Peripheral Anomalies in USH2A Cause Central Auditory Anomalies in a Mouse Model of Usher Syndrome and CAPD

Abstract

Central auditory processing disorder (CAPD) is associated with difficulties hearing and processing acoustic information, as well as subsequent impacts on the development of higher-order cognitive processes (i.e., attention and language). Yet CAPD also lacks clear and consistent diagnostic criteria, with widespread clinical disagreement on this matter. As such, identification of biological markers for CAPD would be useful. A recent genome association study identified a potential CAPD risk gene, USH2A. In a homozygous state, this gene is associated with Usher syndrome type 2 (USH2), a recessive disorder resulting in bilateral, high-frequency hearing loss due to atypical cochlear hair cell development. However, children with heterozygous USH2A mutations have also been found to show unexpected low-frequency hearing loss and reduced early vocabulary, contradicting assumptions that the heterozygous (carrier) state is “phenotype free”. Parallel evidence has confirmed that heterozygous Ush2a mutations in a transgenic mouse model also cause low-frequency hearing loss (Perrino et al., 2020). Importantly, these auditory processing anomalies were still evident after covariance for hearing loss, suggesting a CAPD profile. Since usherin anomalies occur in the peripheral cochlea and not central auditory structures, these findings point to upstream developmental feedback effects of peripheral sensory loss on high-level processing characteristic of CAPD. In this study, we aimed to expand upon the mouse behavioral battery used in Perrino et al. (2020) by evaluating central auditory brain structures, including the superior olivary complex (SOC) and medial geniculate nucleus (MGN), in heterozygous and homozygous Ush2a mice. We found that heterozygous Ush2a mice had significantly larger SOC volumes while homozygous Ush2a had significantly smaller SOC volumes. Heterozygous mutations did not affect the MGN; however, homozygous Ush2a mutations resulted in a significant shift towards more smaller neurons. These findings suggest that alterations in cochlear development due to USH2A variation can secondarily impact the development of brain regions important for auditory processing ability.

Retinal organoids and microfluidic chip-based approaches to explore the retinitis pigmentosa with USH2A mutations

“…These motifs have been most commonly observed in the protein components of the basal laminin, extracellular matrixes, and cell adhesion molecules (Bhattacharya and Cosgrove, 2005). Genetic in vivo studies have shown that usherin is essential for the survival of photoreceptor cells and inner ear hair cell bundle integrity (Zou et al, 2011;Perrino et al, 2021;Schwaller et al, 2021). Although these studies above provide clues for uncovering the functions of the USH2A gene, however, its large size and broad spectrum of mutations raise many challenges for researchers to develop effective gene therapy (Stemerdink et al, 2021).…”

Usher Syndrome on the Island of Ireland: A Genotype-Phenotype Review

“… 8 , 19 – 21 Variable effects on respiratory cilia 22 and fertility 23 have been reported. Some hypomorphic genetic variants can cause non-syndromic RP (e.g., USH2A is also the most frequent cause of nonsyndromic AR-RP) 24 , 25 and may cause isolated deafness (e.g., in MYO7A, USH1C, CDH23, PCDH15 ) even when monoallelic, 26 – 28 further compounding the diagnostic complexity. The characteristics and severity of the phenotype depend on the position and degree of deleteriousness of the causative variant.…”

Genetics of Hearing Impairment

“…Perrino et al employed the mouse to model the potential role of USH2A defects in central auditory processing disorder (CAPD), as was indicated in a genome-wide association study (GWAS) [19]. The authors indeed obtained indications for an effect of Ush2a defects on the structure of the central auditory system, both in homozygous knockout as well as heterozygous knockout mice.…”