A study published in The Journal of Clinical Investigation has identified mutations in the carboxypeptidase D (CPD) gene as a previously unrecognized cause of congenital hearing loss.
Researchers discovered three missense variants in CPD among five individuals with congenital deafness from three unrelated families. All variants affected the enzyme’s active domain. Analysis of data from the 100,000 Genomes Project confirmed that rare CPD mutations were more common in people with hearing loss, indicating a strong genetic association.
CPD is involved in arginine processing, a key step in nitric oxide production. In mouse cochlea tissue, the protein was found in sensory and nerve cells essential for hearing. Functional studies showed that the mutations reduced CPD activity, leading to lower levels of arginine, nitric oxide, and cyclic guanosine monophosphate (cGMP) – molecules critical for maintaining cell health.
Fibroblasts derived from affected patients exhibited increased oxidative stress and cell death, linked to endoplasmic reticulum stress. Similarly, silencing CPD in mouse cochlear cultures triggered apoptosis in sensory cells, suggesting that enzyme loss directly damages the auditory system.
In fruit flies, loss of CPD led to structural and functional defects in the auditory organ. Notably, these defects were partially reversed with arginine supplementation or sildenafil, a drug that boosts cGMP signaling.
The findings identify CPD as a new gene associated with congenital hearing loss. Including this gene in genomic testing panels could improve early detection and expand diagnostic accuracy. The discovery also highlights the value of linking molecular genetics with biochemical analysis, as these pathways may offer future targets for treatment.
Although further research is needed to confirm whether nitric oxide pathway-targeted therapies benefit human patients, this study provides a clear link between genetic enzyme defects, metabolic disruption, and hearing loss.
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