18 results on '"pejvakin"'
Search Results
2. Evolutionary analyses of the gasdermin family suggest conserved roles in infection response despite loss of pore-forming functionality
- Author
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Diego Angosto-Bazarra, Cristina Alarcón-Vila, Laura Hurtado-Navarro, María C. Baños, Jack Rivers-Auty, and Pablo Pelegrín
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Pyroptosis ,Gasdermin ,Pejvakin ,Evolution ,Sepsis ,Infection ,Biology (General) ,QH301-705.5 - Abstract
Abstract Background Gasdermins are ancient (>500million-years-ago) proteins, constituting a family of pore-forming proteins that allow the release of intracellular content including proinflammatory cytokines. Despite their importance in the immune response, and although gasdermin and gasdermin-like genes have been identified across a wide range of animal and non-animal species, there is limited information about the evolutionary history of the gasdermin family, and their functional roles after infection. In this study, we assess the lytic functions of different gasdermins across Metazoa species, and use a mouse model of sepsis to evaluate the expression of the different gasdermins during infection. Results We show that the majority of gasdermin family members from distantly related animal clades are pore-forming, in line with the function of the ancestral proto-gasdermin and gasdermin-like proteins of Bacteria. We demonstrate the first expansion of this family occurred through a duplication of the ancestral gasdermin gene which formed gasdermin E and pejvakin prior to the divergence of cartilaginous fish and bony fish ~475 mya. We show that pejvakin from cartilaginous fish and mammals lost the pore-forming functionality and thus its role in cell lysis. We describe that the pore-forming gasdermin A formed ~320 mya as a duplication of gasdermin E prior to the divergence of the Sauropsida clade (the ancestral lineage of reptiles, turtles, and birds) and the Synapsid clade (the ancestral lineage of mammals). We then demonstrate that the gasdermin A gene duplicated to form the rest of the gasdermin family including gasdermins B, C, and D: pore-forming proteins that present a high variation of the exons in the linker sequence, which in turn allows for diverse activation pathways. Finally, we describe expression of murine gasdermin family members in different tissues in a mouse sepsis model, indicating function during infection response. Conclusions In this study we explored the evolutionary history of the gasdermin proteins in animals and demonstrated that the pore-formation functionality has been conserved from the ancient proto-gasdermin protein. We also showed that one gasdermin family member, pejvakin, lost its pore-forming functionality, but that all gasdermin family members, including pejvakin, likely retained a role in inflammation and the physiological response to infection.
- Published
- 2022
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- View/download PDF
3. Evolutionary analyses of the gasdermin family suggest conserved roles in infection response despite loss of pore-forming functionality.
- Author
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Angosto-Bazarra, Diego, Alarcón-Vila, Cristina, Hurtado-Navarro, Laura, Baños, María C., Rivers-Auty, Jack, and Pelegrín, Pablo
- Subjects
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BACTERIAL proteins , *SEPSIS , *CHONDRICHTHYES , *OSTEICHTHYES , *LYSIS , *ANIMAL species - Abstract
Background: Gasdermins are ancient (>500million-years-ago) proteins, constituting a family of pore-forming proteins that allow the release of intracellular content including proinflammatory cytokines. Despite their importance in the immune response, and although gasdermin and gasdermin-like genes have been identified across a wide range of animal and non-animal species, there is limited information about the evolutionary history of the gasdermin family, and their functional roles after infection. In this study, we assess the lytic functions of different gasdermins across Metazoa species, and use a mouse model of sepsis to evaluate the expression of the different gasdermins during infection. Results: We show that the majority of gasdermin family members from distantly related animal clades are pore-forming, in line with the function of the ancestral proto-gasdermin and gasdermin-like proteins of Bacteria. We demonstrate the first expansion of this family occurred through a duplication of the ancestral gasdermin gene which formed gasdermin E and pejvakin prior to the divergence of cartilaginous fish and bony fish ~475 mya. We show that pejvakin from cartilaginous fish and mammals lost the pore-forming functionality and thus its role in cell lysis. We describe that the pore-forming gasdermin A formed ~320 mya as a duplication of gasdermin E prior to the divergence of the Sauropsida clade (the ancestral lineage of reptiles, turtles, and birds) and the Synapsid clade (the ancestral lineage of mammals). We then demonstrate that the gasdermin A gene duplicated to form the rest of the gasdermin family including gasdermins B, C, and D: pore-forming proteins that present a high variation of the exons in the linker sequence, which in turn allows for diverse activation pathways. Finally, we describe expression of murine gasdermin family members in different tissues in a mouse sepsis model, indicating function during infection response. Conclusions: In this study we explored the evolutionary history of the gasdermin proteins in animals and demonstrated that the pore-formation functionality has been conserved from the ancient proto-gasdermin protein. We also showed that one gasdermin family member, pejvakin, lost its pore-forming functionality, but that all gasdermin family members, including pejvakin, likely retained a role in inflammation and the physiological response to infection. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
