Human Molecular Genetics, 2001, Vol. 10, No. 23 2701-2708
© 2001 Oxford University Press
Suppression of the deafness and thyroid dysfunction in Thrb-null mice by an independent mutation in the Thra thyroid hormone receptor 
gene
Department of Human Genetics, Box 1498, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, NY 10029, USA, 1Physiologisches Institut, Gmelinstrasse 5, and Sektion Sensorische Biophysik, Hals-Nasen-Ohren Klinik, Röntgenweg 11, Universität Tübingen, D-72076 Tübingen, Germany, 2Department of Cell and Molecular Biology, Karolinska Institute, S-17 177 Stockholm, Sweden and 3Department of Biological Sciences, University of Cincinnati, Cincinnati, OH 45221, USA
Deletion of thyroid hormone receptor ß (TRß), 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 
suppresses these phenotypes in mice. Thra encodes a TR1 receptor which is non-essential for hearing and a TR2 splice variant of unknown function that neither binds thyroid hormone nor transactivates. The Thratm2 mutation deletes TR2 and concomitantly causes overexpression of TR1 as a consequence of the exon structure of the gene. Thratm2/tm2 mice have normal auditory thresholds indicating that TR2 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 TRß. These findings reveal a novel modifying function for a Thra allele and suggest that increased expression of TR1 may substitute for the absence of TRß. 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.
+ To whom correspondence should be addressed. Tel: +1 212 659 6735; Fax: +1 212 849 2508; Email: douglas.forrest@mssm.edu Correspondence may also be addressed to Björn Vennström. Email: bjorn.vennstrom@cmb.ki.se
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