title: Hearing impairment in hypothyroid dwarf mice caused by mutations of the thyroid peroxidase gene.
abstract: Thyroid hormone (TH) is essential for proper cochlear development and function, and TH deficiencies cause variable hearing impairment in humans and mice. Thyroid peroxidase (TPO) catalyzes key reactions in TH synthesis, and TPO mutations have been found to underlie many cases of congenital hypothyroidism in human patients. In contrast, only a single mutation of the mouse TPO gene has been reported previously (Tpo(R479C)) but was not evaluated for auditory function. Here, we describe and characterize two new mouse mutations of Tpo with an emphasis on their associated auditory deficits. Mice homozygous for these recessive mutations have dysplastic thyroid glands and lack detectable levels of TH. Because of the small size of mutant mice, the mutations were named teeny (symbol Tpo(tee)) and teeny-2 Jackson (Tpo(tee-2J)). Tpo(tee) is a single base-pair missense mutation that was induced by ENU, and Tpo(tee-2J) is a 64 bp intragenic deletion that arose spontaneously. The Tpo(tee) mutation changes the codon for a highly conserved tyrosine to asparagine (p.Y614N), and the Tpo(tee-2J) mutation deletes a splice donor site, which results in exon skipping and aberrant transcripts. Mutant mice are profoundly hearing impaired with auditory brainstem response (ABR) thresholds about 60 dB above those of non-mutant controls. The maturation of cochlear structures is delayed in mutant mice and tectorial membranes are abnormally thick. To evaluate the effect of genetic background on auditory phenotype, we produced a C3.B6-Tpo(tee-2J) congenic strain and found that ABR thresholds of mutant mice on the C3H/HeJ strain background are 10-12 dB lower than those of mutant mice on the C57BL/6 J background. The Tpo mutant strains described here provide new heritable mouse models of congenital hypothyroidism that will be valuable for future studies of thyroid hormones' role in auditory development and function.
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA, ken.johnson@jax.org.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Johnson
authors.forename: Leona H
authors.initials: LH
authors.lastname: Gagnon
authors.forename: Chantal M
authors.initials: CM
authors.lastname: Longo-Guess
authors.forename: Belinda S
authors.initials: BS
authors.lastname: Harris
authors.forename: Bo
authors.initials: B
authors.lastname: Chang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001309:Auditory Threshold / Q000502:physiology; D003051:Cochlea / Q000473:pathology; D004195:Disease Models, Animal; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D005260:Female; D034381:Hearing Loss / Q000235:genetics* / Q000503:physiopathology*; D006720:Homozygote; D007037:Hypothyroidism / Q000150:complications / Q000235:genetics*; D007453:Iodide Peroxidase / Q000235:genetics*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010641:Phenotype
chemical_list: D007453:Iodide Peroxidase