4. Generation and pathological characterization of a transgenic mouse model carrying a missense PJVK mutation.
- Author
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Cheng, Yen-Fu, Tsai, Yi-Hsiu, Huang, Chun-Ying, Lee, Yi-Shan, Chang, Pin-Chun, Lu, Ying-Chang, Hsu, Chuan-Jen, and Wu, Chen-Chi
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RECESSIVE genes , *TRANSGENIC mice , *MISSENSE mutation , *HAIR cells , *HEARING disorders , *AUDITORY pathways - Abstract
Hearing loss is the most prevalent hereditary sensory disorder in children. Approximately 2 in 1000 infants are affected by genetic hearing loss. The PJVK gene, which encodes the pejvakin protein, has been linked to autosomal recessive non-syndromic hearing loss DFNB59. Previous clinical studies have revealed that PJVK mutations might be associated with a wide spectrum of auditory manifestations, ranging from hearing loss of pure cochlear origin to that involving the retrocochlear central auditory pathway. The phenotypic variety makes the pathogenesis of this disease difficult to determine. Similarly, mouse models carrying different Pjvk defects show phenotypic variability and inconsistency. In this study, we generated a knockin mouse model carrying the c.874G > A (p.G292R) variant to model and investigate the auditory and vestibular phenotypes of DFNB59. • A mouse model of DFNB59 with the Pjvk c.874G > A mutation was established by CRISPR/Cas9 approach. • Pjvk c.874G > A mutant mice exhibited progressive hearing loss, with cochlear hair cell and spiral ganglion degeneration. • Vestibular dysfunction with progressive loss of vestibular ganglion neurons was observed in Pjvk c.874G > A mutant mice. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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5. Audition: Hearing and Deafness
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Petit, Christine, El-Amraoui, Aziz, Avan, Paul, Pfaff, Donald W., editor, and Volkow, Nora D., editor
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- 2016
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6. Pejvakin-mediated pexophagy protects auditory hair cells against noise-induced damage.
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Defourny, Jean, Aghaie, Alain, Perfettini, Isabelle, Avan, Paul, Delmaghani, Sedigheh, and Petit, Christine
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HAIR cells , *AUDITORY pathways , *AUTOPHAGY , *OXIDATIVE stress , *NOISE-induced deafness - Abstract
Noise overexposure causes oxidative stress, leading to auditory hair cell damage. Adaptive peroxisome proliferation involving pejvakin, a peroxisome-associated protein from the gasdermin family, has been shown to protect against this harmful oxidative stress. However, the role of pejvakin in peroxisome dynamics and homeostasis remains unclear. Here we show that sound overstimulation induces an early and rapid selective autophagic degradation of peroxisomes (pexophagy) in auditory hair cells from wild-type, but not pejvakindeficient (Pjvk-/-), mice. Noise overexposure triggers recruitment of the autophagosome-associated protein MAP1LC3B (LC3B; microtubuleassociated protein 1 light chain 3β) to peroxisomes in wild-type, but not Pjvk-/-, mice. We also show that pejvakin-LC3B binding involves an LC3-interacting region within the predicted chaperone domain of pejvakin. In transfected cells and in vivo transduced auditory hair cells, cysteine mutagenesis experiments demonstrated the requirement for both C328 and C343, the two cysteine residues closest to the C terminus of pejvakin, for reactive oxygen species-induced pejvakin-LC3B interaction and pexophagy. The viral transduction of auditory hair cells from Pjvk-/- mice in vivo with both Pjvk and Lc3b cDNAs completely restored sound-induced pexophagy, fully prevented the development of oxidative stress, and resulted in normal levels of peroxisome proliferation, whereas Pjvk cDNA alone yielded only a partial correction of the defects. Overall, our results demonstrate that pexophagy plays a key role in noise-induced peroxisome proliferation and identify defective pexophagy as a cause of noise-induced hearing loss. They suggest that pejvakin acts as a redox-activated pexophagy receptor/adaptor, thereby identifying a previously unknown function of gasdermin family proteins. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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7. Novel Pathogenic Variants in PJVK, the Gene Encoding Pejvakin, in Subjects with Autosomal Recessive Non-Syndromic Hearing Impairment and Auditory Neuropathy Spectrum Disorder
