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From the Clinical Research Centers |
Departments of Medicine (J.P., R.E.W., P.E.M., S.P., S.R.) and Pediatrics (J.P., S.R.) and the J. P. Kennedy, Jr., Mental Retardation Research Center (S.R.), University of Chicago, Chicago, Illinois 60637-1470; the Department of Medicine, Princess Margaret Hospital (I.T.L.), Hong Kong, China; and the Department of Internal Medicine, University of Missouri (H.H.), Columbia, Missouri 65212
Address all correspondence and requests for reprints to: Dr. Samuel Refetoff, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637. E-mail: refetoff{at}medicine.uchicago.bsd.edu
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Of the 65 families with RTH studied in our laboratory, 59 had mutations
in the mutagenic region of the TRß gene that encompasses exons 7–10.
Isolation of a TRß PAC (P1 derived artificial chromosome)
clone provided the intronic sequences necessary to amplify and sequence
the entire TRß gene from genomic DNA. Not a single nucleotide
substitution, deletion, or insertion was found in all coding and
noncoding TRß1- and TRß2-specific and common exons of the five
families with RTH reported herein. Furthermore, linkage analysis using
polymorphic markers excluded involvement of the TRß and TR
genes
in two and three of the five families, respectively.
The phenotype of RTH in patients without TRß gene defects was
not different from that in patients with RTH due to TRß gene
mutations in terms of clinical presentation and reduced responsiveness
of the pituitary and peripheral tissues to TH. However, the degree of
thyrotroph hyposensitivity to TH appeared to be among the more severe,
similar to that of patients with mutant TRßs that have more than
50-fold reduction of T3 binding affinity and strong
dominant negative effect. In these five families and another with
non-TR/non-TRß RTH, previously identified in our laboratory,
evidence for dominant inheritance was secured in two families, and the
appearance of a new defect or recessive inheritance was found in the
remaining four families.
RTH without a structural TRß defect occurs in about 10% of families
expressing the classic phenotype of TH hyposensitivity, and TRß and
TR gene involvement has been excluded in 5%. We postulate that a
cofactor that interacts with TR is potentially responsible for the
manifestation of RTH in these families. As affected subjects are not
infertile, the high prevalence of putative neomutations and the low
rate of transmission in this non-TR form of RTH may be due to reduced
survival of embryos harboring the defect.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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RTH is linked to the TH receptor (TR) ß gene located on chromosome 3. Indeed, with a single exception (4), mutations have been identified in the TRß gene of affected individuals belonging to 191 families (2) (personal information). Mutations are located at the carboxyl-terminus of the TRß, mainly confined to three "hot" areas of the ligand-binding and adjacent hinge domains of the receptor protein (5, 6, 7, 8). The mutant TRß molecules have either a reduced affinity for T3 (6, 9) or impaired interaction with one of the cofactors involved in the mediation of TH action (10, 11). These mutant TRßs interfere with the function of the normal TRs, which explains the dominant mode of inheritance. It is thus not surprising that in the single family with deletion of all coding sequences of the TRß gene, only homozygotes manifest RTH (12).
The clinical presentation of RTH and the severity of hormone resistance
is highly variable. While this is in part due to the degree of
functional impairment of different mutant TRß molecules, less obvious
is the reason for the variable severity of hormonal resistance in
individuals harboring the same TRß gene mutation (5). The possibility
of variable levels of expression of the mutant allele relative to the
normal counterpart has been explored, but results have been
inconsistent (13, 14). The most likely explanation for the variable
severity of hormonal resistance associated with identical TRß
gene mutations is the genetic heterogeneity of the many cofactors
(coactivators and corepressors) (15) that modulate the
receptor-dependent action of TH (16). In support of this hypothesis was
the recent identification of RTH in a family in which affected members
had no mutations in the TRß or TR genes (4) and the finding of RTH
in mice deficient in the in the nuclear coactivator 1 (NCoA 1 or SRC-1)
(17). However, until now it was not clear whether RTH without TR gene
mutations was a unique finding as is TRß gene deletion (12).
