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Original Studies |
Departments of Medicine (J.X., S.P., J.Po., R.E.W., S.R.) and Pediatrics (J.Po., S.R.), The University of Chicago, Chicago, Illinois 60637; the Department of Pediatrics, Yale University (K.M.), New Haven, Connecticut 06512; Kinderkrankenhaus auf der Bult (M.M.), Hannover, Germany; Institute of Endocrine Sciences, University of Milan, Ospedale Maggiore IRCCS, Istituto Clinico Humanitas, and Centro Auxologico Italiano IRCCS (C.A., L.P., P.B.P.), Milan, Italy; and Institut de Recherche Interdisciplinaire, and Service de Génétique Médicale, Faculté de Médicine, Université Libre de Bruxelles, Campus Erasme (J.Pa., G.V.), 1070 Brussels, Belgium
Address all correspondence and requests for reprints to: Dr. Samuel Refetoff, University of Chicago, MC3090, 5841 South Maryland Avenue, Chicago, Illinois 60637. E-mail: refetoff{at}medicine.bsd.uchicago.edu
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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gene of one
family analyzed by GC-clamped denaturing gradient gel electrophoresis.
This study shows that RTSH may be a manifestation of several different
genetic defects that requires the exploration of other candidate genes
involved in the TSH-TSHR-Gs cascade and genes
participating in its regulation. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The interaction between glycoprotein hormones and their receptors is believed to cause a structural change in the receptor activating the G proteins. Being preferentially coupled to Gs, this results in the stimulation of adenylyl cyclase and the generation of intracellular cAMP. At high concentrations of the hormones, the receptors also couple to Gq, stimulating the production of inositol phosphate through the phospholipase C-dependent regulatory cascade (6, 7, 8).
As the TSHR is responsible for mediation of the first step in TSH action, the TSHR gene is a potential candidate for mutations causing thyrocyte dysfunction. Defects at the gene level could, theoretically, affect transcription, translation, or protein structure, resulting in failure of synthesis, membrane localization, binding, or response to the ligand (9). The isolation and sequencing of the human TSHR (10, 11) have provided the opportunity to evaluate TSHR gene abnormalities at the molecular level, which was further facilitated by the availability of genomic sequences at the intron/exon junctions (12).
Somatic and germline mutations causing constitutive activation (gain of function) of the TSHR produce hereditary nonautoimmune hyperthyroidism (13) and toxic thyroid adenomas (14, 15), respectively. This finding preceded by 2 yr the first description of loss of function mutations in the TSHR, producing resistance to TSH (RTSH) in individuals harboring different mutations in each of the two alleles (compound heterozygotes) (16). Within 1 yr, seven additional families manifesting RTSH were identified (17, 18, 19). In these individuals, as in those described earlier, the phenotype of RTSH manifested as elevated serum levels of TSH on repeated determinations in a background of clinical euthyroidism and in association with normal concentrations of free T4, because the syndrome was caused by mutant TSHRs with reduced function. Recently, a family has been identified in which particularly severe loss of TSHR function produced congenital hypothyroidism (high TSH and low free T4) in the homozygotes (20). In all, the inheritance of RTSH was recessive, usually compound heterozygous, except for two families in which it was homozygous (17, 20).
In the present study, we report three unrelated families in whom
affected individuals manifest the phenotype of RTSH. However, in
contrast to those reported previously, no mutations were found in TSHR
or TSHß gene. Furthermore, in two families, linkage of the TSHR gene
to the RTSH phenotype was excluded by haplotyping, and in another
family, no putative mutation in the Gs gene was found by
denaturing gradient gel electrophoresis.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Family 1 (Fig. 1
). The
proposita (II-2) was 38 yr old when a TSH level of 7.2 mU/L was found
on routine testing. Repeat determination gave a value of 9.8 mU/L.
Despite normal free T4 index (FT4I) values of
93 and 129 (normal range for that laboratory, 50–150), treatment with
0.1 mg L-T4 daily was begun. On this regimen,
TSH declined to 0.6 mU/L, with an increase in the FT4I to
only 143. However, the treatment was discontinued because of
nonspecific malaise.
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). All family members had normal concentration of
iodothyronines as well as the FT4I. Serum thyroglobulin
(TG) and pituitary glycoprotein -subunit (SU) concentrations were
also within the normal range. TG and thyroid peroxidase antibodies were
not detectable.
