Impact of HOMER2 frameshift extension variant on auditory function and development.

Area of Science:

• Genetics
• Otolaryngology
• Molecular Biology

Background:

• The HOMER2 gene is vital for auditory system synaptic signaling and calcium homeostasis.
• Variants in HOMER2 are associated with sensorineural hearing loss (SNHL), particularly in older adults.
• Previous studies have identified extension variants, but a novel, longer variant was investigated here.

Purpose of the Study:

• To identify and characterize a novel frameshift extension variant (c.1033delC; p.R345Efs*64) in the HOMER2 gene.
• To investigate the pathogenic mechanisms underlying SNHL caused by this variant using molecular modeling and zebrafish.
• To compare the pathogenicity of the novel variant with a hypothetical truncation variant (p.R345*).

Main Methods:

• Identification of a novel HOMER2 frameshift extension variant in a patient with progressive profound SNHL.
• Molecular modeling using AlphaFold2 to predict structural changes and protein interactions.
• Zebrafish models to assess the functional impact on auditory phenotypes and cardiac anomalies.

Main Results:

• The p.R345Efs*64 variant induces significant structural changes in the HOMER2 EVH1 domain, disrupting Cdc42 interaction.
• Zebrafish models exhibited impaired neuromast hair cell function and exacerbated auditory deficits.
• The novel variant led to increased cardiac anomalies, with a milder impact observed for the p.R345* variant.

Conclusions:

• The pathogenic effect of the p.R345Efs*64 variant is primarily driven by the extended protein sequence beyond the natural stop codon, indicating a gain-of-function mechanism.
• This novel HOMER2 variant is a causative factor in elderly patients with profound SNHL.
• The findings suggest a potential link between HOMER2 variants and cardiac anomalies, warranting further investigation.