In this communication we present five new families with RTH in whom
affected subjects have no mutations in the coding sequences of the TR
gene. Together with the family we previously reported (4), they
represent approximately 10% of the 65 families with RTH for whom the
TRß genes have been sequenced in our laboratory. In affected
subjects of these 5 families we sequenced exons and flanking intronic
areas of the 4 TRß1 and 1 TRß2-specific amino-terminal exons as
well as the 6 exons common to the TRß1 and TRß2 and did not find
any abnormalities. In addition, linkage analysis allowed the exclusion
of TRß and TR genes as the cause of RTH in two and three of the
five families, respectively, which, together with the previously
reported family, excludes TR involvement in 5% of families with RTH.
Although the clinical and laboratory features were indistinguishable
from those of subjects with RTH harboring TRß gene mutations and
inheritance appears to be autosomal dominant, it is of interest that
pedigree analysis indicates de novo appearance of RTH and
thus suggests putative neomutations of a yet unidentified gene(s) in 4
and possibly 5 of the 6 families.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Members of five families were investigated. Affected individuals of families Mch and Mk underwent a detailed evaluation using a protocol for the in vivo assessment of TH action (see below). All tested individuals gave informed consent to participate in this study approved by the institutional review board.
Data from additional subjects were used for comparison. These were 1)
26 unaffected normal controls; 2) 17 subjects with mild RTH
heterozygous for TRß R320H (Ka, 44% of the
wild type) belonging to 4 unrelated families (6, 16, 18, 19); and
3) 19 individuals with severe RTH (Ka, <2% of
the wild type and a strong dominant negative effect) belonging to 9
families and harboring the following TRß gene mutations, I276
,
T337, G344E, G345S, M430, G432, C445R, 448).frameshift 463X,
and 452 frameshift 463X (6, 7, 20, 21, 22, 23, 24, 25, 26); and 4) 3 subjects from a family
(F25) with RTH but no mutations in the TRß of TR genes (4).
Family Msn (Fig. 1
and Table 1). The proposita (II-1), a
31-yr-old woman at the time of diagnosis, was seen 2 yr earlier because
of fatigue and a 4.5-kg weight gain. The serum total
T4 (TT4) concentrations
measured on two occasions, 6 months apart, were 220 and 248 nmol/L
(normal range, 60–157), and the free T4 index
(FT4I) was 345 (normal range, 64-154). The
thyroid gland was homogeneously enlarged on ultrasound, and the patient
was treated with methimazole, which was discontinued after 4 months.
She was seen 1.5 yr later with the same symptoms and, in addition,
occasional palpitations. On physical examination she had a resting
heart rate of 96 beats/min and a thyroid gland 3 times the normal size.
The concentration of TT4 was 251 nmol/L,
FT4I was 322, total T3
(TT3) was 5.2 nmol/L (normal range, 0.9–3.1),
TSH was 3.2 mU/L (normal range, 0.4–5.0), and the 24-h thyroidal
radioiodide uptake (RAIU) was 68% (normal range, 10–35). Serum
thyroid stimulating Igs were 93% (normal, <130), the -glycoprotein
subunit concentration was 0.4 µg/L (normal, <1), and magnetic
resonance imaging of the pituitary gland showed no abnormalities. The
patient was given 50 mg atenolol daily for the treatment of
tachycardia.
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Family Mch (Fig. 2 and Table 1
). The proposita (II-6) presented at the age of 43 yr with
palpitations and mild heat intolerance. There were no other symptoms
suggestive of thyrotoxicosis, and the only positive findings on
physical examination were a mild tremor and slight thyroid gland
enlargement. The following ranges represent the results of thyroid
function tests obtained on three occasions over the period of 3 months:
free T4 (FT4), 32.9–57.2
pmol/L (normal range, 7–21.8); FT3, 11.9–12.6
pmol/L (normal range, 3.3–8.2); and TSH, 1.7–2.0 mU/L (normal range,
0.3–4.0). RAIU at 4 h was 43% (normal range, 12–45) and at
24 h was 62% (normal range, 20–50). Additional studies were
carried out to assess the sensitivity of her pituitary gland to TH (see
Results).
