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FB2025_04
,
released October 2, 2025
This report describes auditory neuropathy, autosomal dominant 1, which is unusual in that other forms of auditory neuropathy exhibit recessive inheritance. Previous investigations had mapped the genetic region harboring the disease variant to an 11Mb region containing 4 genes. A variant in a highly conserved region of the 5' UTR of DIAPH3 (c.-172G>A mutation within a GC box sequence element) was found in affected family members and not in 379 controls. Subsequently, a second family with inherited auditory neuropathy was found to have a defect in the same region of the DIAPH3 5' UTR, within the highly conserved GGCGGG sequence. The mutation in the second family is c.-173C>T (Sanchez-Martinez, et al., 2017; pubmed:27658576).
DIAPH3 encodes an actin nucleation and elongation factor. There is a single gene in Drosophila orthologous to DIAPH3, Dmel\dia, for which loss-of-function mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\dia is orthologous to two additional genes in human, DIAPH1 and DIAPH2; DIAPH1 is also associated with a form of autosomal dominant deafness. None of the human DIAPH genes has been introduced into flies.
It was postulated that the original identified variant in DIAPH3 results in increased expression of the gene. To create a similar mutation in flies, a constitutively active form of dia was created. Expression of the constitutively active form in Johnston's organ (the fly auditory organ) results in hearing impairment in adult flies.
Adult flies heterozygous for a loss-of-function mutation of Dmel\dia have been tested for response to an acoustic stimulus, the Drosophila courtship song, using an electrophysiological assay to record sound-evoked potentials from the antennae. Mean responses are significantly reduced, compared to wild-type flies.
Physical and genetic interactions of Dmel\dia have been described; see below and in the dia gene report.
[updated Dec. 2019 by FlyBase; FBrf0222196]
[AUDITORY NEUROPATHY, AUTOSOMAL DOMINANT 1; AUNA1](https://omim.org/entry/609129)
[DIAPHANOUS-RELATED FORMIN 3; DIAPH3](https://omim.org/entry/614567)
Auditory neuropathy is a type of sensorineural deafness in which the function of the external ciliated cells in the cochlea is normal, but that of the internal ciliated cells, their synapsis with the auditory nerve or that of the auditory nerve itself is altered. It is characterised clinically by a loss of hearing that varies in level, but there is generally great difficulty in understanding speech, above all in noisy surroundings (Sanchez-Martinez, et al., 2017; pubmed:27658576).
Auditory neuropathy is a type of hearing loss defined by the preservation of cochlear outer hair cell function and abnormal or absent auditory brainstem responses. Auditory neuropathy may accompany peripheral neuropathy in a variety of dominant syndromes such as Charcot-Marie-Tooth disease and has been observed in Friedreich ataxia. Auditory neuropathy unassociated with peripheral neuropathy most commonly occurs as a sporadic or recessive trait. [from MIM:609129; 2019.05.02]
Autosomal dominant auditory neuropathy-1 (AUNA1) is caused by heterozygous mutation in the DIAPH3 gene. [from MIM:609129; 2019.05.02]
DIAPH3 encodes an actin nucleation and elongation factor required for the assembly of F-actin structures, such as actin cables and stress fibers; also acts in the nucleus. [Gene Cards, DIAPH3; 2019.05.03]
DIAPH3 belongs to the diaphanous subfamily of formins. These proteins remodel the cytoskeleton by nucleating and elongating nonbranched actin filaments, and they can also bind and stabilize microtubules (summary by DeWard and Alberts, 2009; pubmed:19457867) [from MIM:614567; 2019.05.02]
Many to one: 3 human to 1 Drosophila; the human genes are DIAPH1, DIAPH2, and DIAPH3.
High-scoring ortholog of human DIAPH3, DIAPH1, and DIAPH2 (1 Drosophila to 3 human). Dmel\dia shares 36-39% identity and 53-60% similarity with the human genes.