Family 2 (Fig. 2). The
proposita (III-2) was the product of a normal pregnancy and delivery.
Initial neonatal blood screen was reported as elevated TSH. Serum TSH
concentrations at 3 and 4 weeks were 40.3 and 34.5 mU/L, with
corresponding total T4 values of 125 and 106 nmol/L and
calculated free T4 within the normal range. Her physical
examination was normal, and ultrasound showed a thyroid gland slightly
reduced in size. 99mpertechnetate scan showed a gland
normal in size, shape, and position. L-T4
treatment (50 µg daily) was initiated at 1 month of age. After 2
weeks, her serum TSH level had declined to 8.3 mU/L. After 6 weeks of
this L-T4 regimen, serum total T4
was 154 nmol/L, and TSH was 0.55 mU/L. Her growth and development
proceeded normally.
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The mother of the proposita (II-3) was in her teens when hypothyroidism was diagnosed, allegedly on the basis of an elevated serum TSH level. She was placed briefly on L-T4 replacement. No treatment was given during her pregnancies, and a postpartum 123I scan was normal, as was the perchlorate discharge test. Her TSH level at that time was 10.4 mU/L.
Blood samples were obtained from 12 members of this family, and the
results of thyroid function tests are shown in Fig. 2. Thyroid
peroxidase and TG antibodies were not detected. Serum free
T4 levels, measured by equilibrium dialysis, in subjects
I-1 and I-2 were 21 and 15 pmol/L, respectively (normal range,
10–32).
Family 3 (Fig. 3). The
propositus, a 6-yr-old boy, was born to healthy nonconsanguineous
parents. Pregnancy and delivery were unremarkable. Minor congenital
malformations suggestive of Townes-Brocks syndrome were present and
included a preauricular skin appendage, glandular hypospadias,
cutaneous syndactily of the third and fourth toes, and anal atresia
with fistula (21) that was repaired surgically. A high blood TSH level
of 93 mU/L was detected on neonatal screening, with a total
T4 of 84 nmol/L, which is within the lower limit of normal.
Treatment with 37.5 µg L-T4 daily was
initiated, resulting in a serum T4 level of 232 nmol/L and
undetectable TSH. At the age of 2 yr, an ultrasound showed a normal
thyroid gland, and L-T4 treatment was
discontinued. Two months later, serum T4 was 121 nmol/L,
with a TSH level of 52 mU/L, rising to 117 mU/L 30 min after the iv
administration of 70 µg TRH. The child continued to develop normally
along the 10–25th percentile for height and weight. Two and a half
years after discontinuation of L-T4 treatment,
TSH has risen to 143 mU/L, with a total T4 of 107 mmol/L,
and free T4 and T3 were within the normal
range. Physical and mental development continued to be normal, although
speech therapy was required for progressive sensorineural hearing loss
due to the Townes-Brocks syndrome.
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). Tests of thyroid function
Serum total T4, T3, and rT3
concentrations were measured by RIAs, and TSH was determined by a third
generation chemiluminescence assay (Corning/Nichols Institute, San Juan
Capistrano, CA). The serum free T4 index was calculated as
the product of the serum total T4 and the T4
resin uptake value (22). The serum free T4 concentration
was measured by equilibrium dialysis, and the SU was determined by
RIA at Nichols Institute (San Juan Capistrano, CA). The RIA for serum
TG was an in-house assay, as previously reported (23). Thyroid
peroxidase and TG autoantibodies were measured by agglutination
(Fujirebio, Tokyo, Japan).
Measurement of TSH bioactivity
TSH bioactivity in serum was measured in Chinese hamster ovary cells expressing a recombinant human TSHR, as previously described (24). Two serum pools (A and B) from patients with elevated serum TSH due to mild primary hypothyroidism were processed in the same assay and served as controls.