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Family Mal (Fig. 3 and Table 1). The proposita (II-15) was 28 yr old when she was found to have
a goiter and prominent eyes on routine physical examination. There were
no other findings suggestive of thyroid disease, and the only symptom
was increased sweating. Because thyroid function tests showed a marked
elevation of her FT4 concentration but a normal
TSH level suggestive of RTH, all members of the immediate family
consented to testing.
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).
Family Mk (Fig. 4 and Table 1). Thyroid function tests were first obtained from the proposita
(II-2) when she was 3.8 yr old because of hyperactivity and
irritability. The serum TT4 concentration was 297
nmol/L with a FT4I of 8.4 (upper limit of normal,
<4.3) and a TSH of 1.3 µU/L. She was seen by a pediatric
endocrinologist who noted, in addition to hyperkinesis, a small goiter
and a heart rate of 120 beats/min. Serum TT4 was
265 nmol/L, FT4I was 7.7, and
TT3 was 5.0 nmol/L (normal range, 1.5–3.2). The
baseline TSH concentration was 3.8 mU/L and increased to 22.3 mU/L 30
min after the administration of TRH. Treatment with propylthiouracil
(PTU) was initiated and, due of worsening of the hyperactive behavior,
desipramine was added to her therapeutic regimen. Because of the rapid
increase in goiter size along with an increase in TSH levels while
TT4 and FT4I remained above
the upper limit of normal, treatment with PTU was discontinued. When
seen by another endocrinologist at age 4.5 yr, the child was at the
75th percentile for height and the 25th percentile for weight, was
hyperactive, and had a pulse of 132/min and slight thyromegaly.
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and data not shown).
Family Mgd (Fig. 4 and Table 1). The propositus (II-1) was 7
yr old when he was found to have a goiter on routine physical
examination. The only symptoms suggestive of thyrotoxicosis that could
be elicited were a recent growth spurt, a voracious appetite, and a
history of hyperactivity. His height was at the 40th percentile,
thyroid gland size was 2 times normal, and there were bilateral
myrigotomy tubes. Because TT4 was 199 nmol/L,
FT4I was 329, and RAIU at 24 h was 60%, he
was treated with 100 mg PTU three times daily. It was not until 8 yr
later that RTH was suspected based on elevated TSH concentrations
despite a persistent increase in serum T4.
Blood samples were obtained from the propositus, his parents, and a younger brother. Treatment with PTU was subsequently discontinued without subjective changes.
In vivo determination of the level of resistance to TH
The study protocol has been described previously (27, 28). Briefly, the serum levels of cholesterol, creatine kinase (CK), ferritin, and sex hormone-binding globulin (SHBG) were measured, and the TSH and PRL responses to the iv administration of TRH were determined. These tests were performed at baseline and repeated after the administration of three incremental doses of liothyronine (L-T3), 1, 2, and 4 times the average replacement dose. The daily hormone dose was split and given orally every 12 h for 3 consecutive days. All determinations were repeated at the conclusion of each incremental L-T3 dose, at which time the serum T3 concentration has reached a steady level (27). Clinical studies were carried out in an in-patient setting.
Measurement of hormones and other substances in serum
Total T4, T3, rT3, TSH, thyroglobulin (TG), LH, FSH, estradiol, and ferritin were measured by RIAs. FT4 and FT3 were estimated by calculation of the FT4 and FT3 indexes (FT4I and FT3I) using the results of simultaneous measurements of TT4, TT3, and the resin T4 uptake ratio. FT4 was also expressed as a percentage of the upper limit of normal, as previously described (9, 29). SHBG was measured by a competitive protein-binding assay (30). Cholesterol and CK were measured in an automated clinical laboratory assay system. All samples collected from each subject before and after the administration of L-T3 were analyzed in the same assay as were samples obtained at baseline from most subjects belonging to the same family.
