Thyroid Hormone Resistance Syndrome
Name
07 Datta and Jameson _ Thyroid Resistance Syndrome.pdf
Description
Research Paper
Size
1.98 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Chatterjee, V. Krishna K.
Nagaya, Takashi
Madison, Laird D.
Datta, Shoumen
Rentoumis, Anne
Jameson, Larry J.
Alternative Title
Inhibition of Normal Receptor Function by Mutant Thyroid Hormone Receptors
Date Issued
June 1991
Publisher
The American Society for Clinical Investigation
Citation
Journal of Clinical Investigation (1991) 87 1977-1984
Abstract
Thyroid hormone (T3) resistance is inherited in most cases in an
autosomal dominant manner. The disorder is characterized by
elevated free thyroid hormone levels and partial resistance to
thyroid hormone at the cellular level. Distinct single amino acid
substitutions in the ligand binding domain of the ft form of the
thyroid hormone receptor have been described in two kindreds
with this disorder. We used transient expression assays to characterize
the functional properties of these receptor mutants,
one containing a Gly to Arg change at amino acid 340 (G340R)
and the other a Pro to His change at amino acid 448 (P448H).
A nine amino acid carboxy terminal deletion (A448456), analogous
to an alteration that occurs in v-erbA, was also studied for
comparison with the mutations that occur in the T3 resistance
syndrome. None of the receptor mutants were able to mediate
thyroid hormone dependent activation (TreTKCAT) or repression
(TSHaCAT) of reporter genes when compared with the
wild type receptor. In addition, the mutants inhibited the activity
of normal a and (3 receptor isoforms when examined in coexpression
assays. This activity, referred to as dominant negative
inhibition, was manifest with respect to both the positively and
negatively regulated reporter genes. Although mutant receptor
binding to DNA was unaffected, ligand binding studies showed
that the G340R and A448456 mutants failed to bind T3,
whereas the P448H mutant bound hormone with reduced affinity
(- 10% of normal) compared to the wild type receptor. Consistent
with this finding, the P448H mutant receptor was partially
active at higher T3 concentrations. Furthermore, the dominant
negative inhibition elicited by the P448H receptor mutant
at higher T3 concentrations was reversed in the presence of high
doses of T3. These findings indicate that mutant (3 receptors in
patients with thyroid hormone resistance have reduced affinity
for T3 and are functionally deficient, but impair the activity of
normal receptors, thereby providing a mechanism for the dominant
mode of inheritance in this disorder. (J. Clin. Invest. 1991.
87:1977-1984.) Key words: transcriptional regulation - erbA -
thyroid-stimulating hormone - thyroid hormone resistance * thyroid
hormone
Description
Thyroid hormone (T3) resistance is inherited in most cases in an
autosomal dominant manner. The disorder is characterized by
elevated free thyroid hormone levels and partial resistance to
thyroid hormone at the cellular level. Distinct single amino acid
substitutions in the ligand binding domain of the ft form of the
thyroid hormone receptor have been described in two kindreds
with this disorder. We used transient expression assays to characterize
the functional properties of these receptor mutants,
one containing a Gly to Arg change at amino acid 340 (G340R)
and the other a Pro to His change at amino acid 448 (P448H).
A nine amino acid carboxy terminal deletion (A448456), analogous
to an alteration that occurs in v-erbA, was also studied for
comparison with the mutations that occur in the T3 resistance
syndrome. None of the receptor mutants were able to mediate
thyroid hormone dependent activation (TreTKCAT) or repression
(TSHaCAT) of reporter genes when compared with the
wild type receptor. In addition, the mutants inhibited the activity
of normal a and (3 receptor isoforms when examined in coexpression
assays. This activity, referred to as dominant negative
inhibition, was manifest with respect to both the positively and
negatively regulated reporter genes. Although mutant receptor
binding to DNA was unaffected, ligand binding studies showed
that the G340R and A448456 mutants failed to bind T3,
whereas the P448H mutant bound hormone with reduced affinity
(- 10% of normal) compared to the wild type receptor. Consistent
with this finding, the P448H mutant receptor was partially
active at higher T3 concentrations. Furthermore, the dominant
negative inhibition elicited by the P448H receptor mutant
at higher T3 concentrations was reversed in the presence of high
doses of T3. These findings indicate that mutant (3 receptors in
patients with thyroid hormone resistance have reduced affinity
for T3 and are functionally deficient, but impair the activity of
normal receptors, thereby providing a mechanism for the dominant
mode of inheritance in this disorder. (J. Clin. Invest. 1991.
87:1977-1984.) Key words: transcriptional regulation - erbA -
thyroid-stimulating hormone - thyroid hormone resistance * thyroid
hormone
Subjects
Throid hormone resistance
MIT Department
Massachusetts Institute of Technology. Auto-ID Laboratory
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