Impact of HOMER2 frameshift extension variant on auditory function and development

TL;DR

A new HOMER2 gene variant causes severe hearing loss in elderly people and disrupts auditory and cardiac function in zebrafish models.

Contribution

A novel frameshift extension variant in HOMER2 is identified as a cause of late-onset profound hearing loss.

Findings

The c.1033delC variant introduces a 63-amino acid extension that disrupts the EVH1 domain of HOMER2.

Zebrafish models show impaired auditory function and increased cardiac anomalies with this variant.

The pathogenic effect is primarily driven by the C-terminal extension rather than truncation.

Abstract

The HOMER2 gene, crucial for synaptic signaling and calcium homeostasis in the auditory system, is linked to sensorineural hearing loss (SNHL), with its variants contributing to severe SNHL in older adults, often necessitating cochlear implants in their 60 s or 70 s. In this study, we identified a novel frameshift extension variant, c.1033delC (p.Arg345Glufs*64; p.R345Efs*64), which introduces a significantly longer protein extension than previously reported extension variants, in a patient in their sixties presenting with progressive profound SNHL. To investigate the pathogenic potential of this variant, we employed molecular modeling and zebrafish models, comparing wild-type HOMER2, a hypothetical p.R345* variant involving alteration of the most C-terminal 10 amino acids, and the patient-derived p.R345Efs*64 variant. AlphaFold2 predicts that the p.R345Efs*64 variant causes significant structural changes in the HOMER2 EVH1 domain, disrupting interactions with Cdc42 and contributing to SNHL. Zebrafish models show that this variant, which combines truncation and extension features, impairs neuromast hair cell function and exacerbates auditory phenotypes, while also increasing cardiac anomalies. In comparison, the p.R345* variant showed an obvious milder impact. Our findings suggest that the pathogenic effect of the p.R345Efs*64 variant is more driven by the extension beyond the stop codon. Here we report that a novel frameshift extension variant of HOMER2, which arises as a causative gene in elderly patients with profound SNHL, highlighting the need for genetic diagnosis in this population. Our findings reveal a solid pathogenic gain-of-function effect related to the long extension to the C-terminal of HOMER2, and a possible link to cardiac anomalies.

The online version contains supplementary material available at 10.1007/s00109-025-02556-7.

We report a novel and unique frameshift extension variant, c.1033delC, in HOMER2.This HOMER2 variant leads to profound deafness in people in their 60s or later.The extended 63 amino acids of the variant may disrupt HOMER2’s EVH1 domain.The variant impairs morphological development and auditory function in zebrafish.

We report a novel and unique frameshift extension variant, c.1033delC, in HOMER2.

This HOMER2 variant leads to profound deafness in people in their 60s or later.

The extended 63 amino acids of the variant may disrupt HOMER2’s EVH1 domain.

The variant impairs morphological development and auditory function in zebrafish.

The online version contains supplementary material available at 10.1007/s00109-025-02556-7.

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