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Domínguez-Ruiz, María, Rodríguez-Ballesteros, Montserrat, Gandía, Marta, Gómez-Rosas, Elena, Villamar, Manuela, Scimemi, Pietro, Mancini, Patrizia, Rendtorff, Nanna D., Moreno-Pelayo, Miguel A., Tranebjaerg, Lisbeth, Medà, Carme, Santarelli, Rosamaria, Del Castillo, Ignacio, Domínguez-Ruiz, María, Rodríguez-Ballesteros, Montserrat, Gandía, Marta, Gómez-Rosas, Elena, Villamar, Manuela, Scimemi, Pietro, Mancini, Patrizia, Rendtorff, Nanna D., Moreno-Pelayo, Miguel A., Tranebjaerg, Lisbeth, Medà, Carme, Santarelli, Rosamaria, and Del Castillo, Ignacio
- Abstract
Pathogenic variants in the PJVK gene cause the DFNB59 type of autosomal recessive non-syndromic hearing impairment (AR-NSHI). Phenotypes are not homogeneous, as a few subjects show auditory neuropathy spectrum disorder (ANSD), while others show cochlear hearing loss. The numbers of reported cases and pathogenic variants are still small to establish accurate genotype-phenotype correlations. We investigated a cohort of 77 Spanish familial cases of AR-NSHI, in whom DFNB1 had been excluded, and a cohort of 84 simplex cases with isolated ANSD in whom OTOF variants had been excluded. All seven exons and exon-intron boundaries of the PJVK gene were sequenced. We report three novel DFNB59 cases, one from the AR-NSHI cohort and two from the ANSD cohort, with stable, severe to profound NSHI. Two of the subjects received unilateral cochlear implantation, with apparent good outcomes. Our study expands the spectrum of PJVK mutations, as we report four novel pathogenic variants: p.Leu224Arg, p.His294Ilefs*43, p.His294Asp and p.Phe317Serfs*20. We review the reported cases of DFNB59, summarize the clinical features of this rare subtype of AR-NSHI and discuss the involvement of PJVK in ANSD.
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- 2022
8. Pejvakin, a Candidate Stereociliary Rootlet Protein, Regulates Hair Cell Function in a Cell-Autonomous Manner.
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Kazmierczak, Marcin, Kazmierczak, Piotr, Peng, Anthony W., Harris, Suzan L., Shah, Prahar, Puel, Jean-Luc, Lenoir, Marc, Franco, Santos J., and Schwander, Martin
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GENETIC mutation , *NEUROPATHY , *ACOUSTIC nerve , *PEROXISOMES , *NEURONS - Abstract
Mutations in the Pejvakin (PJVK) gene are thought to cause auditory neuropathy and hearing loss of cochlear origin by affecting noise-induced peroxisome proliferation in auditory hair cells and neurons. Here we demonstrate that loss of pejvakin in hair cells, but not in neurons, causes profound hearing loss and outer hair cell degeneration in mice. Pejvakin binds to and colocalizes with the rootlet component TRIOBP at the base of stereocilia in injectoporated hair cells, a pattern that is disrupted by deafness-associated PJVK mutations. Hair cells of pejvakin-deficient mice develop normal rootlets, but hair bundle morphology and mechanotransduction are affected before the onset of hearing. Some mechanotransducing shorter row stereocilia are missing, whereas the remaining ones exhibit overextended tips and a greater variability in height and width. Unlike previous studies of Pjvk alleles with neuronal dysfunction, our findings reveal a cell-autonomous role of pejvakin in maintaining stereocilia architecture that is critical for hair cell function. [ABSTRACT FROM AUTHOR]
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- 2017
- Full Text
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9. Conditional deletion of pejvakin in adult outer hair cells causes progressive hearing loss in mice.