Sequencing the TRß gene
Genomic DNA was extracted from circulating white blood cells and used for direct sequencing of the TRß gene as well as for genotyping.
The sequences of oligonucleotide primers and conditions for PCR amplification of exons 4–10 of the TRß from genomic DNA were described previously (6). Because the 5'-end sequence of intron 3 of the TRß1 gene was not known, exon 3 could not be amplified from genomic DNA. Therefore, we screened a genomic PAC library (Genome Systems, Inc., St. Louis, MO) using primers that specifically amplify TRß1 from genomic DNA. A PAC clone containing exon 4 (coding exon 2) of the TRß was identified (purchased from Genome Systems) and cultured, and the DNA was then isolated. After digestion with XbaI, the DNA was separated on a 1.2% agarose gel and transferred to a nitrocellulose membrane using standard Southern blotting conditions. The membrane was then baked and hybridized with a labeled DNA probe containing an approximately 600-bp fragment of intron 2 of the TRß gene that was generated by PCR using the primers 5'-aacgttggacctcaagcccat-3' (sense) and 5'-cagggttccttctataaacatg-3' (antisense). The probe containing sequences of intron 2 hybridized with a 5.4-kb fragment that was then subcloned into the cloning vector pGEM 4Z(f)+ (Promega Corp., Madison, WI) and sequenced. The sequence of intron 3 was thus identified, submitted to GenBank (accession no. AF126175) and used to synthesize primers for the amplification of exon 3 [5'-acatatcacatagcccacctatg-3' (sense) and 5'-ctctaggtggaacaaaaatggag-3' (antisense)].
The primers for amplification of exon 1 were 5'-tcgcgcgacgcccagtcgccggcgct-3' (sense) and 5'-atcccgcccaccctgtggacagtt-3' (antisense), and those for exon 2 were, 5'-ctatttaaacatagaaataagaac-3' (sense) and 5'-aagggacaattaatagcaaagatc-3' (antisense).
TRß2, a splice variant, differs from TRß1 at the amino-terminus. The first exon, specific for TRß2, connects with exon 5 of the TRß1 gene. This exon was amplified, as previously described (4), using the primers 5'-ggagctcgagaatgcatgcg-3' (sense) and 5'-cgaagcttatgtaaactg-3' (antisense), where bold letters indicate mismatched nucleotides and underlined sequences identify endonuclease restriction sites usable for cloning.
All PCR products were purified from low melting agarose gels and sequenced directly using automated fluorescence based sequencer (ABI 377, Perkin-Elmer Corp., Foster City, CA).
Genotyping for linkage analysis
Haplotyping of the TRß gene was described previously (4) as
well as primer sequences and PCR conditions. The markers used for
haplotyping the TR gene were D17S1814, D17S800, D17S1299, and a
previously reported intragenic marker (4). These four
polymorphic markers were purchased as fluorescence-labeled
oligonucleotides (Research Genetics, Inc., Huntsville,
AL). To improve the quality of genotyping when dinucleotide markers
were used, the reverse primers were pigtailed as described by
Brownstein et al. (31). PCRs were performed in a 5-µl
volume with buffer containing 2.5 mM Mg, 10
mM dNTPs, 8 µM of each
primer, and 0.2 U Amplitaq Gold DNA polymerase (Perkin Elmer Corp.). The fluorescent PCR products were separated using an
automated sequencer (ABI 377, Perkin Elmer Corp.),
visualized, and printed. Results were read by two investigators and
were scored in increasing numbers for DNA fragments of decreasing
size.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The mode of clinical presentation was typical of RTH caused by
TRß gene mutations (Table 1). Goiter was the presenting symptom in
three of the five key cases, and hyperactivity, palpitations, weight
gain, and fatigue were the other presenting symptoms. An initial
erroneous diagnosis of thyrotoxicosis lead to treatment with
antithyroid drugs in three of the five key cases. Ethnic origin was
diverse. A modest thyroid enlargement was found in all affected
subjects, and RAIU was elevated in the four subjects in whom
the test was carried out. The serum -glycoprotein subunit
concentration was normal.
