Mice with a targeted mutation in the thyroid hormone beta receptor gene exhibit impaired growth and resistance to thyroid hormone.
Patients with mutations in the thyroid hormone receptor beta (TRbeta) gene manifest resistance to thyroid hormone (RTH), resulting in a constellation of variable phenotypic abnormalities. To understand the molecular basis underlying the action of mutant TRbeta in vivo, we generated mice with a targeted mutation in the TRbeta gene (TRbetaPV; PV, mutant thyroid hormone receptor kindred PV) by using homologous recombination and the Cre/loxP system. Mice expressing a single PV allele showed the typical abnormalities of thyroid function found in heterozygous humans with RTH. Homozygous PV mice exhibit severe dysfunction of the pituitary-thyroid axis, impaired weight gains, and abnormal bone development. This phenotype is distinct from that seen in mice with a null mutation in the TRbeta gene. Importantly, we identified abnormal expression patterns of several genes in tissues of TRbetaPV mice, demonstrating the interference of the mutant TR with the gene regulatory functions of the wild-type TR in vivo. These results show that the actions of mutant and wild-type TRbeta in vivo are distinct. This model allows further study of the molecular action of mutant TR in vivo, which could lead to better treatment for RTH patients.
Kaneshige
M
M
Laboratory of Molecular Biology, National Cancer Institute, and Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Kaneshige
K
K
Zhu
X
X
Dace
A
A
Garrett
L
L
Carter
T A
TA
Kazlauskaite
R
R
Pankratz
D G
DG
Wynshaw-Boris
A
A
Refetoff
S
S
Weintraub
B
B
Willingham
M C
MC
Barlow
C
C
Cheng
S
S
D000483:Alleles; D000818:Animals; D001846:Bone Development / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006128:Growth / Q000235:genetics*; D006130:Growth Disorders / Q000235:genetics; D006720:Homozygote; D051379:Mice; D008822:Mice, Transgenic; D010902:Pituitary Gland / Q000254:growth & development / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000235:genetics* / Q000502:physiology*; D011995:Recombination, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013937:Thymidine Kinase / Q000235:genetics; D013961:Thyroid Gland / Q000254:growth & development / Q000502:physiology*; D015430:Weight Gain; D001616:beta-Galactosidase / Q000235:genetics
D011988:Receptors, Thyroid Hormone; D013937:Thymidine Kinase; D001616:beta-Galactosidase