Sequencing of TSH and TSHR
Venous blood samples were collected in ethylenediamine
tetraacetate. Genomic DNA was isolated from leukocytes as previously
described (25). For amplification of the coding sequences of TSHß,
primers were designed to anneal to intronic sequences flanking each
exon. Primers used for the amplification of the TSHR were modified from
those reported by de Roux et al. (12), and those selected
for the amplification of the TSHR promoter were designed according to
the sequence described by Gross et al. (26). The 5'-ends of
the primers were degenerated to create restriction sites suitable for
insertion into cloning vectors. Standard PCR was carried out in a
100-µL volume containing 100 ng genomic DNA, 50 pmol of each primer,
50 mmol/L Tris-HCl (pH 8.3), 1.5 mmol/L MgCl2, 0.01%
gelatin, 200 nmol/L of each deoxy (d)-NTP, and 0.5 U Taq DNA
polymerase (Promega, Madison, WI). Samples were processed in a
Perkin-Elmer/Cetus thermal cycler (Norwalk, CT). After an initial 5-min
denaturation at 94 C, 35 cycles were carried out, consisting of 30
s at 94 C, 30 s at different annealing temperatures (see Table 1), and 1 min at 72 C, followed by a
final extension step of 10 min at 72 C. The primers used are shown in
Table 1, and the precise conditions for amplification by PCR will be
provided upon request.
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For manual sequencing, the amplified DNA fragments were cloned into the
M13 bacteriophage vector and sequenced by the dideoxynucleotide chain
termination reaction (28) (Sequenase version 2.0, U.S. Biochemical
Corp., Cleveland, OH). Reaction products were analyzed on 6%
acrylamide gel containing 7 mol/L urea. All sequencing primers are
listed in Table 1.
Haplotyping
Four intragenic polymorphic markers were used to haplotype the TSHR alleles to determine linkage of the TSHR gene to the RTSH phenotype in families 1 and 2. Polymorphic nucleotide at position 253 (C/A) in exon 1 was determined by endonuclease digestion (Tth111I, New England BioLabs, Beverly, MA) of the PCR product as previously described (29). A polymorphic nucleotide at position -445 (G/T) in the promoter region was determined by sequencing using primers according to the published sequence (26).
Two microsatellite markers (CA and CT repeats) located in intron 7 of
the TSHR (12) were also used for haplotyping. Fragments containing the
dinucleotide repeats were amplified by PCR using 10 ng genomic DNA and
0.8 pmol [
-32P]dATP end-labeled forward primers. Each
reaction contained, in addition to the labeled primer, 0.2 mmol/L each
of dATP, dCTP, dGTP, and dTTP; 0.1 U Taq DNA polymerase; 3.2
pmol unlabeled forward primers; and 4 pmol unlabeled reverse primers in
a final volume of 10 µL. The PCR was performed in a Perkin-Elmer 9600
thermal cycler. After initial denaturation for 3 min at 95 C, 30 cycles
were applied (1 min at 95 C, 1 min at 58 C, and 30 s at 72 C)
along with a terminal extension of 5 min at 72 C. The PCR product was
denatured for 10 min at 95 C, mixed with loading buffer in 98%
formamide, and electrophoresed in a 6% denaturing polyacrylamide gel.
Gels were subsequently dried and autoradiographed. A sequence was run
in parallel to determine fragment size, and allele numbers were
assigned as reported by de Roux et al. (12).
Screening mutations in the Gs gene by
denaturing gradient gel electrophoresis (DGGE)
Each of the 12 exons of the Gs gene were
amplified using primers that annealed to flanking intronic sequences.
Two microliters of the PCR product were reamplified using one original
primer and a primer to which a 40-nucleotide GC sequence adapter was
added to the 5'-end to serve as a GC clamp. The principle of the
technique and primers sequences have been previously described (30, 31).
The DGGE apparatus and method were those we used and described previously (30). Polyacrylamide gel slabs containing a linear gradient of denaturants (0–7 mol/L urea and 0–40% formamide) were prepared in 6.5% acrylamide in 40 mmol/L Tris, 20 mmol/L sodium acetate, and 1 mmol/L ethylenediamine tetraacetate, pH 7.4. Electrophoresis was performed at 150 V for 8 h at 60 C, maintained by a heater, with continuous mixing of the two chamber buffers with a peristaltic pump. Gels were stained with ethidium bromide for approximately 15 min and photographed under UV light.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The results of thyroid function tests for members of the three
families are shown in
Figs. 1–3. All had the cardinal features of
RTSH, namely an elevated serum TSH concentration with normal thyroid
hormone levels, including free T4. These findings were
confirmed on repeated determinations, and interference in the TSH assay
was excluded by recovery of added TSH to the serum samples.
Furthermore, as found in other individuals with this syndrome (16, 17, 18, 19, 32), their thyroid glands were normal in size and location and, when
determined, the perchlorate discharge test was normal. The response to
TRH in subject II-4 (family 2) was proportional to the basal TSH value.