Serum tests of thyroid function were compatible with the diagnosis of
RTH in six of the seven affected subjects from the five families (
Figs. 1–4). They showed elevation of all three iodothyronine
(TT4, TT3, and
TrT3) concentrations as well as the
FT4I in the presence of normal levels of TSH.
FT3I was also high in all affected subjects,
ranging from 3.80–10.4 (normal, 1.46–2.92). Only in the subject
receiving PTU at the time of testing (II-1, family Mgd) was
TT3 in the normal range, whereas TSH was elevated
at a concentration of 15.3 mU/L (Fig. 4). Serum TG concentrations were
high in five of the seven patients with RTH (II-1, family Msn; II-14,
II-15, and III-2, family Mal; II-2, family Mk). Thyroid peroxidase
(TPO) antibodies were positive in two affected subjects (II-14 and
II-15) of family Mal (Fig. 3). This appears to be coincidental, as
other members of the family, without RTH, had TPO autoantibodies but
not high serum TG levels. Subject II-8, without RTH, had subclinical
thyrotoxicosis due to autoimmune thyroid disease. Subject II-13, who
was not a blood relative of family Mal, had subclinical hypothyroidism
during treatment with lithium carbonate.
The sensitivity of the pituitary thyrotrophs to exogenous TH was
reduced in the two patients in whom graded doses of
L-T3 were administered (Fig. 5). Even 4-fold the physiological dose of
L-T3 (200 µg/day given to an adult
and 160 µg/day given to a 5-yr-old child) failed to completely
suppress the TSH response to TRH (subjects II-6 and II-2 from families
Mch and Mk, respectively). This contrasts with the full suppression
observed in the normal subject, I-2, in family Mk. Resistance of the
lactotrophs to L-T3 was also
observed. The response of PRL to TRH remained unchanged in the two
affected individuals who were tested compared to the partial
suppression in the unaffected family member (I-2 in family Mk; Fig. 4).
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). Data were comparable to those from
patients with severe thyrotroph resistance to T4
(Ka of mutant TRßs <2% the wild-type value,
with strong dominant negative activity) rather than those with mild
thyrotroph resistance to T4
(Ka of the mutant TRß 44% of the wild-type
value). The mean ± SE of the TTSI for all subjects
with RTH without TRß gene mutations, including family F25 (4), was
1559 ± 623. This value was not significantly different from the
TTSI of 747 ± 120 for patents with severe thyrotroph resistance
to T4, but was significantly higher
(P < 0.0001) than the value of 308 ± 34 for
patients with mild thyrotroph resistance to T4;
the TTSI of normal subjects was 136 ± 14.
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. In contrast to the stimulatory
responses of serum ferritin and SHBG and the inhibitory responses of
serum cholesterol and CK in the normal subject, the responses of the
affected member of the same family were severely attenuated and even
paradoxical (those of ferritin) as described for RTH (27).
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. All values were below the upper
limit of normal for the corresponding sex and age. Estradiol, LH, and
FSH concentrations were measured in all postpubertal and premenopausal
affected women (Msn II-1, Mch II-6, Mal II-14 and II-15, and Mk II-2 at
age 17 yr) and their unaffected female siblings (Msn II-2 and II-3, Mch
II-8, Mal II-8, and Mk II-1) not taking birth control medication. Only
subject II-6 of family Mch had an abnormal value: a high estradiol
concentration of 1.84 nmol/L (broad normal range, 0.18–1.47) LH of 35
mU/L (normal range excluding peak value, 0.9–12.8) and FSH of 11
nmol/L (broad normal range, 0.6–9.3). This finding is often seen in
the premenopausal period, and, in fact, 1 yr later the estradiol
concentration had declined to 0.60 nmol/L, with LH and FSH values of
3.7 and 7.0 mU/L, respectively. Pedigree analysis
Affected individuals in three of the five families (Msn, Mk, and
Mgd) had parents without RTH as confirmed by thyroid function tests
(Figs. 1 and 4). This suggests either recessive inheritance or
neomutations. There was no evidence for consanguinity. The situation in
family Mch may be similar. Although the phenotype of the deceased
parents of the proposita is unknown, none of her five tested siblings
expressed the RTH phenotype (Fig. 2). In the case of family Mal, as in
the previously published family with non-/non-ß TR-associated RTH
(4), the inheritance was autosomal dominant, as evidenced by the
transmission of the phenotype from mother to daughter, whose
unrelated father (II-13) was unaffected (Fig. 3).
