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Original Studies |
Genes1
Departments of Medicine (Si.R., S.P., J.P., G.A.C., P.E.M., R.E.W., S.R.), Pathology (P.M.S.), 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
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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involvement was excluded. Candidate genes were then
evaluated for their possible involvement in the RTH phenotype in these
4 families: 2 coactivators [NCoA-1 (SRC-1) and NCoA-3 (AIB-1)], 2
corepressors (NCoR and SMRT), and a coregulator (RXR
). DNA was
obtained from 8 affected subjects and 41 of 45 living first degree
relatives. In 2 of the 4 families, the mode of inheritance could be
determined by pedigree analysis and was found to be autosomal dominant.
Linkage analyses were performed using polymorphic markers near or
within the 5 candidate genes. When analyses were not informative or
linkage could not be excluded, direct sequencing of the genes in
question was performed.
Involvement of NCoA-1 was excluded in all four families assuming
autosomal dominant inheritance. Roles for NCoR, SMRT, and NCoA-3 were
excluded in three and a role for RXR was excluded in two of the four
families. However, if the two families without proven dominant mode of
inheritance were compound heterozygous, only the involvement of NCoA-1
could be excluded in both. Roles for NCoR, SMRT, and RXR were
excluded in one of these two families. Thus, NCoA-1 and RXR genes
were not found to be the cause of RTH in subjects without TR gene
mutations even though the absence of NCoA-1 and RXR is the cause of
RTH in mice. Involvement of other candidate genes in the mediation of
thyroid hormone action as well as intracellular hormone transport needs
to be explored in these families with non-TRß, TR RTH.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Mutations in the TRß gene were not found in a subgroup of patients
with RTH. We first described one such family in 1996 (15), and more
recently, we reported 5 additional families (16). They represent
approximately 10% of the 65 families with RTH studied in our
laboratory. In addition to having normal TRß1 and TRß2 genes, as
determined by sequencing, involvement of the TRß and TR genes was
excluded by linkage analysis in 2 and 4 of these 6 families,
respectively (15, 16). Their clinical phenotype was similar to that of
individuals with RTH due to TRß gene mutations and has been
previously described in detail (15, 16, 17, 18).
TRs homodimerize or form heterodimers with retinoid X receptors (RXRs) and bind to specific DNA sequences, termed thyroid hormone response elements (TREs). In the absence of T3, TR homodimers and heterodimers are associated with corepressors (NCoR and SMRT) that repress or silence the transcription of genes positively regulated by the ligand. Binding of T3 to TRs releases the corepressors and recruits nuclear coactivators, such as NCoA-1 (SRC-1), NCoA-2 (SRC-2/TIF-2/GRIP-1), and NCoA-3 (SRC-3/pCIP/AIB-1), which stimulate gene transcription (19). Mutant TRßs interfere with the functions of the wild-type TRs, a phenomenon termed the dominant negative effect (DNE) (20). The DNE involves the occupation of a TRE by a mutant TR that cannot bind T3 or has reduced affinity for the ligand, tighter affinity for the corepressors (21, 22, 23), or reduced ability to recruit coactivators (24, 25) necessary to enhance gene transcription. For DNE to occur, TR has to bind to TRE, which explains why no mutations have been identified in the DNA-binding domain.
In the absence of TRß mutations, a RTH phenotype could theoretically
be caused by abnormal corepressors, coactivators, or coregulators that
have altered interaction with TR. This was recently found to be true in
mice deficient in SRC-1, which, in addition to sex hormone resistance,
manifested the phenotype of RTH (26). Additionally, RXR-deficient
mice were found to have biochemical changes consistent with mild RTH
(27).
In this study we explored the possibility that a defective cofactor or
RXR may be the cause of RTH in individuals without mutations in
TRß or TR genes. Of the six families we have previously reported
(15, 16), the pedigrees of four were potentially amenable to linkage
analysis because more then one family member was affected, or affected
subjects had sufficient number of unaffected siblings and progeny. We
performed linkage studies for two corepressors (NCoR and SMRT), two
coactivators (NCoA-1 and NCoA-3), and RXR. When the linkage to one
of these genes could not be excluded or the result of linkage analysis
was not informative, the gene in question was sequenced. We were able
to show that expression of the RTH phenotype in these four families
does not involve a defect in SRC-1. The involvement of NCoR, SMRT, and
NCoA-3 was excluded in three and the involvement of RXR was excluded
in two of the four families.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Members of four families were investigated. Their clinical
presentation and features were previously described in detail (15, 16, 17, 18).