Serum PRL concentrations were normal in all subjects, as were serum
calcium and PTH determined in one affected subject from each family
(data not shown). Serum LH, FSH, and estrogen values were also normal
in subject II-3 (family 1). These data suggest that the abnormality was
confined to the thyroid.
The pattern of inheritance, however, was unusual in families 1 and 2. Contrary to all other cases previously reported (16, 17, 18, 19), the phenotype followed a dominant mode of inheritance, whether subjects with borderline increases in TSH were considered to be affected or not. The slight increase in serum TG concentration in the affected subjects of family 2 is reminiscent of the case of congenital hypothyroidism and homozygous TSHR mutation described recently (20).
TSH bioactivity and sequence of the TSHß gene
Bioactivity was measured by the relative potency of serum TSH to
stimulate cAMP accumulation in cells stably expressing the human TSHR.
As shown in Table 2, values were
proportional to the immunoreactive TSH in the three affected subjects
tested, each a member of one of the three families. These data are in
agreement with the normal concentration of SU in the serum of
subjects in family 1. It is also supported by our failure to identify
sequence differences in the coding exons of TSHß and 10–100 flanking
intronic nucleotides. Both sense and antisense strands of TSHß were
sequenced from DNAs of subjects I-1 and I-2 (family 1) and the
propositi (III-2 and II-1) of families 2 and 3, respectively.
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All coding exons and flanking intron junctions as well as 514 bp (nucleotides -1 to -514 from the translation start point) of the promoter region of the TSHR of subject III-2 from family 2 and subject II-1 of family 3 were sequenced directly in both sense and antisense directions. The TSHR gene of subjects III-1 of family 2 and that of subject II-1 from family 3 were also sequenced independently in Brussels. All coding exons flanking intronic sequences of the TSHR of subjects I-1 and II-3 of family 1 were amplified and subcloned into the M13 vector, and at least 10 templates were sequenced in both directions as described in Materials and Methods. The 5'-untranslated region of the TSHR of subject II-2 of family 1 was sequenced directly from the PCR product. Although heterozygosity for the polymorphic nucleotides was detected by direct sequencing, as described below, no other differences were found compared to the wild-type sequence.
Linkage analysis
To exclude the possibility that TSHR gene mutations in the
noncoding regions that may affect transcription or produce splicing
defects escaped detection by sequencing, we used all known intragenic
polymorphic markers for haplotyping. Several of these markers were
identified after completion of the sequencing. The analysis was
particularly useful because the four markers could identify unique
haplotypes for each of the four parental alleles. Results are shown in
Figs. 1 and 2. In both families the haplotype data exclude linkage of
the TSHR gene to the phenotype of RTSH. Linkage is broken by several
members of the family 1 regardless of whether TSH values in the upper
limit of normal are included or excluded from the RTSH phenotype. In
family 2 (Fig. 2), linkage of the phenotype to the TSHR gene is
definitely excluded, as the two affected children have inherited a
different allele from their affected mother and the same allele from
their unaffected father.
Analysis of the Gs gene
No putative mutations in the Gs gene were
identified by DGGE in the affected members (I-1, I-2, and II-3) of
family 1 (data not shown). A positive control, heterozygous for a
mutations in the Gs gene was provided by Dr. Kyoko
Takeda. It was used in the analyses and gave positive results.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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and 4). In all of these subjects, mutations
in the TSHR gene that reduce the function of its product have been
detected and are responsible for the clinical manifestations
characteristic of the syndrome. With one exception (32), affected
individuals harbor mutations in both alleles and are either compound
heterozygotes or homozygous when consanguineous (17).
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and 4). The
transversion of C to G in nucleotide 583 that results in the
replacement of the normal proline 162 with an alanine has been found in
three unrelated families (16, 17, 32), suggesting that it may be
relatively prevalent in the population. Furthermore, this mutation has
produced increases in serum TSH of variable magnitude, and the
researchers have postulated the existence of another, as yet
unidentified, mutation in the promoter region of the other allele
(32).
Although the majority of individuals with RTSH maintain a euthyroid
state through compensatory hyperthyrotropinemia (16, 17, 18, 19), the phenotype
encompasses a broader range of thyroid function, with transient and
even permanent congenital hypothyroidism at the extreme (20). This
depends in part on the residual function displayed by the least
affected mutant allele. In all cases a eutopic thyroid gland deviates
only slightly from the normal size. Absolute hormone values are quite
variable. TSH concentrations range from just above the upper limit of
normal to 115 mU/L, whereas free T4 values span the broad
range of normal, with the majority of cases in the low normal range
(Table 3). These differences do not correlate with the degree of
functional impairment of the mutant TSHR, with the exception of
complete loss of function, resulting in hypothyroidism (20).
