Abstract
Hearing impairment is the most frequent sensory deficit in humans. Deafness genes, which harbor pathogenic mutations that have been identified in families with hereditary hearing loss, are commonly expressed in the auditory end organ or the cochlea and may contribute to normal hearing function, yet some of the mouse models carrying these mutations fail to recapitulate the hearing loss phenotype. In this study, we find that distinct expression patterns of those deafness genes in the cochlea of a non-human primate, the common marmoset (Callithrix jacchus). We examined 20 genes whose expression in the cochlea has already been reported. The deafness genes GJB3, CRYM, GRHL2, DFNA5, and ATP6B1 were expressed in marmoset cochleae in patterns different from those in mouse cochleae. Of note, all those genes are causative for progressive hearing loss in humans, but not in mice. The other tested genes, including the deafness gene COCH, in which mutation recapitulates deafness in mice, were expressed in a similar manner in both species. The result suggests that the discrepancy in the expression between rodents and primates may account for the phenotypic difference. This limitation of the rodent models can be bypassed by using non-human primate models such as the marmoset.
Highlights
As of 2015, the genes responsible for hearing loss have been identified in 99 autosomal recessive[2, 67] autosomal dominant[3], and six X-chromosomal recessive loci[4]
The genes tested include well-known genes causal for hereditary progressive hearing loss such as gap junction beta-3 protein (GJB3) (CX31, DFNA2B, DFNB91), CRYM, GRHL2 (DFNA28), DFNA5, and ATP6B1 (distal renal tubular acidosis with hearing loss), all of whose pathophysiology remains unknown because their rodent models did not recapitulate the deafness phenotype
Our results suggest that the discrepancy of the expression between rodents and primates accounts for the phenotypic difference between them, and that the limitations of rodent models in researching human hereditary hearing loss could be bypassed by using non-human primate models such as the common marmoset
Summary
As of 2015, the genes responsible for hearing loss have been identified in 99 autosomal recessive[2, 67] autosomal dominant[3], and six X-chromosomal recessive loci[4]. There are differences in the physiology of individual cell types and/or proteins in the cochlea between humans and rodents (including mice, rats, guinea pigs, and gerbils), which are frequently used as animal models for examining gene expression patterns and determining the pathophysiology. The genes tested include well-known genes causal for hereditary progressive hearing loss such as GJB3 (CX31, DFNA2B, DFNB91), CRYM, GRHL2 (DFNA28), DFNA5, and ATP6B1 (distal renal tubular acidosis (dRTA) with hearing loss), all of whose pathophysiology remains unknown because their rodent models did not recapitulate the deafness phenotype We found that these genes had distinct expression patterns, in which the proteins were distributed in the cochlea differently in primates and rodents. Our results suggest that the discrepancy of the expression between rodents and primates accounts for the phenotypic difference between them, and that the limitations of rodent models in researching human hereditary hearing loss could be bypassed by using non-human primate models such as the common marmoset
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