IQGAP3 deficiency leads to non-syndromic hearing loss via inhibition of CDC42 enzyme activity

Abstract

Background

Genetic factors are important causes of congenital hearing loss. To better understand hereditary hearing loss, we performed in-depth clinical and molecular analysis of families with congenital hearing loss and a new disease-related gene, IQGAP3, was identified in this process. This gene encodes a protein that belongs to the IQGAP family which is well known as a GTPase-activating protein involved in various cellular functions. However, there is no research on the relationship between IQGAP3 and the auditory system.

Method

This study was conducted at Guangzhou Women and Children's Medical Center and Nantong University from 2019 to 2023 to confirm the relationship between defective IQGAP3 and hearing loss, and further explore the underlying molecular mechanism. We constructed the iqgap3 knockdown zebrafish model, primary mouse inner progenitor cell model and IQGAP3-knockout HEK293T cell line for this research.

Result

We found that IQGAP3 deficiency led to abnormal development of the auditory system and impaired auditory function in zebrafish. In vitro studies showed that loss of this gene's function resulted in a 40.29 % reduction in EdU-positive cells and a 44.25 % decrease in Ki67-positive cells in mouse inner ear progenitor cells, indicating reduced proliferation. This can be linked with inhibition of CDC42 enzymatic activity and the blockade of the Wnt-catenin pathway.

Conclusion

We identified IQGAP3 as a novel potential causative gene in hereditary hearing loss. Our findings provide important insights into the molecular basis of hereditary hearing loss.