Sequencing of the TRß gene
Isolation of the human TRß gene from a PAC library provided intronic sequences necessary for the amplification of all TRß gene exons. Accordingly, all exons and flanking intronic nucleotides of the TRß gene of all affected individuals from the five families were sequenced using genomic DNA. Not a single nucleotide substitution, deletion, or insertion was found in the two noncoding and two coding TRß1-specific exons, the one amino-terminal TRß2-specific exon, and the six coding exons common to both TRß1 and TRß2. It is this finding that led to further investigation.
Haplotyping of the TRß and TR genes.
Linkage analysis using polymorphic markers within the TRß gene
excluded involvement of the latter gene in the expression of the RTH
phenotype in two families. In family Msn, the affected mother
transmitted both alleles to her unaffected children (Fig. 1), and in
family Mal, affected (II-14 and II-15) and unaffected (II-3, II-10, and
II-12) siblings shared identical alleles (Fig. 3). Results from family
Mch were not informative because a maternal allele could not be
assigned to one of the unaffected children (III-2; Fig. 2).
Linkage analysis using polymorphic markers, intragenic or within 1
centimorgan of the TR gene excluded involvement of this gene in the
expression of the RTH phenotype in three of the five families. In
families Msn and Mch, affected mothers transmitted both alleles to
their unaffected children (Figs. 1 and 2). In the case of family Mal,
affected and unaffected siblings shared identical alleles (Fig. 3).
Linkage analysis could not be carried out in families Mk and Mdg
because the single affected individuals of each family in whom the
putative mutation appeared de novo had no children of their
own (Fig. 4).
A new polymorphism was identified in intron 3 of the TRß1. The distal stretch of multiple thymidines has seven or six thymidines. The probands of families Mch and Mk were polymorphic with seven and six thymidines in each allele.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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gene in 4
of the 6 families. Although a TR gene mutation has not been excluded
in the remaining two families, it is highly unlikely in view of the
recent finding that TR-deficient mice do not express the RTH
phenotype (32, 33).
The phenotype of RTH in these subjects is not overtly different from
that of individuals with RTH due to TRß gene mutations. The mode of
presentation with goiter, hyperactivity, tachycardia, or incidental
thyroid test abnormalities is not different from that found in the
common form of RTH (27, 34). The reduced responsiveness of the
pituitary and peripheral tissues to the administration of
L-T3 is also not different. The
magnitude of thyrotroph hyposensitivity to TH, as assessed by the TTSI
of 1559 ± 623 (mean ± SE, including family
F25), was comparable to that of subjects with TRß gene mutations
having severe thyrotroph resistance to TH with mean TTSI of 747 ±
120 (P > 0.05). Both TTSI values were significantly
higher than those of patients with mild thyrotroph resistance to TH
(308 ± 34; P < 0.0001) and the TTSI of normal
individuals (136 ± 14). It is of note that the only two patients
with TTSIs higher than those of members of family F25 are a child
homozygous for the TRß gene mutation T337 (TTSI of 217,672) (20)
and a subject with a nucleotide deletion causing a frame shift at codon
438 and a stop at 441 (35) (TTSI of 12,260). Both were severely
retarded, and the former died at 8 yr of age from heart failure
complicating septicemia.
