Journal Article

Suppression of the deafness and thyroid dysfunction in <i>Thrb</i>-null mice by an independent mutation in the <i>Thra</i> thyroid hormone receptor α gene

Lily Ng, Alfons Rüsch, Lori L. Amma, Kristina Nordström, Lawrence C. Erway, Björn Vennström and Douglas Forrest

in Human Molecular Genetics

Volume 10, issue 23, pages 2701-2708
Published in print November 2001 | ISSN: 0964-6906
Published online November 2001 | e-ISSN: 1460-2083 | DOI:
Suppression of the deafness and thyroid dysfunction in Thrb-null mice by an independent mutation in the Thra thyroid hormone receptor α gene

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Deletion of thyroid hormone receptor β (TRβ), a ligand-dependent transcription factor encoded by the Thrb gene, causes deafness and thyroid hyperactivity in Thrb-null (Thrbtm1/tm1) mice and in a recessive form of the human syndrome of resistance to thyroid hormone. Here, we have determined that a targeted mutation (Thratm2) in the related Thra gene, encoding thyroid hormone receptor α suppresses these phenotypes in mice. Thra encodes a TRα1 receptor which is non-essential for hearing and a TRα2 splice variant of unknown function that neither binds thyroid hormone nor transactivates. The Thratm2 mutation deletes TRα2 and concomitantly causes overexpression of TRα1 as a consequence of the exon structure of the gene. Thratm2/tm2 mice have normal auditory thresholds indicating that TRα2 is dispensable for hearing, and have only marginally reduced thyroid activity. However, a potent function for the Thratm2 allele is revealed upon its introduction into Thrbtm1/tm1 mice, where it suppresses the auditory and thyroid phenotypes caused by loss of TRβ. These findings reveal a novel modifying function for a Thra allele and suggest that increased expression of TRα1 may substitute for the absence of TRβ. The TR isotypes generated by the distinct Thrb and Thra genes represent a small family of receptors that have diverged to mediate different physiological roles; however, the ability of changes in Thra expression to compensate for loss of Thrb indicates that many functions of these genes remain closely related.

Journal Article.  6751 words.  Illustrated.

Subjects: Genetics and Genomics

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