino oligonucleotides (MO1 and MO2) caused exon-2 skip and intron-2 retention of prps1a and exon-2 skip and intron-1 retention of prps1b to knock down functions of the genes, respectively. MO1 and MO2 morphants had smaller otic vesicles and otoliths, fewer inner ear hair cells, and lower microphonic response amplitude and sensitivity than control zebrafish. Therefore, knockdown of either prps1a or prps1b resulted in significant sensorineural hearing loss in zebrafish. We conclude that the prps1 genes are essential for hearing in zebrafish, which has the potential to help us understand the biology of human deafness DFNX1/DFN2. Anat Rec, 2019.

Original languageEnglish (US)
JournalAnatomical Record
DOIs
StatePublished - Jan 1 2019

Fingerprint

deafness
Ribose-Phosphate Pyrophosphokinase
Deafness
Zebrafish
Danio rerio
pyrophosphates
hearing
ligases
gene
ears
Inner Ear
mutation
genes
Inner Auditory Hair Cells
Introns
exons
introns
Exons
Gene Knockdown Techniques
Otolithic Membrane

Keywords

  • hearing loss
  • inner ear
  • microphonic potential recording
  • PRPS1
  • zebrafish model

ASJC Scopus subject areas

  • Anatomy
  • Biotechnology
  • Histology
  • Ecology, Evolution, Behavior and Systematics

Cite this

Zebrafish Model for Nonsyndromic X-Linked Sensorineural Deafness, DFNX1. / DeSmidt, Alexandra A.; Zou, Bing; Grati, M'hamed; Yan, Denise; Mittal, Rahul; Yao, Qi; Richmond, Michael T.; Denyer, Steven; Liu, Xue Z; Lu, Zhongmin.

In: Anatomical Record, 01.01.2019.

Research output: Contribution to journalArticle

DeSmidt, Alexandra A. ; Zou, Bing ; Grati, M'hamed ; Yan, Denise ; Mittal, Rahul ; Yao, Qi ; Richmond, Michael T. ; Denyer, Steven ; Liu, Xue Z ; Lu, Zhongmin. / Zebrafish Model for Nonsyndromic X-Linked Sensorineural Deafness, DFNX1. In: Anatomical Record. 2019.
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