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Harris, Suzan L., Kazmierczak, Marcin, Pangršič, Tina, Shah, Prahar, Chuchvara, Nadiya, Barrantes-Freer, Alonso, Moser, Tobias, and Schwander, Martin
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ANIMAL fibers , *HAIR cells , *HEARING disorders , *CORTI'S organ , *CYTOPROTECTION - Abstract
Mutations in the Pejvakin ( Pjvk ) gene cause autosomal recessive hearing loss DFNB59 with audiological features of auditory neuropathy spectrum disorder (ANSD) or cochlear dysfunction. The precise mechanisms underlying the variable clinical phenotypes of DFNB59 remain unclear. Here, we demonstrate that mice with conditional ablation of the Pjvk gene in all sensory hair cells or only in outer hair cells (OHCs) show similar auditory phenotypes with early-onset profound hearing loss. By contrast, loss of Pjvk in adult OHCs causes a slowly progressive hearing loss associated with OHC degeneration and delayed loss of inner hair cells (IHCs), indicating a primary role for pejvakin in regulating OHC function and survival. Consistent with this model, synaptic transmission at the IHC ribbon synapse is largely unaffected in sirtaki mice that carry a C-terminal deletion mutation in Pjvk . Using the C-terminal domain of pejvakin as bait, we identified in a cochlear cDNA library ROCK2, an effector for the small GTPase Rho, and the scaffold protein IQGAP1, involved in modulating actin dynamics. Both ROCK2 and IQGAP1 associate via their coiled-coil domains with pejvakin. We conclude that pejvakin is required to sustain OHC activity and survival in a cell-autonomous manner likely involving regulation of Rho signaling. [ABSTRACT FROM AUTHOR]
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- 2017
- Full Text
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10. DFNB59 Gene Mutation Screening Using PCR-SSCP/HA Technique in Non-syndromic Genetic Hearing Loss in Bushehr Province
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Fatemeh Azadegan Dehkordi, Effat Farrokhi, Mostafa Montazer Zohouri, Gholamreza Mobini, Maryam Taherzadeh, Marzieh Raiesi, Gol andam Banitalebi, Somaieh Raiesi, Mehdi Banitalebi, and Morteza Hashemzadeh Chaleshtari
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hearing impairment ,pejvakin ,DFNB59 gene ,polymorphism ,single- strand conformation polymorphism ,hetero duplex analysis ,Medicine (General) ,R5-920 - Abstract
Background: Hearing impairment (HI) is the most prevalent Neurosensory disorder which is heterogenous and can also occur due to environmental causes. The majority of hearing deficiencies are of genetic origin affecting about 60% of the HI cases. A novel gene DFNB59 encodes pejvakin has been recently shown to cause deafness. This study aims to determine the frequency of DFNB59 gene mutations in coding region the gene in Bushehr province. Methods: In this descriptive experimental study, we investigated the presence of DFNB59 gene mutations in Exons (2-7) of the gene in 80 deaf subjects. DNA was extracted using standard phenol –chloroform method. The screening of gene mutations was performed by PCR-SSCP/HA procedure. Finally, the possible mutations were confirmed by direct sequencing. Results: In all, 9 polymorphisms 793C>G were found in 80 non-syndromic, genetic hearing loss subjects studied. However no DFNB59 gene mutation was identified. Conclusion: We conclude that the association of DFNB59 gene mutations with hearing loss is very low in samples studies
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- 2010
11. Novel Pathogenic Variants in PJVK, the Gene Encoding Pejvakin, in Subjects with Autosomal Recessive Non-Syndromic Hearing Impairment and Auditory Neuropathy Spectrum Disorder
- Author
