Impact of HOMER2 frameshift extension variant on auditory function and development

Area of Science:

• Genetics
• Auditory Neuroscience
• Molecular Biology

Background:

• The HOMER2 gene is vital for synaptic signaling and calcium homeostasis in the auditory system.
• Variants in HOMER2 are associated with sensorineural hearing loss (SNHL), particularly in older adults.
• Severe SNHL may necessitate cochlear implants for individuals in their 60s or 70s.

Purpose of the Study:

• To identify and characterize a novel frameshift extension variant in the HOMER2 gene.
• To investigate the pathogenic mechanisms of the identified variant using molecular modeling and zebrafish.
• To compare the effects of the novel variant with a hypothetical truncation variant.

Main Methods:

• Identification of a novel frameshift extension variant (c.1033delC; p.R345Efs*64) in a patient with progressive profound SNHL.
• Utilized AlphaFold2 for molecular modeling to predict structural changes.
• Employed zebrafish models to assess functional impacts on auditory and cardiac systems.

Main Results:

• The p.R345Efs*64 variant induces significant structural alterations in the HOMER2 EVH1 domain, disrupting Cdc42 interactions.
• Zebrafish models exhibited impaired neuromast hair cell function and exacerbated auditory phenotypes.
• The novel variant also increased cardiac anomalies, with a milder impact observed for a hypothetical p.R345* truncation variant.

Conclusions:

• The pathogenic effect of the p.R345Efs*64 variant is primarily driven by the extended C-terminal protein sequence, suggesting a gain-of-function mechanism.
• This novel HOMER2 variant is a causative factor in elderly patients with profound SNHL.
• Findings highlight the importance of genetic diagnosis for SNHL in the elderly and suggest a potential link between HOMER2 variants and cardiac anomalies.