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Dev Biol 2021 Aug 01;476:200-208. doi: 10.1016/j.ydbio.2021.04.002.
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Molecular mechanisms of hearing loss in Nager syndrome.

Nager syndrome is a rare human developmental disorder characterized by hypoplastic neural crest-derived craniofacial bones and limb defects. Mutations in SF3B4 gene, which encodes a component of the spliceosome, are a major cause for Nager. A review of the literature indicates that 45% of confirmed cases are also affected by conductive, sensorineural or mixed hearing loss. Conductive hearing loss is due to defective middle ear ossicles, which are neural crest derived, while sensorineural hearing loss typically results from defective inner ear or vestibulocochlear nerve, which are both derived from the otic placode. Animal model of Nager syndrome indicates that upon Sf3b4 knockdown cranial neural crest progenitors are depleted, which may account for the conductive hearing loss in these patients. To determine whether Sf3b4 plays a role in otic placode formation we analyzed the impact of Sf3b4 knockdown on otic development. Sf3b4-depleted Xenopus embryos exhibited reduced expression of several pan-placodal genes six1, dmrta1 and foxi4.1. We confirmed the dependence of placode genes expression on Sf3b4 function in animal cap explants expressing noggin, a BMP antagonist critical to induce placode fate in the ectoderm. Later in development, Sf3b4 morphant embryos had reduced expression of pax8, tbx2, otx2, bmp4 and wnt3a at the otic vesicle stage, and altered otic vesicle development. We propose that in addition to the neural crest, Sf3b4 is required for otic development, which may account for sensorineural hearing loss in Nager syndrome.

PubMed ID: 33864777
PMC ID: PMC8634618
Article link: Dev Biol
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: bmp4 dmrta1 ebf2 eya1 foxi4 foxi4.2 krt12.4 nog otx2 pax8 sf3b4 six1 sox2 tbx2 wnt3a
GO keywords: otic vesicle formation [+]
Morpholinos: sf3b4 MO3

Disease Ontology terms: sensorineural hearing loss [+]

Article Images: [+] show captions
References [+] :
Abdollahi Fakhim, A case report: nager acrofacial dysostosis. 2012, Pubmed