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María Domínguez-Ruiz, Montserrat Rodríguez-Ballesteros, Marta Gandía, Elena Gómez-Rosas, Manuela Villamar, Pietro Scimemi, Patrizia Mancini, Nanna D. Rendtorff, Miguel A. Moreno-Pelayo, Lisbeth Tranebjaerg, Carme Medà, Rosamaria Santarelli, and Ignacio del Castillo
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Auditory neuropathy spectrum disorder ,DFNB59 ,Genetic epidemiology ,Non-syndromic hearing impairment ,Pejvakin ,PJVK ,non-syndromic hearing impairment ,auditory neuropathy spectrum disorder ,pejvakin ,genetic epidemiology ,Genetics ,QH426-470 ,Genetics (clinical) - Abstract
Pathogenic variants in the PJVK gene cause the DFNB59 type of autosomal recessive non-syndromic hearing impairment (AR-NSHI). Phenotypes are not homogeneous, as a few subjects show auditory neuropathy spectrum disorder (ANSD), while others show cochlear hearing loss. The numbers of reported cases and pathogenic variants are still small to establish accurate genotype-phenotype correlations. We investigated a cohort of 77 Spanish familial cases of AR-NSHI, in whom DFNB1 had been excluded, and a cohort of 84 simplex cases with isolated ANSD in whom OTOF variants had been excluded. All seven exons and exon-intron boundaries of the PJVK gene were sequenced. We report three novel DFNB59 cases, one from the AR-NSHI cohort and two from the ANSD cohort, with stable, severe to profound NSHI. Two of the subjects received unilateral cochlear implantation, with apparent good outcomes. Our study expands the spectrum of PJVK mutations, as we report four novel pathogenic variants: p.Leu224Arg, p.His294Ilefs*43, p.His294Asp and p.Phe317Serfs*20. We review the reported cases of DFNB59, summarize the clinical features of this rare subtype of AR-NSHI and discuss the involvement of PJVK in ANSD.
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- 2022
- Full Text
- View/download PDF
12. Novel Pathogenic Variants in
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María, Domínguez-Ruiz, Montserrat, Rodríguez-Ballesteros, Marta, Gandía, Elena, Gómez-Rosas, Manuela, Villamar, Pietro, Scimemi, Patrizia, Mancini, Nanna D, Rendtorff, Miguel A, Moreno-Pelayo, Lisbeth, Tranebjaerg, Carme, Medà, Rosamaria, Santarelli, and Ignacio, Del Castillo
- Subjects
Male ,pejvakin ,genetic epidemiology ,Adolescent ,Infant ,Nerve Tissue Proteins ,Article ,Pedigree ,PJVK ,Child, Preschool ,Mutation ,auditory neuropathy spectrum disorder ,Humans ,Female ,Hearing Loss, Central ,Child ,Hearing Loss ,DFNB59 ,Genetic Association Studies ,non-syndromic hearing impairment - Abstract
Pathogenic variants in the PJVK gene cause the DFNB59 type of autosomal recessive non-syndromic hearing impairment (AR-NSHI). Phenotypes are not homogeneous, as a few subjects show auditory neuropathy spectrum disorder (ANSD), while others show cochlear hearing loss. The numbers of reported cases and pathogenic variants are still small to establish accurate genotype-phenotype correlations. We investigated a cohort of 77 Spanish familial cases of AR-NSHI, in whom DFNB1 had been excluded, and a cohort of 84 simplex cases with isolated ANSD in whom OTOF variants had been excluded. All seven exons and exon-intron boundaries of the PJVK gene were sequenced. We report three novel DFNB59 cases, one from the AR-NSHI cohort and two from the ANSD cohort, with stable, severe to profound NSHI. Two of the subjects received unilateral cochlear implantation, with apparent good outcomes. Our study expands the spectrum of PJVK mutations, as we report four novel pathogenic variants: p.Leu224Arg, p.His294Ilefs*43, p.His294Asp and p.Phe317Serfs*20. We review the reported cases of DFNB59, summarize the clinical features of this rare subtype of AR-NSHI and discuss the involvement of PJVK in ANSD.
