title: Suppression of the deafness and thyroid dysfunction in Thrb-null mice by an independent mutation in the Thra thyroid hormone receptor alpha gene.
abstract: Deletion of thyroid hormone receptor beta (TR beta), a ligand-dependent transcription factor encoded by the Thrb gene, causes deafness and thyroid hyperactivity 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 thyroid hormone receptor alpha suppresses these phenotypes in mice. Thra encodes a TR alpha 1 receptor which is non-essential for hearing and a TR alpha 2 splice variant of unknown function that neither binds thyroid hormone nor transactivates. The Thra(tm2) mutation deletes TR alpha 2 and concomitantly causes overexpression of TR alpha 1 as a consequence of the exon structure of the gene. Thra(tm2/tm2) mice have normal auditory thresholds indicating that TR alpha 2 is dispensable for hearing, and have only marginally reduced thyroid activity. However, a potent function for the Thra(tm2) allele is revealed upon its introduction into Thrb(tm1/tm1) mice, where it suppresses the auditory and thyroid phenotypes caused by loss of TR beta. These findings reveal a novel modifying function for a Thra allele and suggest that increased expression of TR alpha 1 may substitute for the absence of TR beta. 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.
authors.affiliation: Department of Human Genetics, Box 1498, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, NY 10029, USA.
authors.forename: L
authors.initials: L
authors.lastname: Ng
authors.forename: A
authors.initials: A
authors.lastname: Rüsch
authors.forename: L L
authors.initials: LL
authors.lastname: Amma
authors.forename: K
authors.initials: K
authors.lastname: Nordström
authors.forename: L C
authors.initials: LC
authors.lastname: Erway
authors.forename: B
authors.initials: B
authors.lastname: Vennström
authors.forename: D
authors.initials: D
authors.lastname: Forrest
mesh_terms: D000818:Animals; D001835:Body Weight; D003051:Cochlea / Q000166:cytology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D003638:Deafness / Q000235:genetics / Q000503:physiopathology*; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D017353:Gene Deletion; D015870:Gene Expression; D005838:Genotype; D006199:Hair Cells, Auditory, Inner / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009154:Mutation; D015221:Potassium Channels / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000502:physiology; D011988:Receptors, Thyroid Hormone / Q000235:genetics* / Q000502:physiology; D013489:Suppression, Genetic; D013961:Thyroid Gland / Q000378:metabolism / Q000503:physiopathology*; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood
chemical_list: D004268:DNA-Binding Proteins; D015221:Potassium Channels; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D013972:Thyrotropin; D013974:Thyroxine