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

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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-Pou1f1dw/dw 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 the location of Mdwh by genotyping 196 animals with 876 informative SNPs, 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.

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Acknowledgements

We thank the March of Dimes for funding (Grant N018020 to SAC), the NIH (T32GM00754 and T32HG000040 to AZD), Stephen H. Hinshaw for access to the dermestid beetle colony at the University of Michigan Ruthven Museum, Dr. Robert H. Lyons, Jr. and members of the University of Michigan DNA Sequencing Core Facility for sequencing and genotyping, members of the Kresge Hearing Research Institute including Jennifer Benson, Lisa Kabala, and David F. Dolan for auditory brainstem response testing, and Jun Z. Li, David T. Burke, Ronald J. Koenig, and Miriam H. Meisler for helpful discussions.

Funding

March of Dimes Foundation (N018020) Sally A. Camper. National Institutes of Health (T32GM007544) Alexandre Z. Daly. National Institutes of Health (T32HG000040) Alexandre Z. Daly.

Author information

Author notes

  1. Amanda H. Mortensen, Qing Fang are co-first authors.

Authors and Affiliations

  1. Department of Human Genetics, University of Michigan, 5705 Medical Science II, 1241 Catherine St., Ann Arbor, MI, 48109-5618, USA

    Amanda H. Mortensen, Qing Fang, Michelle T. Fleming, Thomas J. Jones, Alexandre Z. Daly & Sally A. Camper

  2. The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA

    Kenneth R. Johnson

Authors
  1. Amanda H. Mortensen
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  2. Qing Fang
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  3. Michelle T. Fleming
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  4. Thomas J. Jones
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  5. Alexandre Z. Daly
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  6. Kenneth R. Johnson
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  7. Sally A. Camper
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Corresponding author

Correspondence to Sally A. Camper.

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Mortensen, A.H., Fang, Q., Fleming, M.T. et al. Genetic variation in thyroid folliculogenesis influences susceptibility to hypothyroidism-induced hearing impairment. Mamm Genome 30, 5–22 (2019). https://doi.org/10.1007/s00335-019-09792-6

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  • DOI: https://doi.org/10.1007/s00335-019-09792-6

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