Journal Club: Carboxypeptidase D (CPD) gene variants as the cause of familial, recessive hearing loss

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Today's journal article

Ramzan M, Ortiz-Vega N, Zafeer MF, Lobato AG, Atik T, Abad C, Vadgama N, Duman D, Bozan N, Avcı Durmuşalioǧlu E, Greene S, Guo S, Tokgöz-Yılmaz S, Yekedüz MK, Eminoğlu FT, Aydın M, Seyhan S, Karakikes I, Camarena V, Robayo MC, Canic T, Bademci G, Wang G, Farooq A, Joiner ML, Walz K, Eberl DF, Nasir J, Zhai RG, Tekin M. Carboxypeptidase D deficiency causes hearing loss amenable to treatment. 

Why I picked this article

Sensorineural hearing loss is a permanent hearing loss that occurs from damage to the inner ear hearing organ, the cochlea, and the auditory nerve. Some pathological gene variability can cause sensorineural hearing loss. In genetic hearing loss, hearing loss can be evident at birth or develop later in life, and it will have familial traits. More genetic variants are being discovered by ongoing research. 

This research focuses on a genetic variant for the Carboxypeptidase D (CPD) gene, observed in three different families. CPD is an enzyme that helps generate arginine for nitric oxide (NO) synthase. Nitric oxide (NO) signalling has been suspected in cochlear physiology for years, but a direct human genetic link to hearing loss has been missing until this study.  This research then conducts in vivo and in vitro experimental research to provide evidence that reduced arginine/NO/cGMP signalling harms cells in the cochlear. 

Some of the research findings

Analysis of three families with CPD genetic variants: 
  • Five affected individuals from three unrelated families carried biallelic CPD missense variants. 
    • Missense variants are essentially where the CPD gene becomes non-functional as a consequence of the variation. 
    • The variants occur in the catalytically active domain 2: p.Met563Arg, p.Gln791Arg, and p.Arg833His. 
  • Hearing loss phenotype: 
    • Congenital or early-childhood sensorineural hearing loss on both ears
    • Severe–profound
    • Several received unilateral or bilateral cochlear implants.
    • Ages at diagnosis ranged 1–20 months; ages at report 6–46 years. 
Figure 1A, pedigree of three families described in this research. Black color indicate the individuals with hearing loss. Ramzan et al. 2025

Population-wide search for CPD impact on hearing loss: 
  • Analysis was doe on the UK 100,000 Genomes Project cohort
  • The cohort include 3,802 with hearing loss & 27,503 controls
  • All protein-altering CPD variants showed modest enrichment in cases (OR 1.23, 95% CI 1.06–1.44). Prioritised rare/damaging missense variants showed a stronger association (OR 1.81, 95% CI 1.11–2.96).
The role of CPD in the cochlea: 
Mouse model: 
  • In mouse cochlea, CPD protein was found in the inner and outer hair cells, stria vascularis, and auditory neurons.
In vitro experiments with fibrocytes: 
  • Structural/biochemical assays indicated that the patient variants disrupt the catalytic site, reducing intracellular arginine and lysine availability. This will impair NO → cGMP signaling. 
  • When fibrocytes were isolated from affected CPD variant patients:
    • Compared with controls, patient-derived fibroblasts had lower arginine and lysine. 
    • Compared with controls, patient-derived fibroblasts had lower NO and cGMP
    • Compared with controls, patient-derived fibroblasts had higher cell death by apoptosis and markers of ER stress and oxidative stress. 
    • Therapeutic potential: Supplementing l-arginine restored NO and cGMP toward normal. 
Organotypic mouse cochlea
  • Silencing Cpd in embryonic cochlear explants increased apoptosis in the sensory epithelium. Adding l-arginine (5 mM) for 24 h at E17.5 reduced cell death when assessed at E18.5. 
Drosophila model
  • Knockdown or mutation of silver (the fly CPD ortholog) disrupted the Johnston’s organ (the hearing organ), impaired auditory transduction and locomotor behaviour; feeding l-arginine or sildenafil (cGMP enhancer) partially rescued behavioural deficits.
Taken together, this research combines the reported association of CPD-variants and sensorineural hearing loss. Suggested underlying mechanism is that CPD loss-of-function reduces arginine supply, dampening NO/cGMP signaling and triggering ER-stress–linked apoptosis in auditory hair cells. Researchers suggest that providing the supplementation of l-arginine may be a therapeutic strategy for this particular genetic sensorineural hearing loss. 

Haruna's takeaway

This is another massive research publication.... from patient-derived fibrocytes, mice to Drosophila. But it is a very impactful publication linking the observed genetic variation to hearing loss and suggesting the pathological mechanism. There are probably many more rare recessive genetic hearing loss genes that we have yet to discover. 

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This is Haruna's 94/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.