Hearing loss is a prevalent congenital sensory disorder. The World Health Organization (WHO) estimates that by 2050, approximately 2.5 billion individuals globally will experience hearing loss, with at least 700 million enduring moderate or more severe forms (World Health Organization, 2021). Notably, hereditary factors are anticipated to account for nearly half of these cases (World Health Organization, 2021). Non-syndromic hearing loss (NSHL) constitutes approximately 70% of congenital genetic hearing impairments (Sheffield and Smith, 2019). In the majority of NSHL cases (80%), the hearing loss correlates with biallelic pathogenic variants and is typically inherited in an autosomal recessive pattern (Shearer et al., 1993).

To date, 153 genes implicated in NSHL have been identified, including 63 genes associated with autosomal dominant non-syndromic hearing loss (ADNSHL) and 86 genes associated with autosomal recessive non-syndromic hearing loss (ARNSHL) (Hereditary Hearing Loss, retrieved 28 May 2024, from https://hereditaryhearingloss.org/).

PTPRQ is located on chromosome 12q21.31, comprising 58 exons (Schraders et al., 2010). It encodes protein tyrosine phosphatase receptor Q, which plays an important role in maintaining the stereocilia structure and function of hair cells (Goodyear et al., 2003). Its loss or dysfunction may result in shaft connector malformation of stereocilia in the inner ear (Goodyear et al., 2003). The loss of PTPRQ may cause the detachment of the hair cell’s apical membrane from the underlying actin cytoskeleton, allowing the membranes of adjacent stereocilia to “zipper” upward (Goodyear et al., 2012). This process prevents the fusion of stereocilia and results in both structural and functional impairments in vestibular hair cells, predominantly observed within the first 2 weeks of life in mutant mice (Goodyear et al., 2012). By 3 months of age, these impairments manifest as either undetectable vestibular evoked potentials or significantly elevated thresholds (Goodyear et al., 2012). Variants in the PTPRQ gene cause hereditary sensorineural hearing loss. The Online Mendelian Inheritance in Man (OMIM) database (https://www.omim.org/entry/603317, accessed on 28 May 2024) indicates that DFNB84A (MIM 613391), a variant of ARNSHL, is associated with PTPRQ variants, typically resulting in progressive moderate to profound familial hearing loss (Shahin et al., 2010). Additionally, some PTPRQ variants may lead to ADNSHL, such as DFNA73(MIM 617663) (Eisenberger et al., 2018). Through whole-exome sequencing (WES), we identified two novel compound heterozygous variants (c.977G>A and c.6742C>T) in the PTPRQ gene within a Chinese family. These variants have not been previously reported in association with ARNSHL. Our findings enhance the understanding of genotype-phenotype correlations in PTPRQ-related hearing loss and may inform clinical management and genetic counseling.

In this study, patient II-1 exhibited severe to profound hearing loss, while Patient II-2 experienced moderate to severe hearing loss. Both cases were attributed to variants in the PTPRQ gene, which is predominantly associated with postlingual deafness and follows an autosomal recessive inheritance pattern (DFNB84A type). Out of the documented cases involving PTPRQ variants, approximately seven also reported postlingual onset of symptoms (Table 4).

In summary, we identified two novel compound heterozygous variants in the PTPRQ gene in two sisters experiencing postlingual HL, which is presumed to be inherited in an autosomal recessive manner. Both variants result in premature termination of translation, leading to the production of truncated proteins through nonsense-mediated mRNA decay. This decay affects the functionality or results in the absence of function in the extracellular, transmembrane, and phosphatase structural domains. The proband exhibited progressive hearing loss without vestibular dysfunction symptoms such as tinnitus or vertigo. However, vestibular evoked potentials were absent in most PTPRQ knockout mice, and the reason for this difference remains unclear (Goodyear et al., 2012; Sakuma et al., 2015).

A total of 32 pathogenic PTPRQ variants associated with hearing loss have been reported (Table 4). We have summarized the corresponding nucleotide and amino acid changes. The majority of these variants were detected in Asian populations, predominantly in Chinese and Japanese groups, and have also been observed in European (Germany, France and the Netherlands) and African (Algeria and Morocco) countries. The two variants identified in this study are novel and previously unreported.

PTPRQ encodes a membrane protein of the stereocilia, which plays a key role in the function of the hair cell as a sound receptor in the acoustic system. Protein tyrosine phosphatase receptor-type Q consists of three domains: an extracellular domain with 18 FNIII repeats, a short hydrophobic transmembrane region, and an intracellular domain featuring a single consensus PTPase catalytic site (Wright et al., 1998). It belongs to the type III tyrosine phosphatase receptor (R3 PTPR) family (Zhang et al., 2022). PTPRQ expression in the inner ear is confined to the hair bundles of the cochlea and vestibule, with its distribution varying by the type or location of the hair cells, primarily in the basal region of the hair bundles (Oziębło et al., 2019). In mice, PTPRQ is crucial for the formation of shaft connectors in the hair bundle, normal maturation of cochlear hair bundles, and the long-term survival of high-frequency auditory hair cells (Goodyear et al., 2003). PTPRQ ^−/− mice exhibit a reduction in stereocilia number in mutant hair bundles (Goodyear et al., 2012), and stereocilia in mice with PTPRQ variants typically develop during embryogenesis but deteriorate postnatally (Salles et al., 2014), leading to a loss of high-frequency auditory hair cells and deafness (Goodyear et al., 2012).