- Published
- 2021
13. Identification of a novel mutation of PJVK in the Chinese non-syndromic hearing loss population with low prevalence of the PJVK mutations.
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Zhang, Qiu-Jing, Lan, Lan, Li, Na, Qi, Yue, Zong, Liang, Shi, Wei, Yu, Lan, Wang, Hui, Yang, Ju, Xie, Lin-Yi, Zhao, Feifan, WANG, DA-YONG, Han, Bing, and Wang, Qiu-Ju
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GENETICS of deafness , *AUDIOMETRY , *IMPEDANCE audiometry , *AUDITORY evoked response , *BRAIN stem , *COMPUTED tomography , *MAGNETIC resonance imaging , *GENETIC mutation , *OTOSCOPY , *POLYMERASE chain reaction , *RESEARCH funding , *FAMILY history (Medicine) , *DATA analysis software , *DESCRIPTIVE statistics - Abstract
Conclusion: To our knowledge, this is the first report of PJVK gene mutation in a Chinese non-syndromic sensorineural hearing loss (NSHL) family. Our data indicate that the PJVK gene contributes to hearing impairment in the Chinese population, but it is not a major cause. Objective: To investigate the contribution of PJVK mutations to NSHL in the Chinese population. Methods: We screened for the PJVK gene in a sample of 65 autosomal recessive NSHL families without GJB2, SLC26A4, or mitochondrial 12S rRNA gene mutations. Seven pairs of PCR primers were designed to amplify all of the exons and their flanking regions of the PJVK gene. The PCR products were sequenced and analyzed for identification of mutations. Results: In all, we identified one novel frameshift mutation, c.930_931del AC (p.C312W fsX19), co-segregating with the phenotype in one consanguineous family with a prevalence of 1.5% (1/65). The p.C312W fsX19 mutation was just positioned in the zinc-fingers domain, which was important to the function of pejvakin, and resulted in a stop codon after 19 additional amino acids. It was not identified in the controls and was considered as the causative mutation of family 804566 with autosomal recessive, non-syndromic, prelingual sensorineural hearing impairment. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
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14. Distribution of pejvakin in human spiral ganglion: An immunohistochemical study.
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Liu, Wei, Kinnefors, Anders, Boström, Marja, Edin, Fredrik, and Rask-Andersen, Helge
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AUDITORY pathways , *CILIARY ganglion , *IMMUNOHISTOCHEMISTRY , *HEARING disorders in children , *PRECANCEROUS conditions , *NEUROPATHY , *GENETIC mutation - Abstract
Up to 10% of permanent hearing impairments in children originate from lesions in the neuronal auditory pathway. This form of auditory neuron injury called auditory neuropathy features a preservation of outer hair cell integrity but an impaired inner hair cell function and/or neuronal transmission. DFNB59 gene encodes the protein pejvakin (PJVK) and its mutations cause autosomal recessive auditory neuropathy as well as other forms of sensorineural hearing loss. The finding of distinct forms of hearing anomalies was based on studies of consanguineous families from different ethnic groups as well as studies in mice with PJVK gene mutations. In the present immunohistochemical study, the distribution of pejvakin protein in surgically obtained human cochleae was for the first time investigated. The human cochleae had normal hearing thresholds before the operation. The expression of pejvakin was located in the cell bodies of all spiral ganglion neurons rather than the nerve fibers that were labeled with Tuj 1 antibody. As Tuj 1 antibody stained the cytoplasm of Type 1 cells, pejvakin antibody labeled both type 1 and type 2 cells. The nuclei of the neurons were also PJVK-positive. No labeling was seen in the structures within the organ of Corti and the stria vascularis. In the previous study, PJVK had been detected in the hair cells, the spiral ganglion, the cochlear nuclei, the superior olivary nucleus, and the inferior colliculus in mouse. Our study demonstrated for the first time the expression of PJVK in human spiral ganglion neurons. Its functional role in neural signal propagation and synchrony needs further elucidation. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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15. A p.C343S missense mutation in PJVK causes progressive hearing loss
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Mujtaba, Ghulam, Bukhari, Ihtisham, Fatima, Amara, and Naz, Sadaf