Although a defect in type II 5'-deiodinase has not been yet demonstrated in mice or in man, such an abnormality should produce a high TTSI. However, due to the selective tissue distribution of this enzyme (36), the resulting resistance to T4 would spare most peripheral tissues except for brown fat. Demonstration of reduced peripheral tissue responses to the administration of L-T3 excludes a type II 5'-deiodinase defect in two of the families (F25 and Mk). In the remaining four families, such a defect is also unlikely because of normal serum SHBG concentrations despite the high levels of free T3. This liver marker is particularly sensitive to modest increases in TH action (37). Parenthetically, the family with presumed type II 5-deiodinase defect reported by Rösler et al. in 1982 (38) was recently shown to harbor a mutation in the TRß gene (Goss, D. J., P. R. Larsen, and W. W. Chin, unpublished observations).
This communication demonstrates that the occurrence of RTH without a structural TRß gene mutation, previously reported in a single family (4), is not that uncommon. The inheritance in two of the six families (F25 and Mal) is clearly dominant. Although we cannot exclude recessive inheritance in four families, given that the normal parents of the affected individuals in three of these families are not consanguineous, it is more likely that they represent putative neomutations in a gene, the expression of which is also dominant. This was the case in family F25 in which 14 yr elapsed from the identification of the key case (39) and the demonstration of neomutation and dominant mode of inheritance after the birth of two affected children of two unrelated fathers (4). The occurrence of neomutations in four of these six families, is much higher than the 13% prevalence of neomutations in RTH caused by TRß gene mutations (40).
In addition to the apparent high frequency of neomutations, the transmission rate of the defect is low for a dominantly inherited condition. In fact, of the 22 children born to affected parents, only 5 express the RTH phenotype. A possible explanation is reduced penetrance. Equally possible is reduced retention of embryos carrying the defect. This, often age-related phenomenon is suggested by the consecutive birth of 2 affected individuals (II-14 and II-15 in family Mal) to a mother at ages 40 and 42 yr, after the earlier birth of 11 normal siblings.
Central to the pathogenesis of RTH is the interference of mutant TRßs with the function of the wild-type TRs (41, 42), a phenomenon that explains the dominant mode of RTH inheritance. This effect is dependent on 1) ability of TR to bind to DNA at promoter sequences of target genes (43), 2) homodimerization (44, 45) and heterodimerization with RXR (46), 3) interaction with corepressors (10, 47), and 4) recruitment of coactivators (7, 11). Thus, it is theoretically possible for defective cofactors to cause RTH that is dominantly inherited. Although there is no direct evidence for a cofactor defect in the pathogenesis of RTH in humans, deletion of the coactivator, SRC-1, produces the phenotype of RTH in mice (17). Contrary to the SRC-1-deficient mouse, the subjects reported herein showed no clear evidence of resistance to estrogens. However, subtle abnormalities in these other functions that may be regulated by a defective cofactor with overlapping activity (15, 48) cannot be excluded.
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Acknowledgments |
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Footnotes |
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2 Supported in part by Deutsche Forschungsgemeinschaft (Po 556–1/1)
and recipient of the 1999 Knoll Thyroid Research Fellowship Award.
3 Current address: 2710 Dimasalang Street, Pasay City 1300,
Philippines.
Received February 11, 1999.
Revised June 30, 1999.
