Alternative titles; symbols
HGNC Approved Gene Symbol: PJVK
Cytogenetic location: 2q31.2 Genomic coordinates (GRCh38) : 2:178,451,378-178,462,102 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q31.2 | Deafness, autosomal recessive 59 | 610220 | Autosomal recessive | 3 |
Delmaghani et al. (2006) isolated the complete DFNB59 sequence from a human testis cDNA library and denoted the gene product pejvakin from the Persian word for echo, reflecting the fact that mutations in the gene were found to cause neuronal deafness (DFNB59; 610220) in 4 Iranian families. The 352-amino acid pejvakin protein shares significant similarity with the DFNA5 (608798) protein in the respective N-terminal regions, with 32% identity over a stretch of 250 amino acids. The pejvakin sequence contains a nuclear localization signal (residues 249-258) and a zinc-binding motif (residues 305-331). Delmaghani et al. (2006) showed that pejvakin belongs to a family of proteins, including DFNA5 and the gasdermins (see GSDMA, 611218), found only in vertebrates. Immunohistofluorescence microscopy detected pejvakin in the cell bodies of neurons of the afferent auditory pathway.
Delmaghani et al. (2006) found that the DFNB59 gene consists of 7 exons spanning 9.8 kb of genomic sequence. Exon organization between the pejvakin and DFNA5 genes throughout the region of similarity is identical, indicating that these 2 genes share a common origin.
By genomic sequence analysis, Delmaghani et al. (2006) mapped the DFNB59 gene to chromosome 2q31.1-q31.3.
In affected members of 4 Iranian families with autosomal recessive auditory neuropathy, Delmaghani et al. (2006) found homozygosity for missense mutations in pejvakin. Three families had an arg183-to-trp substitution (R183W; 610219.0001), and the fourth a thr54-to-ile substitution (T54I; 610219.0002). Analyses of sequence conservation and solvent accessibility showed that thr54 is conserved throughout the gene family to which pejvakin belongs and is exposed to solvent, suggesting a functional role. Although arg183 was less well conserved, it was shown to be exposed to solvent. Unlike previously described sensorineural deafness genes, all of which underlie cochlear cell pathologies, DFNB59 was the first human gene implicated in nonsyndromic deafness due to a neuronal defect. Dfnb59 knockin mice homozygous for the R183W mutation showed abnormal auditory brainstem responses indicative of neuronal dysfunction along the auditory pathway. Consideration of audiologic data of Dfnb59 knockin mice and DFNB59 subjects led Delmaghani et al. (2006) to conclude that pejvakin is essential in the activity of auditory pathway neurons.
Although the DFNB59 locus is completely contained within the critical interval established for DFNB27 (605818), no mutations in pejvakin exons or splice junctions were detected in individuals with DFNB27, suggesting that causative genes in the 2 forms of hearing impairment are distinct.
Collin et al. (2007) identified a homozygous mutation in the DFNB59 gene (610219.0004) in 2 Turkish sibs with autosomal recessive nonsyndromic hearing loss. However, screening of 67 additional Turkish probands found the R183W mutation in 1 family, and screening of 83 Dutch patients failed to detect confirmatory mutations, suggesting that mutations in DFNB59 are not a common cause of hearing loss in these populations.
In a large consanguineous Iranian pedigree with progressive hearing loss, Schwander et al. (2007) identified homozygosity for a 1-bp deletion in the DFNB59 gene (610219.0007) in affected individuals; unaffected parents and sibs were heterozygous for the mutation.
In a study of mouse lines with auditory defects, Schwander et al. (2007) analyzed 'sirtaki' mice and identified homozygosity for a point mutation within the gene for pejvakin in all affected mice, with heterozygosity for the mutation in the unaffected parents. The authors noted that in contrast to the Dfnb59 knockin mice studied by Delmaghani et al. (2006), which had only an auditory defect, the sirtaki mice displayed both auditory and vestibular defects. Schwander et al. (2007) suggested that the phenotypic difference might be accounted for by the fact that the missense mutation in the Dfnb59 mice was positioned outside the zinc finger domain, whereas the mutation in the sirtaki mice is predicted to truncate pejvakin before the zinc finger domain. Auditory analysis of the Dfnb59 knockin mice suggested that only afferent auditory neurons were affected, with maintenance of outer hair cell function (Delmaghani et al., 2006), whereas analysis of the sirtaki mice indicated dysfunction in both. Schwander et al. (2007) proposed that functional null alleles of pejvakin inactivate its function in both hair cells and neurons, whereas the previously reported missense mutations represent hypomorphic alleles that selectively affect its function only in neurons. In addition, morphology and survival of hair cells and spiral ganglion neurons appeared unaffected, suggesting that pejvakin is important for the function but not development or maintenance of the 2 cell types.
In a consanguineous Iranian family with multiple members affected by nonsyndromic deafness due to a neuronal defect (DFNB59; 610220) Delmaghani et al. (2006) found homozygosity for an arg183-to-trp (R183W) substitution in pejvakin that arose from a 547C-T transition in exon 4 of the gene. The same mutation was found in 2 other Iranian families cosegregating a neuronal type of autosomal recessive nonsyndromic deafness.