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MISSENSE mutation , *GENETICS of deafness , *BARTTER syndrome , *GAP junctions (Cell biology) , *MESSENGER RNA , *MYOSIN , *OTOACOUSTIC emissions , *POLYMERASE chain reaction - Abstract
Abstract: Mutations in PJVK, encoding Pejvakin, cause autosomal recessive nonsyndromic hearing loss in humans at the DFNB59 locus on chromosome 2q31.2. Pejvakin is involved in generating auditory and neural signals in the inner ear. We have identified a consanguineous Pakistani family segregating sensorineural progressive hearing loss as a recessive trait, consistent with linkage to DFNB59. We sequenced PJVK and identified a novel missense mutation, c.1028G>C in exon 7 (p.C343S) co-segregating with the phenotype in the family. The p.C343 residue is fully conserved among orthologs from different vertebrate species. We have also determined that mutations in PJVK are not a common cause of hearing loss in families with moderate to severe hearing loss in Pakistan. This is the first report of PJVK mutation in a Pakistani family and pinpoints an important residue for PJVK function. [Copyright &y& Elsevier]
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- 2012
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16. Pejvakin-mediated pexophagy protects auditory hair cells against noise-induced damage
- Author
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Sedigheh Delmaghani, Christine Petit, Alain Aghaie, Paul Avan, Isabelle Perfettini, Jean Defourny, Génétique et Physiologie de l'Audition, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ED 515 - Complexité du vivant, Sorbonne Université (SU), Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), This work was supported by the Louis-Jeantet Foundation, Fondation Bettencourt Schueller, Fondation Agir pour l’Audition, Humanis Novalis-Taitbout, Réunica-Prévoyance, BNP Paribas, and the French Investissements d’Avenir program (ANR-10-LABX-65, to C.P.)., Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Chaire Génétique et physiologie cellulaire
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intracochlear viral transduction ,pejvakin ,[SDV]Life Sciences [q-bio] ,Peroxisome Proliferation ,medicine.disease_cause ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Hair Cells, Auditory ,Macroautophagy ,medicine ,Animals ,LC3B ,Receptor ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,biology ,Chemistry ,Autophagy ,Proteins ,Transfection ,Peroxisome ,pexophagy ,Cell biology ,noise-induced hearing loss ,PNAS Plus ,Hearing Loss, Noise-Induced ,Chaperone (protein) ,biology.protein ,Microtubule-Associated Proteins ,MAP1LC3B ,030217 neurology & neurosurgery ,Oxidative stress - Abstract
International audience; Noise overexposure causes oxidative stress, leading to auditory hair cell damage. Adaptive peroxisome proliferation involving pejvakin, a peroxisome-associated protein from the gasdermin family, has been shown to protect against this harmful oxidative stress. However, the role of pejvakin in peroxisome dynamics and homeostasis remains unclear. Here we show that sound overstimulation induces an early and rapid selective autophagic degradation of peroxisomes (pexophagy) in auditory hair cells from wild-type, but not pejvakin-deficient (Pjvk -/-), mice. Noise overexposure triggers recruitment of the autophagosome-associated protein MAP1LC3B (LC3B; microtubule-associated protein 1 light chain 3β) to peroxisomes in wild-type, but not Pjvk -/-, mice. We also show that pejvakin-LC3B binding involves an LC3-interacting region within the predicted chaperone domain of pejvakin. In transfected cells and in vivo transduced auditory hair cells, cysteine mutagenesis experiments demonstrated the requirement for both C328 and C343, the two cysteine residues closest to the C terminus of pejvakin, for reactive oxygen species-induced pejvakin-LC3B interaction and pexophagy. The viral transduction of auditory hair cells from Pjvk -/- mice in vivo with both Pjvk and Lc3b cDNAs completely restored sound-induced pexophagy, fully prevented the development of oxidative stress, and resulted in normal levels of peroxisome proliferation, whereas Pjvk cDNA alone yielded only a partial correction of the defects. Overall, our results demonstrate that pexophagy plays a key role in noise-induced peroxisome proliferation and identify defective pexophagy as a cause of noise-induced hearing loss. They suggest that pejvakin acts as a redox-activated pexophagy receptor/adaptor, thereby identifying a previously unknown function of gasdermin family proteins.
