A Modifier Gene Alleviates Hypothyroidism-Induced Hearing Impairment in Pou1f1(dw) Dwarf Mice

作者：Fang Qing; Longo Guess Chantal; Gagnon Leona H; Mortensen Amanda H; Dolan David F; Camper Sally A; Johnson Kenneth R^*

来源：Genetics, 2011, 189(2): 665-673.

DOI：10.1534/genetics.111.130633

Thyroid hormone has pleiotropic effects on cochlear development, and genomic variation influences the severity of associated hearing deficits. DW/J-Pou1f1(dw/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 F-1 intercross was generated between DW/J-Pou1f1(dw/+) carriers and an inbred strain with excellent hearing derived from Mus castaneus, CAST/EiJ. Approximately 24% of the (DW/J x CAST/EiJ) Pou1f1(dw/dw) F-2 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-Pou1f1(dw/+) 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 x AKR) Pou1f1(dw/dw) F-2 progeny. Thus, protective alleles of Mtap1a are not sufficient to rescue DW/J-Pou1f1(dw/dw) hearing. We expect that identification of protective modifiers will enhance our understanding of the mechanisms of hypothyroidism-induced hearing impairment.

• 出版日期2011-10