Collin et al. (2007) identified homozygosity for the R183W mutation in 1 of 67 unrelated consanguineous Turkish families with autosomal recessive nonsyndromic hearing loss. Haplotype analysis did not suggest a founder effect for the Turkish and Iranian families with the mutation. In contrast to the Iranian patients reported by Delmaghani et al. (2006), Collin et al. (2007) found that transiently evoked otoacoustic emissions (OAE) were absent in the Turkish patients, indicating altered outer hair cell function.
In a single consanguineous Iranian family, Delmaghani et al. (2006) found that autosomal recessive nonsyndromic deafness due to a neuronal defect (DFNB59; 610220) segregated with a homozygous thr54-to-ile (T54I) mutation in pejvakin. The amino acid substitution arose from a 161C-T transition in exon 2.
In 3 affected sibs from a consanguineous Moroccan family with autosomal recessive nonsyndromic deafness (610220), Ebermann et al. (2007) identified a homozygous 1-bp insertion (113insT) in exon 2 of the DFNB59 gene, predicted to result in a truncated protein of 47 amino acids. The hearing loss was progressive, but hearing aids compensated for the deficit in childhood. Audiologic tests excluded auditory neuropathy, and other tests showed impaired central vestibular function.
In 2 affected sibs of a consanguineous Turkish family with nonsyndromic deafness (610220), Collin et al. (2007) identified a homozygous 499C-T transition in exon 4 of the DFNB59 gene, resulting in an arg167-to-ter (R167X) substitution and expression of a truncated protein. Transiently evoked otoacoustic emissions (OAE) were absent, indicating altered outer hair cell function.
In affected members of a large consanguineous Iranian family with nonsyndromic deafness (610220), Hashemzadeh Chaleshtori et al. (2007) identified a homozygous 1-bp deletion (726delT) in the DFNB59 gene, predicted to result in a frameshift and premature termination at codon 248.
In affected members of a large consanguineous Iranian family with nonsyndromic deafness (610220), Hashemzadeh Chaleshtori et al. (2007) identified a homozygous 1-bp deletion (988delG) in the DFNB59 gene, predicted to result in a frameshift and premature termination at codon 336. Audiologic evaluation showed absent auditory brainstem responses without otoacoustic emissions, suggesting a hearing loss of cochlear origin.
In affected members of a large consanguineous Iranian pedigree segregating autosomal recessive progressive hearing loss (610220), Schwander et al. (2007) identified homozygosity for a 1-bp deletion (122delA) in the DFNB59 gene, predicted to result in a premature termination codon at amino acid 58 and likely generating a functionally null protein. Affected children showed moderate to profound deafness that was progressive in nature.
Collin, R. W. J., Kalay, E., Oostrik, J., Caylan, R., Wollnik, B., Arslan, S., den Hollander, A. I., Birinci, Y., Lichtner, P., Strom, T. M., Toraman, B., Hoefsloot, L. H., Cremers, C. W. R. J., Brunner, H. G., Cremers, F. P. M., Karaguzel, A., Kremer, H. Involvement of DFNB59 mutations in autosomal recessive nonsyndromic hearing impairment. Hum. Mutat. 28: 718-723, 2007. [PubMed: 17373699] [Full Text: https://doi.org/10.1002/humu.20510]
Delmaghani, S., del Castillo, F. J., Michel, V., Leibovici, M., Aghaie, A., Ron, U., Van Laer, L., Ben-Tal, N., Van Camp, G., Weil, D., Langa, F., Lathrop, M., Avan, P., Petit, C. Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy. Nature Genet. 38: 770-778, 2006. [PubMed: 16804542] [Full Text: https://doi.org/10.1038/ng1829]
Ebermann, I., Walger, M., Scholl, H. P. N., Issa, P. C., Luke, C., Nurnberg, G., Lang-Roth, R., Becker, C., Nurnberg, P., Bolz, H. J. Truncating mutation of the DFNB59 gene causes cochlear hearing impairment and central vestibular dysfunction. Hum. Mutat. 28: 571-577, 2007. [PubMed: 17301963] [Full Text: https://doi.org/10.1002/humu.20478]
Hashemzadeh Chaleshtori, M., Simpson, M. A., Farrokhi, E., Dolati, M., Rad, L. H., Geshnigani, S. A., Crosby, A. H. Novel mutations in the pejvakin gene are associated with autosomal recessive non-syndromic hearing loss in Iranian families. (Letter) Clin. Genet. 72: 261-263, 2007. [PubMed: 17718865] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00852.x]
Schwander, M., Sczaniecka, A., Grillet, N., Bailey, J. S., Avenarius, M., Najmabadi, H., Steffy, B. M., Federe, G. C., Lagler, E. A., Banan, R., Hice, R., Grabowski-Boase, L., Keithley, E. M., Ryan, A. F., Housley, G. D., Wiltshire, T., Smith, R. J. H., Tarantino, L. M., Muller, U. A forward genetics screen in mice identifies recessive deafness traits and reveals that pejvakin is essential for outer hair cell function. J. Neurosci. 27: 2163-2175, 2007. [PubMed: 17329413] [Full Text: https://doi.org/10.1523/JNEUROSCI.4975-06.2007]