Phenotypes Associated with This Genotype

Genotype
MGI:2657251

• Allelic Composition: Thrb^tm1Df/Thrb^tm1Df
• Genetic Background: involves: 129S1/Sv * C57BL/6J

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

endocrine/exocrine glands

abnormal thyroid follicle morphology ( J:34421 )

• number and size of follicles both increased

enlarged thyroid gland ( J:34421 )

• 1.5-2 fold increase in thyroid size

thyroid gland hyperplasia ( J:34421 )

increased activity of thyroid gland ( J:34421 )

• hyperactive state with increased epithelial cell turnover

behavior/neurological

behavior/neurological phenotype ( J:34421 , J:63101 )

N • homozygotes behave normally in learning tests such as the Morris water task and in contextual fear conditioning as well as in open field and Y maze tests (J:34421)

N • adult homozygotes do not display circling or any other behavioral or neuroanatomical defects (J:63101)

nervous system

short cochlear outer hair cells ( J:118178 )

• at P8, mutant OHCs are smaller than wild-type OHCs, based on linear, voltage-independent capacitances

abnormal cochlear inner hair cell physiology ( J:48666 , J:73382 , J:118178 )

• in neonatal mutant IHCs, expression of the fast voltage-activated conductance starts ~7 days later and requires >1 month to reach adult wild-type levels (J:48666)

• homozygotes exhibit a delay in the induction of the fast-activating potassium current I_K,f which is associated with IHC maturation and is normally induced by P13 and plateaus after P20 (J:73382)

• I_K,f is largely absent at P15-P18, when hearing impairment is first evident in young homozygotes (J:118178)

• I_K,f eventually appears with a significant delay and reaches half-maximal expression at ~P28 (J:118178)

• at P50, I_K,f approaches magnitudes detected in wild-type IHCs (J:118178)

• despite retarded expression of I_K,f, development of the endocochlear potential, other hair cell transducer conductances, and OHC electromotility, appear normal (J:118178)

abnormal cochlear outer hair cell physiology ( J:73382 )

decreased cochlear outer hair cell electromotility ( J:73382 , J:118178 )

• at P8, homozygotes exhibit a slight impairment of electromechanical transduction in OHCs, as shown by slightly reduced nonlinear capacitance (150 46 fF/pF) relative to wild-type mice (290 47 fF/pF) or mice that are double homozygous for for Thra^tm1Ven and Thrb^tm1Df (87 32 fF/pF) (J:73382)

• at P9, homozygotes exhibit a nonlinear capacitance of 271 27 fF/pF, suggesting that differences in voltage-dependent capacitance of mutant OHCs at P8 are not functionally significant (J:118178)

hearing/vestibular/ear

delayed inner ear development ( J:63101 , J:73382 )

• at 15 weeks, adult homozygotes display normal inner ear innervation with no major hypothyroid-like defects in the sensorineural epithelium, tectorial membrane, stria vascularis, or spiral ganglion (J:63101)

• despite an absence of gross cochlear malformations, adult homozygotes exhibit a delay in early postnatal development of the organ of Corti, that is milder than that observed in mice that are double homozygous for Thra^tm1Ven and Thrb^tm1Df (J:73382)

abnormal organ of Corti morphology ( J:73382 )

• at P9, inner sulcus differentiation is delayed, and the tunnel of Corti remains unopened

• at P20, the inner sulcus has opened, but the undelying epithelium is slightly thicker than normal

short cochlear outer hair cells ( J:118178 )

• at P8, mutant OHCs are smaller than wild-type OHCs, based on linear, voltage-independent capacitances

abnormal tectorial membrane striated-sheet matrix morphology ( J:73382 )

• ultrastructurally, adult homozygotes display a mild disorganization of the striated sheet matrix only in the upper regions of the tectorial membrane

enlarged tectorial membrane ( J:73382 )

• at P9, the tectorial membrane is slightly enlarged although not to the extent observed in mice that are double homozygous for Thra^tm1Ven and Thrb^tm1Df

• at P20, the tectorial membrane remains slightly enlarged, although it extends to the hair cells and is not grossly misshapen as in mice that are double homozygous for Thra^tm1Ven and Thrb^tm1Df

abnormal cochlear inner hair cell physiology ( J:48666 , J:73382 , J:118178 )

• in neonatal mutant IHCs, expression of the fast voltage-activated conductance starts ~7 days later and requires >1 month to reach adult wild-type levels (J:48666)

• homozygotes exhibit a delay in the induction of the fast-activating potassium current I_K,f which is associated with IHC maturation and is normally induced by P13 and plateaus after P20 (J:73382)

• I_K,f is largely absent at P15-P18, when hearing impairment is first evident in young homozygotes (J:118178)

• I_K,f eventually appears with a significant delay and reaches half-maximal expression at ~P28 (J:118178)

• at P50, I_K,f approaches magnitudes detected in wild-type IHCs (J:118178)

• despite retarded expression of I_K,f, development of the endocochlear potential, other hair cell transducer conductances, and OHC electromotility, appear normal (J:118178)

abnormal cochlear outer hair cell physiology ( J:73382 )

decreased cochlear outer hair cell electromotility ( J:73382 , J:118178 )

• at P8, homozygotes exhibit a slight impairment of electromechanical transduction in OHCs, as shown by slightly reduced nonlinear capacitance (150 46 fF/pF) relative to wild-type mice (290 47 fF/pF) or mice that are double homozygous for for Thra^tm1Ven and Thrb^tm1Df (87 32 fF/pF) (J:73382)

• at P9, homozygotes exhibit a nonlinear capacitance of 271 27 fF/pF, suggesting that differences in voltage-dependent capacitance of mutant OHCs at P8 are not functionally significant (J:118178)

increased or absent threshold for auditory brainstem response ( J:63101 , J:118178 )

• at 9-15 weeks, adult homozygotes show significantly elevated ABR thresholds for a click stimulus (1-16 kHz) and for all test pure tones (8, 16, 32 kHz) (J:63101)

• ~95% of adult homozygotes exhibit ABR thresholds in the 70-100 dB SPL range, while 5% display thresholds in the upper limit of the normal range (J:63101)

• ~10% of adult homozygotes are unresponsive to any stimulus frequency tested at 100 SPL (J:63101)

• young homozygous mutant progeny (P18-P28) display significantly elevated ABR thresholds, independent of the maternal genotype (i.e. homozygous (hyperthyroid) vs heterozygous (euthyroid) mutant mothers) (J:63101)

• although ABR responses are diminished in amplitude, ABR waveforms display a normal pattern of peaks, suggesting that the defect resides in the primary response of the cochlea (J:63101)

• at 2-3 months, homozygotes exhibit significantly elevated ABR thresholds for click, 8-, 16-, and 32-kHz frequency stimuli relative to wild-type or heterozygous littermates (J:118178)

deafness ( J:63101 )

• homozygotes exhibit a profound hearing loss across a wide range of frequencies

homeostasis/metabolism

decreased circulating thyroxine level ( J:34421 )

• T4 levels are reduced at 1.5 years of age

increased circulating thyroxine level ( J:34421 )

• elevated serum levels of T4 between 5 and 40 weeks of age

increased circulating triiodothyronine level ( J:34421 )

• serum T3 levels elevated

increased thyroid-stimulating hormone level ( J:34421 )

• elevated TSH levels are present although no morphological abnormalities are seen in the pituitary

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
thyroid hormone resistance syndrome		DOID:11633	OMIM:188570 OMIM:274300	J:34421 , J:63101