Accepted July 12, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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or ß genes may be due to
a defective co-factor. J Clin Endocrinol Metab. 81:4196–4203.[Abstract]
1. EMBO J. 17:455–461.[CrossRef][Medline]
and TRß
in the control of thyroid hormone production and post-natal
development. EMBO J. 18:623–631.[CrossRef][Medline]
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Y. Bayer, S. Neumann, B. Meyer, F. Ruschendorf, A. Reske, T. Brix, L. Hegedus, P. Langer, P. Nurnberg, and R. Paschke Genome-Wide Linkage Analysis Reveals Evidence for Four New Susceptibility Loci for Familial Euthyroid Goiter J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 4044 - 4052. [Abstract] [Full Text] [PDF]
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P. J. O'Shea, C. B. Harvey, H. Suzuki, M. Kaneshige, K. Kaneshige, S.-Y. Cheng, and G. R. Williams A Thyrotoxic Skeletal Phenotype of Advanced Bone Formation in Mice with Resistance to Thyroid Hormone Mol. Endocrinol., July 1, 2003; 17(7): 1410 - 1424. [Abstract] [Full Text] [PDF]
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H. Suzuki, X.-Y. Zhang, D. Forrest, M. C. Willingham, and S.-Y. Cheng Marked Potentiation of the Dominant Negative Action of a Mutant Thyroid Hormone Receptor {beta} in Mice by the Ablation of One Wild-Type {beta} Allele Mol. Endocrinol., May 1, 2003; 17(5): 895 - 907. [Abstract] [Full Text] [PDF]
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 P. Kopp Perspective: Genetic Defects in the Etiology of Congenital Hypothyroidism Endocrinology, June 1, 2002; 143(6): 2019 - 2024. [Abstract] [Full Text] [PDF]
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G. J. Kahaly, C. H. Matthews, S. Mohr-Kahaly, C. A. Richards, and V. K. K. Chatterjee Cardiac Involvement in Thyroid Hormone Resistance J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 204 - 212. [Abstract] [Full Text] [PDF]
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S. A. Phillips, P. Rotman-Pikielny, J. Lazar, S. Ando, P. Hauser, M. C. Skarulis, F. Brucker-Davis, and P. M. Yen Extreme Thyroid Hormone Resistance in a Patient with a Novel Truncated TR Mutant J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5142 - 5147. [Abstract] [Full Text] [PDF]
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S. Ando, N. J. Sarlis, J. Krishnan, X. Feng, S. Refetoff, M. Q. Zhang, E. H. Oldfield, and P. M. Yen Aberrant Alternative Splicing of Thyroid Hormone Receptor in a TSH-Secreting Pituitary Tumor Is A Mechanism for Hormone Resistance Mol. Endocrinol., September 1, 2001; 15(9): 1529 - 1538. [Abstract] [Full Text] [PDF]
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 W. E. Winter and M. R. Signorino Molecular Thyroidology Ann. Clin. Lab. Sci., July 1, 2001; 31(3): 221 - 244. [Abstract] [Full Text] [PDF]
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 P. M. Yen Physiological and Molecular Basis of Thyroid Hormone Action Physiol Rev, July 1, 2001; 81(3): 1097 - 1142. [Abstract] [Full Text] [PDF]
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 G. Buchanan, N. M. Greenberg, H. I. Scher, J. M. Harris, V. R. Marshall, and W. D. Tilley Collocation of Androgen Receptor Gene Mutations in Prostate Cancer Clin. Cancer Res., May 1, 2001; 7(5): 1273 - 1281. [Abstract] [Full Text]
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S. Reutrakul, P. M. Sadow, S. Pannain, J. Pohlenz, G. A. Carvalho, P. E. Macchia, R. E. Weiss, and S. Refetoff Search for Abnormalities of Nuclear Corepressors, Coactivators, and a Coregulator in Families with Resistance to Thyroid Hormone without Mutations in Thyroid Hormone Receptor {beta} or {alpha} Genes J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3609 - 3617. [Abstract] [Full Text]
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M. Anafi, Y.-F. Yang, N. A. Barlev, M. V. Govindan, S. L. Berger, T. R. Butt, and P. G. Walfish GCN5 and ADA Adaptor Proteins Regulate Triiodothyronine/GRIP1 and SRC-1 Coactivator-Dependent Gene Activation by the Human Thyroid Hormone Receptor Mol. Endocrinol., May 1, 2000; 14(5): 718 - 732. [Abstract] [Full Text]
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 S.-K. Lee, B. Lee, and J. W. Lee Mutations in Retinoid X Receptor That Impair Heterodimerization with Specific Nuclear Hormone Receptor J. Biol. Chem., October 20, 2000; 275(43): 33522 - 33526. [Abstract] [Full Text] [PDF]
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