Noncoding Microdeletion in MouseHgfDisrupts Neural Crest Migration into the Stria Vascularis, Reduces the Endocochlear Potential, and Suggests the Neuropathology for Human Nonsyndromic Deafness DFNB39

Abstract

Hepatocyte growth factor (HGF) is a multifunctional protein that signals through the MET receptor. HGF stimulates cell proliferation, cell dispersion, neuronal survival, and wound healing. In the inner ear, levels of HGF must be fine-tuned for normal hearing. In mice, a deficiency of HGF expression limited to the auditory system, or an overexpression of HGF, causes neurosensory deafness. In humans, noncoding variants in HGF are associated with nonsyndromic deafness DFNB39. However, the mechanism by which these noncoding variants causes deafness was unknown. Here, we reveal the cause of this deafness using a mouse model engineered with a noncoding intronic 10 bp deletion (del10) in Hgf. Male and female mice homozygous for del10 exhibit moderate-to-profound hearing loss at 4 weeks of age as measured by tone burst auditory brainstem responses. The wild type (WT) 80 mV endocochlear potential was significantly reduced in homozygous del10 mice compared with WT littermates. In normal cochlea, endocochlear potentials are dependent on ion homeostasis mediated by the stria vascularis (SV). Previous studies showed that developmental incorporation of neural crest cells into the SV depends on signaling from HGF/MET. We show by immunohistochemistry that, in del10 homozygotes, neural crest cells fail to infiltrate the developing SV intermediate layer. Phenotyping and RNAseq analyses reveal no other significant abnormalities in other tissues. We conclude that, in the inner ear, the noncoding del10 mutation in Hgf leads to developmental defects of the SV and consequently dysfunctional ion homeostasis and a reduction in the EP, recapitulating human DFNB39 nonsyndromic deafness.

Characterization of rare spindle and root cell transcriptional profiles in the stria vascularis of the adult mouse cochlea

“…Intriguingly, Bergeron and colleagues demonstrate that overexpression of Nr2f1 in the Spot Tg/Tg mutant mouse results in expansion of the endolymphcontaining scala media with melanocytes failing to migrate to their proper locations in the vestibule but not the cochlea 68 . Despite, the apparent absence of hair cell degeneration in the face of Nr2f1 downregulation, hearing www.nature.com/scientificreports/ loss associated with changes in the endolymph ion homeostasis may occur in a delayed fashion [69][70][71] . The difficulty with Spot Tg/Tg mutant mouse model is that the vast majority of offspring die at birth with few that survive to young adulthood, thus making auditory testing inconclusive.…”

Next-Generation Sequencing Identifies Pathogenic Variants in HGF, POU3F4, TECTA, and MYO7A in Consanguineous Pakistani Deaf Families

“…The c.482+1986_1988del variant identified in this study has been previously reported to cause prelingual, profound deafness (DFNB39, MIM 608265) [ 43 ]. A Hgf 10 bp deletion in homozygous mutant mice, which fully encompasses the 3 bp deletion in humans, also displayed profound hearing loss at 4 weeks age ( Figure 3(d) ) [ 55 ]; Hgf 10 bp deletion in homozygous mice causes low expression of Hgf in the cochlea, which leads to developmental defect of the stria vascularis and reduced endocochlear potential in the cochlea [ 55 ]. The 3 bp deletion in the intronic region possibly has a similar mechanism to cause hearing loss.…”

Mouse Models of Human Pathogenic Variants of TBC1D24 Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness

“…For example, a dominant variant of METTL13 (DFNM1) completely suppresses recessive non-syndromic deafness DFNB26, associated with a variant of GAB2 with both genes functioning in the HGF/MET signaling pathway [64][65][66].…”