A new mutation in the human pres gene and its effect on prestin function

Area of Science:

• Genetics
• Auditory Neuroscience
• Molecular Biology

Background:

• Cochlear outer hair cells (OHCs) are crucial for hearing sensitivity through electromotility, mediated by the protein prestin.
• Prestin mutations can lead to hearing impairment, as demonstrated by prestin knockout mice lacking OHC electromotility and exhibiting reduced hearing sensitivity.
• Genetic screening is essential for identifying novel mutations associated with hearing loss.

Purpose of the Study:

• To investigate the role of a novel pres gene mutation in non-syndromic mild-to-moderate hearing impairment.
• To analyze the functional consequences of the identified R150Q prestin mutation on OHC electromotility.

Main Methods:

• Direct sequencing of the pres gene in 47 patients with hearing impairment and 50 controls, after excluding GJB mutations.
• Electrophysiological studies using transient transfection of wild-type and R150Q prestin mutants into TSA 201 cells.
• Analysis of nonlinear capacitance (NLC) functions and voltage dependence (V1/2) of prestin-mediated charge displacement.

Main Results:

• A heterozygous missense mutation, R150Q, was found in one patient and their father, but not in 50 control subjects.
• Electrophysiological studies showed that the R150Q prestin mutant exhibited nonlinear capacitance, indicating preserved OHC electromotility.
• The voltage (V1/2) for maximal charge displacement was significantly shifted in the hyperpolarizing direction for the R150Q mutant compared to wild-type prestin.

Conclusions:

• This study presents the first genetic and electrophysiological analysis of a human pres gene mutation (R150Q) in a coding exon.
• The R150Q mutation affects prestin's voltage-dependent properties, potentially contributing to hearing impairment.
• The pathogenic role of the R150Q mutation requires further investigation, as its impact on hearing is not yet fully unambiguous.