PJVK – DFNB59-Related Autosomal Recessive Nonsyndromic Hearing Loss

PJVK encodes pejvakin, a protein critical for auditory nerve integrity and hair cell function. Biallelic pathogenic variants in PJVK cause autosomal recessive nonsyndromic hearing loss type DFNB59 (MONDO:0012445). Patients present with severe-to-profound sensorineural hearing impairment often accompanied by vestibular dysfunction. The inheritance is strictly autosomal recessive, with clinical onset in infancy or early childhood. Genetic testing for PJVK should be considered in individuals with auditory neuropathy spectrum disorder and non-syndromic hearing loss. Unaffected carriers are clinically normal and heterozygous variants do not typically manifest disease.

In 2007, a consanguineous Moroccan family segregating DFNB59-associated ARNSHL was mapped to 2q31.1–2q32.1 and found to harbor a homozygous 1-bp insertion in exon 2 (c.113dup), predicting a truncated protein of 47 residues, in three affected siblings (PMID:17301963). Affected individuals exhibited nonsyndromic profound hearing impairment with central vestibular dysfunction but no evidence of auditory neuropathy. In 2024, a Mauritanian child with severe to profound congenital deafness was found to carry a novel homozygous intronic splice acceptor variant, c.550-6A>G, which creates a cryptic splice site leading to p.Phe184TyrfsTer26 (PMID:39230647). The variant segregated with disease in the family and was absent in population controls. In a cohort of 76 Chinese sporadic auditory neuropathy patients, a heterozygous missense change c.548G>A (p.Arg183Gln) was detected in one individual, but lacking a second allele or segregation, its pathogenicity remains uncertain (PMID:21935370). Together, these studies describe four probands from two unrelated families with PJVK-associated DFNB59.

The PJVK variant spectrum comprises loss-of-function alleles including frameshift insertions (c.113dup), nonsense substitutions (c.499C>T, p.Arg167Ter), and splice-site alterations (c.550-6A>G). Missense variants (e.g., p.Arg183Gln) have been reported in heterozygous state but interpretation is hampered by lack of segregation data. The recurrent LOF alleles appear family-specific with no common founder across populations. All pathogenic variants described to date affect canonical splice sites or coding exons, resulting in premature truncation or absence of functional pejvakin. No deep intronic or structural variants have been conclusively reported. Carrier frequency remains undefined, although PJVK mutations account for a small fraction of ARNSHL cases globally.

Functional characterization in a transgenic mouse model demonstrated that missense mutations equivalent to human p.Arg183Trp and p.Thr54Ile lead to auditory neuropathy phenotypes, confirming a critical role for pejvakin in inner ear function (PMID:17301963). Additionally, minigene assays of the c.550-6A>G variant revealed aberrant splicing with inclusion of a 5-bp insertion, causing frameshift and premature termination p.Phe184TyrfsTer26, consistent with a loss-of-function mechanism (PMID:39230647). These experimental findings align with the observed sensorineural hearing loss and vestibular dysfunction in patients. The absence of detectable mutant pejvakin in affected individuals supports haploinsufficiency or null effect as the predominant mechanism. No significant dominant-negative effects have been documented. Overall, functional studies provide robust support for pathogenicity of PJVK LOF variants.

Collectively, the genetic and functional data indicate that DFNB59 arises from ARNSHL due to biallelic loss-of-function variants in PJVK, resulting in defective auditory neuron signaling and vestibular impairment. The strictly recessive inheritance and absence of phenotype in heterozygous carriers underscore the requirement for two pathogenic alleles. Concordance across human pedigrees, mouse models, and cellular splice assays substantiates a loss-of-function disease mechanism. While heterozygous missense variants such as p.Arg183Gln may warrant further evaluation, established pathogenic alleles are truncating or splice-disrupting. Additional studies are needed to define full allelic heterogeneity and population prevalence. Diagnostic genetic testing of PJVK should be integrated into ARNSHL gene panels.

In summary, PJVK is a validated gene for DFNB59-associated autosomal recessive nonsyndromic hearing loss, supported by multiple independent families and functional evidence. The moderate level of clinical validity reflects data from four affected individuals with biallelic LOF variants and corroborating experimental models. Genetic testing for PJVK variants enables definitive diagnosis, prognostic counseling, and reproductive risk assessment. Early identification of PJVK mutations may inform intervention strategies and vestibular function monitoring. Population screening and allele frequency studies will refine carrier rates and aid variant interpretation. Key Take-home: PJVK loss-of-function variants cause DFNB59 ARNSHL and should be included in diagnostic gene panels to facilitate timely and accurate clinical decision-making.

References

• PLoS One • 2011 • Variants of OTOF and PJVK genes in Chinese patients with auditory neuropathy spectrum disorder. PMID:21935370
• Human Mutation • 2007 • Truncating mutation of the DFNB59 gene causes cochlear hearing impairment and central vestibular dysfunction. PMID:17301963
• Journal of Applied Genetics • 2024 • Splice-altering variant of PJVK gene in a Mauritanian family with non-syndromic hearing impairment. PMID:39230647

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