Delmaghani, S., del Castillo, F. J., Michel, V., Leibovici, M., Aghaie, A., Ron, U. et al. Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy. Nat. Genet. 38, 770-778

University of Auvergne, Clermont, Auvergne, France
Nature Genetics (Impact Factor: 29.35). 08/2006; 38(7):770-8. DOI: 10.1038/ng1829
Source: PubMed


Auditory neuropathy is a particular type of hearing impairment in which neural transmission of the auditory signal is impaired, while cochlear outer hair cells remain functional. Here we report on DFNB59, a newly identified gene on chromosome 2q31.1-q31.3 mutated in four families segregating autosomal recessive auditory neuropathy. DFNB59 encodes pejvakin, a 352-residue protein. Pejvakin is a paralog of DFNA5, a protein of unknown function also involved in deafness. By immunohistofluorescence, pejvakin is detected in the cell bodies of neurons of the afferent auditory pathway. Furthermore, Dfnb59 knock-in mice, homozygous for the R183W variant identified in one DFNB59 family, show abnormal auditory brainstem responses indicative of neuronal dysfunction along the auditory pathway. Unlike previously described sensorineural deafness genes, all of which underlie cochlear cell pathologies, DFNB59 is the first human gene implicated in nonsyndromic deafness due to a neuronal defect.

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    • "Deafness autosomal-dominant 5 (DFNA5) belongs to the DFNA5-Gsdm family. The N-terminus region of DFNA5 has the same amino acid sequence as the Gsdm family proteins and is referred to as the DFNA5-Gasdermin domain (Delmaghani et al. 2006; Tamura et al. 2007). Germline mutations in DFNA5 have been discovered in human families and cause autosomal-dominant hearing loss (Van Laer et al. 1998; Yu et al. 2003; Cheng et al. 2007). "
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    ABSTRACT: Mouse Gasdermin A3 (Gsdma3) is the causative gene for dominant skin mutations exhibiting alopecia. Mouse has two other Gsdma3-related genes, Gsdma and Gsdma2, whereas human and rat have only one related gene. To date, no skin mutation has been reported for human GSDMA and rat Gsdma as well as mouse Gsdma and Gsdma2. Therefore, it is possible that only Gsdma3 has gain-of-function type mutations to cause dominant skin phenotype. To elucidate functional divergence among the Gsdma-related genes in mice, and to infer the function of the human and rat orthologs, we examined in vivo function of mouse Gsdma by generating Gsdma knockout (KO) mice and transgenic mice that overexpress wild type Gsdma or Gsdma harboring a point mutation (Alanine339Threonine). The Gsdma KO mice shows no visible phenotype, indicating that Gsdma is not essential for differentiation of epidermal cells and maintenance of the hair cycle, and that Gsdma is expressed specifically both in the inner root sheath of hair follicles and in suprabasal cell layers, whereas Gsdma3 is expressed only in suprabasal layers. By contrast, both types of the transgenic mice exhibited epidermal hyperplasia resembling the Gsdma3 mutations, although the phenotype depended on the genetic background. These results indicate that the mouse Gsdma and Gsdma3 genes share common function to regulate epithelial maintenance and/or homeostasis, and suggest that the function of human GSDMA and rat Gsdma, which are orthologs of mouse Gsdma, is conserved as well.
    G3-Genes Genomes Genetics 08/2013; 3(10). DOI:10.1534/g3.113.007393 · 3.20 Impact Factor
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    • "Since p.C343S is also a missense mutation, it is tempting to speculate that the affected individuals in these families may also suffer from ANSD. However, in the absence of otoacoustic emissions data, a definite conclusion cannot be reached since it has been shown that one missense mutation (p.R183W) can cause either auditory neuropathy spectrum disorder or cochlear deafness (Collin et al., 2007; Delmaghani et al., 2006). "
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    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.
    Gene 05/2012; 504(1):98-101. DOI:10.1016/j.gene.2012.05.013 · 2.14 Impact Factor
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    • "So far, mutations associated with auditory neuropathy provide the best information. Such mutations are in genes associated with hair cell synapses or the neurons of the auditory pathway (Khimich et al., 2005; Delmaghani et al., 2006; Santarelli et al., 2009; Schoen et al., 2010). However, the physiology of these mutations have not been analyzed sufficiently to show how the defects might produce the symptoms of neuropathy. "
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    ABSTRACT: The cochlea is a delicate and complex structure designed to transduce sound into the electrical activity of neurons. Damage to any of the components of the cochlea can result in hearing impairment. The development, structure, and vulnerability of the cochlea are the subject of the other chapters in this volume. Here, the focus is on the consequences of cochlear malfunction for the representation of sound in the brain. To make the task feasible in the face of the many known physiological causes of hearing impairment, this chapter discusses the well-studied effects of damage to inner (IHCs) or outer hair cells (OHCs) and to spiral ganglion neurons (SGNs). For most cochlear malfunctions, the hair cells and the SGNs are the final common path for the effects of the damage, so that the implications of a particular type of damage can usually be understood in terms of its effects on these cells and the consequent changes in the brain. Most of the chapter focuses on the effects of acoustic trauma (i.e., exposure to a sustained loud sound), with some discussion of the effects of ototoxic substances, because these have most often been used in experimental studies to produce controlled cochlear lesions.
    12/2011: pages 87-135;
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