title: A modifier gene alleviates hypothyroidism-induced hearing impairment in Pou1f1dw dwarf mice.
abstract: 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.
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Fang
authors.forename: Chantal
authors.initials: C
authors.lastname: Longo-Guess
authors.forename: Leona H
authors.initials: LH
authors.lastname: Gagnon
authors.forename: Amanda H
authors.initials: AH
authors.lastname: Mortensen
authors.forename: David F
authors.initials: DF
authors.lastname: Dolan
authors.forename: Sally A
authors.initials: SA
authors.lastname: Camper
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Johnson
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics; D003433:Crosses, Genetic; D005260:Female; D060045:Genes, Modifier / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D034381:Hearing Loss / Q000209:etiology / Q000235:genetics*; D007037:Hypothyroidism / Q000150:complications*; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics; D050817:Transcription Factor Pit-1 / Q000172:deficiency / Q000235:genetics*
chemical_list: D008869:Microtubule-Associated Proteins; D050817:Transcription Factor Pit-1; C490547:MAP1A protein, mouse; C494185:Pou1f1 protein, mouse