Carboxypeptidase D deficiency causes hearing loss amenable to treatment

Area of Science:

• Genetics
• Otolaryngology
• Molecular Biology

Background:

• Genetic factors are a significant cause of heterogeneous hearing loss (HL).
• Effective treatments for congenital deafness are limited.
• Carboxypeptidase D (CPD) is a protein with a role in cellular processes, but its link to hearing has not been established.

Purpose of the Study:

• To investigate the genetic basis of congenital hearing loss.
• To identify novel genes associated with non-syndromic deafness.
• To explore the functional role of CPD in auditory function and potential therapeutic strategies.

Main Methods:

• Whole-exome sequencing and analysis of large genetic datasets (100,000 Genomes Project).
• Localization studies of CPD in mouse cochlea.
• Biochemical assays measuring enzyme activity, arginine, NO, and cGMP levels in patient cells.
• In vitro studies using organotypic mouse cochlea cultures and in vivo studies using Drosophila models.

Main Results:

• Identified 3 missense variants in CPD associated with congenital deafness in 5 individuals from 3 families.
• Found an enrichment of rare protein-altering CPD variants in individuals with HL.
• Demonstrated that CPD deficiency impairs NO production, decreases arginine, NO, and cGMP levels, induces endoplasmic reticulum stress, and increases apoptosis in cochlear cells.
• CPD deficiency in Drosophila models caused auditory defects and movement abnormalities, partially rescued by arginine or sildenafil.

Conclusions:

• Mutations in CPD are a novel cause of congenital hearing loss.
• The nitric oxide (NO) signaling pathway is implicated in auditory function.
• CPD and the NO pathway represent a promising therapeutic target for certain types of hearing loss.