Family Mma (Fig. 1
), previously reported
as family F25, and family Mal (Fig. 2)
each have three affected individuals. The inheritance pattern is
autosomal dominant. Family Mch (Fig. 3)
and family Msn (Fig. 4), each have one
affected individual with normal siblings and progeny (16). All affected
individuals displayed the clinical features characteristic of RTH with
elevated free T3 and T4 and
nonsuppressed TSH. Furthermore, in three of the four families (Mma,
Mal, and Mch), reduced sensitivity to T3 in
central and peripheral tissues was documented by the response to
administration of supraphysiological doses of the hormone (16, 17, 18).
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Genotyping of the NCoR gene
At the time of the study, the location of the human NCoR gene was not known. We obtained human NCoR genomic clones containing the 3'-fragment from Kathryn B. Horwitz and Jennifer K. Richer, University of Colorado Health Sciences Center (Denver, CO). Partial sequencing in our laboratory provided the 3'-untranslated nucleotide sequence. This allowed the synthesis of oligonucleotide probes to screen a G3 radiation hybrid library (Research Genetics, Inc., Huntsville, AL). The forward primer was 5'-CATCTGTGGGCTGGCTCTCCT-3', and the reverse primer was 5'-CATTGCTCTCAGCACAGTACGA-3'. PCR was performed in a volume of 12 µL with 8 µmol/L of each primer, buffer containing 2.5 mmol/L Mg, 10 nmol/L deoxy (d)-NTPs, 10% dimethylsulfoxide, and 0.2 U Taq DNA polymerase. The PCR product had the expected size of 183 bp. The PCR conditions were denaturation at 94 C for 1 min, annealing at 60 C for 1 min, and extension at 72 C for 20 s for a total of 35 cycles. The results of the library screen were submitted to the Stanford Radiation Hybrid Mapping Program for two-point maximum likelihood analysis. Linkage to marker AFMb357yg9, located on chromosome 17, had a logarithm of odds score of 14.46. For a clear separation of polymorphic bands, genotyping was carried out using the tetranucleotide marker, GATA185H04, located 1.6 centimorgans (cM) from AFMb357yg9. The location is within the broader area of chromosome 17, reported previously (29). For family Mma, we used a second marker, D17S918, because of technical difficulties in identification of the proposita’s genotype using marker GATA185H04. The distance between the latter marker is 3.5 cM from GATA185H04 and 1.9 cM from AFMb357yg9.
Genotyping of the SMRT gene
Although at the time of the study it was known that the SMRT gene is on chromosome 12, its exact location had not been identified. We screened a G3 radiation hybrid library using an oligonucleotide primer complimentary to the 3'-untranslated region of the SMRT gene. Eight micromoles per L of the forward primer 5'-AGAGACCTTACTCAGGGGAT-3' and the same amount of the reverse primer 5'-CTGACTTGGTTTCCAGCAAT-3', to yield a PCR product of 334 bp, were used in a PCR performed in a volume of 12 µL with buffer containing 2.5 mmol/L Mg, 10 nmol/L dNTPs, 10% dimethylsulfoxide, and 0.2 U Taq DNA polymerase. The PCR conditions were denaturation at 94 C for 30 s, annealing at 58 C for 1 min, and extension at 72 C for 1 min for a total of 35 cycles. The results of the library screen were submitted to the Stanford Radiation Hybrid Mapping Program for two-point maximum likelihood analysis. The linkage to the marker GATA5H03, located on chromosome 12, had a logarithm of odds score of 9.79. A second marker, GATA41E12, was also selected for genotyping. The distance between the two markers is 9.4 cM. In addition, we identified a single nucleotide polymorphism in the 3'-untranslated region of the gene [A/G at nucleotide 5281 (SMRT-A5281G)]. This creates a unique restriction site for the enzyme BsaWI. Digestion of the 334-bp DNA fragment, amplified with the primers used for the screening of the radiation hybrid library, produced a 282-bp fragment in the presence of G at position 5281, which was detected by separation on a 2% agarose gel. The 334- and 282-bp fragments were designated 1 and 2, respectively. Genotyping using this intragenic marker was performed in family Mal in addition to the above two markers.