Heterozygotes have no distinct phenotype, although borderline increases
in serum TSH have been observed (Table 4).
We now report three unrelated families expressing the typical RTSH phenotype, yet it occurs in the absence of a defect in the TSHR. Although failure to identify a mutation by sequencing of genomic DNA does not fully exclude the presence of a mutation that affects expression, the absence of genetic linkage to the phenotype in families 1 and 2 definitely excludes the involvement of TSHR. The normal TSH bioactivity and normal coding sequence of TSHß in all three families also exclude involvement of the TSH gene in expression of the phenotype.
Mutations in the signaling pathway, downstream of the TSHR, that
produce a partial loss of function could manifest as RTSH, although the
defect may not be confined to the thyroid. In fact, germline mutations
causing loss of function of the Gs protein have been
found to produce RTSH even in the heterozygous individual (33).
Depending on the severity of the defect, the phenotype may be overt
hypothyroidism or euthyroidism with elevated serum TSH. However, owing
to the ubiquitous expression of Gs, the phenotype shows
a broader spectrum of disorders involving the parathyroid gland and
gonads as well as somatic and skeletal abnormalities, collectively
termed Albright’s hereditary osteodystrophy (34). Although this was
not the clinical picture observed in affected members of the three
families, we screened for a putative defect in the Gs
gene using DGGE in one family and found none.
Several other mechanisms may be considered in the manifestation of RTSH. We cannot exclude a reduction in the expression of the TSHR. This could not be due to a defect in the promoter region of the TSHR, as we have sequenced the entire 5'-region containing the nucleotide sequences that bind regulatory factors such as insulin growth factor I, thyroid transcription factor-1 (TTF-1), thyroid hormone receptor, and cAMP (5). It is, however, possible for full expression of the TSHR to be prevented by a defect in one of these cofactors. TTF-1 is one such candidate, although it exerts only a modest effect on TSHR gene expression (35, 36). Considering the more important role of TTF-1 in the regulation of TG and thyroid peroxidase (37), one would have expected at least an abnormality in the perchlorate discharge test, which was not found in affected subjects from families 1 and 2. A recent search for mutations in the TTF-1 in 76 patients with thyroid dysgenesis yielded negative results (38, 39). A complete lack of TTF-1, on the other hand, is not compatible with life, because of the role of TTF-1 in the embryogenesis of several vital tissues (40).
Another possibility is a defect downstream of Gs. The
human G protein-coupled receptor kinase 5 (GRK5) appears to be the
predominant isoform in the thyroid cells (41). However, the level of
its GRK5 messenger ribonucleic acid in the thyroid is not higher than
that in other tissues, such as lung, colon, heart, and kidney. Thus, a
functional alteration in GRK5 is not expected to produce a phenotype
limited to the thyroid. Nevertheless, specific alterations of the
molecule could predominantly influence cAMP production in thyroid
cells.
In family 2, the modest increase in serum TG may indicate a slight overstimulation of the thyroid gland, which would, in turn, point to the possibility of a minor hormonogenic defect. However, the absence of thyroid hyperplasia is against this view. Of note is the observation of high serum TG levels in two families with TSHR mutations producing a total loss of function and hypothyroidism (20, 42). Although no definite explanation can be offered, it can be suggested that defective activation of the cAMP regulatory cascade during embryogenesis might lead to a mild disorganization of the follicle structure, resulting in TG leakage.
As is the case with other genetic defects, the same phenotype may be caused not only by defects at different gene levels, but also by the interplay of several genetic and environmental conditions. The syndrome of RTSH does not seem to escape this rule.
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Acknowledgments |
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gene, and
Ms. M. Nguyen for expert technical assistance at the Free University of
Brussels. Special thanks are due to members of the families for their
gracious consent to participate in this study. |
Footnotes |
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2 Supported by Deutsche Forschungsgemeinschaft (Po 556–1/1).
3 Supported by Ospedale Maggiore IRCCS.
Received July 23, 1997.
Accepted August 19, 1997.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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, Mean value of
determinations on three blood samples obtained at different times.
