Suppression of the deafness and thyroid dysfunction in Thrb-null mice by an independent mutation in the Thra thyroid hormone receptor alpha gene

Deletion of thyroid hormone receptor beta (TR beta), a ligand-dependent tra nscription factor encoded by the Thrb gene, causes deafness and thyroid hyp eractivity in Thrb-null (Thrb(tm1/tm1)) mice and in a recessive form of the human syndrome of resistance to thyroid hormone. Here, we have determined that a targeted mutation (Thra(tm2)) in the related Thra gene, encoding thy roid hormone receptor alpha suppresses these phenotypes in mice. Thra encod es a TR alpha1 receptor which is non-essential for hearing and a TR alpha2 splice variant of unknown function that neither binds thyroid hormone nor t ransactivates. The Thra(tm2) mutation deletes TR alpha2 and concomitantly c auses overexpression of TR alpha1 as a consequence of the exon structure of the gene. Thra(tm2/tm2) mice have normal auditory thresholds indicating th at TR alpha2 is dispensable for hearing, and have only marginally reduced t hyroid activity. However, a potent function for the Thra(tm2) allele is rev ealed upon its introduction into Thrb(tm1/tm1) mice, where it suppresses th e auditory and thyroid phenotypes caused by loss of TR beta. These findings reveal a novel modifying function for a Thra allele and suggest that incre ased expression of TR alpha1 may substitute for the absence of TR beta. The TR isotypes generated by the distinct Thrb and Thra genes represent a smal l family of receptors that have diverged to mediate different physiological roles; however, the ability of changes in Thra expression to compensate fo r loss of Thrb indicates that many functions of these genes remain closely related.