A modifier gene alleviates hypothyroidism-induced hearing impairment in Pou1f1dw dwarf mice.

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Alleles, Animals, Base Sequence, Chromosome Mapping, Chromosomes, Mammalian, Crosses, Genetic, Female, Genes, Modifier, Genetic Predisposition to Disease, Hearing Loss, Hypothyroidism, Male, Mice, Mice, Inbred AKR, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Inbred Strains, Mice, Knockout, Mice, Mutant Strains, Microtubule-Associated Proteins, Molecular Sequence Data, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Transcription Factor Pit-1

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Genetics 2011 Oct; 189(2):665-73.




Thyroid hormone has pleiotropic effects on cochlear development, and genomic variation influences the severity of associated hearing deficits. DW/J-Pou1f1dw/dw mutant mice lack pituitary thyrotropin, which causes severe thyroid hormone deficiency and profound hearing impairment. To assess the genetic complexity of protective effects on hypothyroidism-induced hearing impairment, an F1 intercross was generated between DW/J-Pou1f1dw/+ carriers and an inbred strain with excellent hearing derived from Mus castaneus, CAST/EiJ. Approximately 24% of the (DW/J×CAST/EiJ) Pou1f1dw/dw F2 progeny had normal hearing. A genome scan revealed a locus on chromosome 2, named modifier of dw hearing, or Mdwh, that rescues hearing despite persistent hypothyroidism. This chromosomal region contains the modifier of tubby hearing 1 (Moth1) locus that encodes a protective allele of the microtubule-associated protein MTAP1A. DW/J-Pou1f1dw/+ carriers were crossed with the AKR strain, which also carries a protective allele of Mtap1a, and we found that AKR is not protective for hearing in the (DW/J×AKR) Pou1f1dw/dw F2 progeny. Thus, protective alleles of Mtap1a are not sufficient to rescue DW/J-Pou1f1dw/dw hearing. We expect that identification of protective modifiers will enhance our understanding of the mechanisms of hypothyroidism-induced hearing impairment.