- Published
- 2019
- Full Text
- View/download PDF
17. Novel Pathogenic Variants in PJVK , the Gene Encoding Pejvakin, in Subjects with Autosomal Recessive Non-Syndromic Hearing Impairment and Auditory Neuropathy Spectrum Disorder.
- Author
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Domínguez-Ruiz M, Rodríguez-Ballesteros M, Gandía M, Gómez-Rosas E, Villamar M, Scimemi P, Mancini P, Rendtorff ND, Moreno-Pelayo MA, Tranebjaerg L, Medà C, Santarelli R, and Del Castillo I
- Subjects
- Adolescent, Child, Child, Preschool, Female, Genetic Association Studies, Hearing Loss complications, Hearing Loss genetics, Hearing Loss, Central complications, Hearing Loss, Central genetics, Humans, Infant, Male, Pedigree, Hearing Loss pathology, Hearing Loss, Central pathology, Mutation, Nerve Tissue Proteins genetics
- Abstract
Pathogenic variants in the PJVK gene cause the DFNB59 type of autosomal recessive non-syndromic hearing impairment (AR-NSHI). Phenotypes are not homogeneous, as a few subjects show auditory neuropathy spectrum disorder (ANSD), while others show cochlear hearing loss. The numbers of reported cases and pathogenic variants are still small to establish accurate genotype-phenotype correlations. We investigated a cohort of 77 Spanish familial cases of AR-NSHI, in whom DFNB1 had been excluded, and a cohort of 84 simplex cases with isolated ANSD in whom OTOF variants had been excluded. All seven exons and exon-intron boundaries of the PJVK gene were sequenced. We report three novel DFNB59 cases, one from the AR-NSHI cohort and two from the ANSD cohort, with stable, severe to profound NSHI. Two of the subjects received unilateral cochlear implantation, with apparent good outcomes. Our study expands the spectrum of PJVK mutations, as we report four novel pathogenic variants: p.Leu224Arg, p.His294Ilefs*43, p.His294Asp and p.Phe317Serfs*20. We review the reported cases of DFNB59, summarize the clinical features of this rare subtype of AR-NSHI and discuss the involvement of PJVK in ANSD.
- Published
- 2022
- Full Text
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18. The contribution of autosomaul recessive non-syndromic deafness to DFNB59 mutations (Pejvakin)
- Author
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Morteza Hashmzadeh, Azam Asgari, Fatemeh Azadegan, Maryam Taherzadeh, Mohsen Noorbakhsh, Effat Farrokhi, and Marzieh Abolhasani
- Subjects
pejvakin ,deafness ,lcsh:R ,lcsh:Medicine ,PCR-SSCP ,heteroduplex analysis - Abstract
Background: Hearing loss is a common disorder affecting millions of individuals worldwide with opproximately 1 in 1000 newborns. A novel gene, DFNB59 encods Pejvakin has been recently shown to cause neural deafness. The aim of this study was to determine the frequency of DFNB59 gene mutations in 93 deaf pupils in Sistan & Baluchestan province.Materials and Method: We investigated the frequency of DFNB59 gene mutations in the coding regions (exons 2-7) of the gene.DNA was extracted following the standard phenol chloroform procedure, the frequency of DFNB59 gene mutations was investigated using PCR-SSCP /HA strategy.Results: No pathogenic variant was detected in samples studied. However, one polymorphism including 793C>G was determined in 3 of 93 (3.2%) subject examined.Conclusion: The results of this study showed no association between DFNB59 gene mutations and hearing loss in Sistan va Baluchestan province
- Published
- 2010
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