Genetic variation in thyroid folliculogenesis influences susceptibility to hypothyroidism-induced hearing impairment

Abstract

Maternal and fetal sources of thyroid hormone are important for the development of many organ systems. Thyroid hormone deficiency causes variable intellectual disability and hearing impairment in mouse and man, but the basis for this variation is not clear. To explore this variation we studied two thyroid hormone-deficient mouse mutants with mutations in pituitary-specific transcription factors, POU1F1 and PROP1, that render them unable to produce thyroid stimulating hormone. DW/J-Pou1f1dwldw mice have profound deafness and both neurosensory and conductive hearing impairment, while DF/B-Prop1df/df mice have modest elevations in hearing thresholds consistent with developmental delay, eventually achieving normal hearing ability. The thyroid glands of Pou1f1 mutants are more severely affected than those of Prop1df/df mice, and they produce less thyroglobulin during the neonatal period critical for establishing hearing. We previously crossed DW/J-Pou1f1dw/+ and Cast/Ei mice and mapped a major locus on Chromosome 2 that protects against hypothyroidism-induced hearing impairment in Pou1f1dw/dw mice: Modifier of dw hearing (Mdwh). Here we refine that map with additional animals and genotypes, and we conduct novel mapping with a DW/J-Pou1f1dw/+ and 129/P2 cross that reveals 129/P2 mice also have a protective Mdwh locus. Using DNA sequencing of DW/J and DF/B strains, we determined that the genes important for thyroid gland function within Mdwh vary in amino acid sequence between strains that are susceptible or resistant to hypothyroidism-induced hearing impairment. These results suggest that the variable effects of congenital hypothyroidism on the development of hearing ability are attributable to genetic variation in postnatal thyroid gland folliculogenesis and function.

Benign paroxysmal positional vertigo: is hypothyroidism a risk factor for recurrence?

“…Thyroid hormone replacement with levothyroxine is the standard treatment for patients with hypothyroidism 3 . The most typical clinical manifestations of hypothyroidism include fatigue, lethargy, bradycardia, weight gain and cold intolerance, but it has been also recently associated with ENT disorders, such as hearing loss 4 , tinnitus 5 and vestibular disorders 6 . Among the different vestibular pathologies, the association between hypothyroidism and benign paroxysmal positional vertigo (BPPV) has recently been investigated 7 .…”