PTPRQ mutant mice exhibit malformations in shaft connectors and immature cochlear hair bundles, leading to deafness (Goodyear et al., 2003; Wu et al., 2018). However, the pathogenesis in humans remains unclear. Most cases of ARNSHL are attributed to hair cell dysfunction. The hair bundle atop the hair cell comprises approximately 100 static cilia laden with actin, facilitating the conversion of mechanical signals into electrical ones (Wang and Zhou, 2021). Additionally, inositol phospholipids are pivotal regulators of the actin cytoskeleton and membrane trafficking (Takenawa and Itoh, 2001). As a membrane-associated inositol lipid phosphatase, PTPRQ may regulate the local phosphoinositide content of the hair cells’ apical membrane (Goodyear et al., 2003; Oganesian et al., 2003). Using quantitative PCR analysis on fragments encoding the intracellular region of PTPRQ, Schraders et al. demonstrated its expression in all but two tested human fetal tissues, with the highest expression in the fetal kidney, followed by the lung and cochlea (Schraders et al., 2010). Further studies have shown that PTPRQ possesses both phosphotyrosine phosphatase and phosphatidylinositol phosphatase activities, influencing cell proliferation, apoptosis, differentiation, and survival (Zhang et al., 2022).

We hypothesize that PTPRQ variants result in the synthesis of truncated proteins that cannot sustain normal physiological functions, thereby leading to organismal dysfunction. Nevertheless, the precise mechanisms underlying our findings require further validation.

As the identification of genes associated with deafness expands, efforts to develop viable and effective treatments for inherited hearing loss have intensified, alongside an emphasis on proactive prevention. Traditional interventions such as hearing aids and cochlear implants have limitations: cochlear implants are expensive and produce inconsistent outcomes, whereas hearing aids require a degree of residual hearing, thus restricting their utility. Consequently, there is increasing interest in innovative treatments like gene therapy, which aims to reduce hearing loss and restore cochlear function. Recent studies have successfully established various mouse models, strengthening the foundation for gene therapy research. However, considerable debate persists regarding methods of gene delivery and the choice of vectors. Due to the limitations imposed by the size of a single AAV vector, Lv et al., 2024 administered the AAV1-hOTOF dual vector via round-window injections to six patients suffering from severe to profound autosomal recessive deafness. All but one patient exhibited significant hearing recovery (Lv et al., 2024). Initial signs of hearing improvement were noted 4–6 weeks after injection in responsive patients, with ongoing improvement over time, illustrating a time-dependent recovery of hearing (Lv et al., 2024). This marks the first documented case of hearing restoration in congenitally deaf patients via gene therapy (Reisinger and Trapani, 2024). Following this, a dose of 1.5 × 10¹² vg of the AAV1-hOTOF dual vector was administered to the bilateral inner ears of five children by the team, leading to bilateral hearing improvement, enhanced auditory and speech capabilities, and restored sound source localization (Wang et al., 2024). These outcomes demonstrate the feasibility of binaural gene therapy for DFNB9 patients using the AAV1-hOTOF dual vector, offering a novel method for the clinical translation of gene therapy for genetic deafness caused by other genes (Wang et al., 2024). Additionally, the co-regulation and interactions among proteins are crucial in the early development of cochlear morphology, affecting the timing of gene therapy (Liu and Rask-Andersen, 2022), the age window for gene therapy intervention remains to be determined through further research. Despite progress in gene therapy for hearing loss, research on PTPRQ and its involvement in auditory impairment is limited, highlighting the need for comprehensive functional studies on PTPRQ variants. Future research could explore personalized gene therapy targeting specific variants.

In conclusion, our study has identified two novel variants in the PTPRQ gene associated with deafness. These variants lead to the production of truncated PTPRQ proteins, which are likely contributors to hearing loss. Further investigations will be conducted on these variants to elucidate the underlying pathogenic mechanisms. Our findings suggest an association between the compound heterozygous variant of PTPRQ and the observed hearing phenotypes. However, the absence of ethnolinguistic hearing controls from the same ethnic group limits our study. Including such controls would help confirm the specificity of the association between these variants and the hearing phenotypes. In future research, we aim to determine the frequency of these variants in unaffected individuals from identical ethnic and residential backgrounds to further validate their role in hearing phenotypes. Additionally, while most existing studies have utilized mutant mice as animal models, indicating significant vestibular dysfunction alongside hearing loss, few reported cases have explicitly confirmed vestibular dysfunction (Goodyear et al., 2012; Sakuma et al., 2015). This discrepancy may stem from developmental differences in the cochlea between rodents and humans, necessitating further investigation into PTPRQ’s role in hearing loss.