LAUSR

In their recent publication “Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice,” Bademci et al. (1) studied both humans and mice to discover and characterize a gene responsible for human hearing loss. In human families they identified multiple variants in MINAR2 that led to loss of function of the gene and were perfectly coinherited with autosomal recessive hearing loss. A mouse with loss of function of Minar2 was known to have hearing loss (2), strongly supporting the interpretation that loss of function of the gene was also responsible for hearing loss in the human families. Further characterization of the Minar2 mutant mice helped to elucidate the basis of this hearing loss in both species. This discovery also illustrates the complexity of the mouse as a model for human hearing loss: Mice and humans with mutations causing loss of function of MINAR2 did not display the same overall phenotypes. Specifically, in addition to hearing loss, Minar2 mutant mice developed motor deficits, including bradykinesia and rigidity reminiscent of Parkinson’s disease (3). These motor deficits were not present in even the oldest humans with comparably severe mutations in MINAR2. Since the earliest research in genetics of hearing loss, gene discovery efforts have very fruitfully integrated studies of humans and mice. In this commentary, we review this experience and suggest that the many mice now created by modern tools of gene engineering may reveal additional complex genotype–phenotype relationships between the species that will inform the biology of both. In 1929, Lord and Gates described a mutant mouse with a peculiar behavioral phenotype including head tossing and circling behavior along with hearing loss (4). They Fig. 1. Correspondence of hearing loss genotypes and phenotypes in humans and mice. (Middle) Approaches to gene discovery and characterization include mutagenesis in mice, genetic engineering of mice, and observational genetics studies of human families. (Top) Mouse models have been reported for 80 genes implicated in human nonsyndromic hearing loss. Human and mouse phenotypes were considered different if syndromic effects were present in one but not both species; if hearing losses differed substantially between species in age at onset, severity, progression, or pattern of affected sound frequencies; or if mouse mutations comparable to human alleles led to preweaning lethality in mice. (Bottom) Chronology of discovery. For 27 genes (primarily those discovered early), genes for hearing loss in mouse were discovered first, and human families were subsequently discovered with hearing loss due to mutations in the same gene. For 53 genes (primarily those discovered more recently), candidate genes emerged from studies of human families and were confirmed by studies of engineered mice, or in a few cases of mice identified by mutagenesis screens. Thickness of arcs is proportional to the number of genes in each category.