Filling the Silent Void: Genetic Therapies for Hearing Impairment

Table 1

Genes that regulate the development of the ear
Gene	Description	References
Homeobox gene superfamily
Pax	Pax2 required for organ of Corti formation, expression of Pax5 can compensate for loss of Pax2 expression.	[16]
Otx	Otx1 required for saccule and utricle segregation and formation of the horizontal canal. Otx2 required for segregation of inner ear and trigeminal progenitors.	[17, 18]
Gbx	Gbx2 required in posterior otic placode formation.	[18]
Msx	Msx1 expressed in the preotic placodal region, possibly a regulator of neural development. Plays role in regulating epithelial-mesenchymal interaction.	[15, 19, 20]
Dlx	Dlx5 and Dlx6 required for formation of semicircular ducts, saccule, and utricle. Inhibits Pax2 and activates Gbx2 expression.	[21]
Hmx	Hmx2 and Hmx3 coexpressed in the dorsolateral otic epithelium, controls cell proliferation, and regulates morphology of inner ear.	[22]
Retinoblastoma (Rb) family
Rb1	Cell cycle regulator (G to S phase transition), required for hair cell quiescence. Deletion of Rb1 induces proliferation and differentiation of hair cells. However deletion of Rb1 in adult mice is insufficient for inducing hair cell proliferation.	[23–26]
Rbl1	Cell cycle regulator (G to S phase transition).	[24]
Rbl2	Cell cycle regulator (G to S phase transition). Deletion results in additional rows of hair and supporting cells.	[27]
Myosin superfamily
MYO1A	Located within DFNA48 locus, expressed within cochlear, mutation results in sensorineural hearing impairment. Myo1b located at apical surface of supporting cells, Myo1c concentrated at hair cell stereocilia, Myo1e located at hair cells of auditory epithelia.	[28, 29]
MYO6	Required for the structural maintenance of hair cell stereocilia, mutation leads to autosomal dominant hearing loss.	[30, 31]
MYO7A	Required for inner ear endocytosis, mutations can result in Usher syndrome or nonsyndromic deafness.	[32, 33]
MYO15	Required for development and elongation of hair cell stereocilia, mutation associated with hearing impairment.	[34, 35]
Other genes
Atoh1 (Math1)	Helix-loop-helix transcription factor required for the development, differentiation, and regeneration of functional hair cells.	[36, 37]
E2F1	Transcription factor involved in cell cycle regulation. Mediates pRb (Rb1) function.	[23, 38, 39]
Fgf	Expression of Fgf3 and Fgf10 required for Dlx5 and Dlx6 expression. Fgf10 required for posterior canal and hair cell cilia formation.  Fgf8 binds to Fgfr3 and is involved in pillar cell formation and cellular patterning in cochlea.	[40–42]
Foxg1	Required for inner ear sensory cristae formation, regulates sensory fate and embryonic neurosensory development. Mutation results in a shortened cochlea and loss of crista neurons.	[43–45]
Hes1	Controls patterning of inner hair cells in organ of Corti, functions with Hey2 .	[46]
Hes5	Controls patterning of outer hair cells in organ of Corti, functions with Hey2.	[46]
Hey2	Activated by Fgf, prevents pillar cells from differentiating into hair cells. Controls patterning in organ of Corti, functions with Hes1 and Hes5.	[46, 47]
Notch	Regulates hair cell fate and patterning in cochlea, regulated by Notch ligands DLL1 and JAG2.	[48]
Ngn1	Regulates transition from neurogenesis to sensory cell development. Process cross-regulated by both Ngn1 and Atoh1.	[49]
𝑝27^𝐾𝑖𝑝1	Regulated by Notch-Hes1 signalling pathway. Cyclin-dependent kinase cell cycle inhibitor. Loss of 𝑝27^𝐾𝑖𝑝1 initiates cellular proliferation in organ of Corti.	[50, 51]
Sox2	Promoted by Notch1 signalling, regulates hair cell differentiation and proliferation. Mutation results in sensorineural hearing impairment.	[52]