Genotyping of the NCoA-1 gene
The NCoA-1 gene has been mapped to chromosome 2. Two markers, ATA3G09 and GATA8F07, located less than 0.01 cM apart, were used for genotyping. Both are within 1.1 cM of the NCoA-1 gene.
Genotyping of the NCoA-3 gene
The NCoA-3 gene is located on chromosome 20. We used the intragenic polymorphism in the polyQ region of the coding sequence (AIB1-polyQ) as previously reported (30). A second marker, D20S432, located within 6.1 cM of the NCoA-3 gene was also used for genotyping.
Genotyping of the RXR gene
The RXR gene has been mapped to chromosome 1. The marker
D1S1158, located within 4.1 cM of the RXR, was first selected. Due
to technical difficulties and failure in some instances to obtain
informative results with this marker, the markers D1S1677 and ATA38A05
were also used. D1S1677and D1S1158 are 2.8 and 0.7 cM on either side of
ATA38A05, respectively. RXR has been mapped to a region of 3.4 cM
spanning the markers D1S1677 and ATA38A05, and thus is within 1.5 cM of
at least one of the three markers.
Methods for marker identification
With the exception of SMRT-A5281G and AIB1-polyQ, all polymorphic markers were purchased from Research Genetics, Inc. as fluorescence-labeled oligonucleotides. PCRs were performed in a 5-µL volume with buffer containing 2.5 mmol/L Mg, 10 mmol/L dNTPs, 8 µmol/L of each primers, and 0.2 U Taq DNA polymerase. The fluorescent PCR products were separated using an automated sequencer (ABI 377, Perkin-Elmer Corp., Foster City, CA), visualized, and printed.
Sequencing of the SMRT gene
SMRT complementary DNA (cDNA) from fibroblasts of the proposita
of family Mma along with cDNA from 3 normal, unrelated individuals were
sequenced. Primer sequences are shown in Table 1. PCR was performed in a volume of 100
µL with 8 µmol/L of each primer and buffer containing 2.5 mmol/L
Mg, 10 nmol/L dNTPs, and 0.2 U Taq DNA polymerase. The
conditions were denaturation at 94 C for 1 min, annealing at the
temperature indicated in Table 1 for 1 min, and extension at 72 C for 1
min for a total of 35 cycles. All PCR products were purified by
electrophoresis on a low melting agarose gel and sequenced using an
automated fluorescence based sequencer (ABI 377, Perkin-Elmer Corp.).
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NCoA-1 cDNAs of the propositi of families Mma and Mch were sequenced. Messenger ribonucleic acid was extracted from Epstein-Barr virus-transformed circulating lymphocytes obtained from the affected subject of family Mch (31). Cultures of skin fibroblasts collected from affected members of families Mma and Mch were also used as a source of messenger ribonucleic acid. cDNA was prepared using a RT system (Promega Corp., Madison, WI).
The entire cDNA sequences of the two splice variants (32) were
amplified using the primers listed in Table 2. PCR was performed in a volume of 100
µL with 8 µmol/L of each primer and buffer containing 2.5 mmol/L
Mg, 10 nmol/L dNTPs, and 0.2 U Taq DNA polymerase. The
conditions were denaturation at 94 C for 1 min, annealing at the
temperature indicated in Table 2 for 1 min, and extension at 72 C for 1
min for a total of 35 cycles. The sizes of the PCR products are shown
in Table 2. All were purified by electrophoresis using low melting
point agarose gel and sequenced (ABI 377, Perkin-Elmer Corp.).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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genes are shown in
Figs. 1–4
and results are summarized in
Table 3.
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In this family, the pattern of RTH transmission is consistent with
autosomal dominant inheritance. Furthermore, the proposita probably has
a new mutation, as neither parent and none of five siblings (not shown
in Fig. 1) expressed the RTH phenotype (15, 17). The study for linkage
to SMRT was not informative because the proposita is homozygous for
both markers. We could not use the intragenic marker SMRT-A5281G
because the proposita was also homozygous (G/G) for this marker.
Partial sequence of SMRT cDNA of the proposita was normal (nucleotides
722-3388, 3700–4069, 4081–4539, 4620–5005, 5060–5466, and
5470–5826; coding sequence spanning from nucleotides 496-4984). We
found two differences in our sequences from the published sequence (33)
that produced amino acid changes. In the proposita and two unaffected
and unrelated individuals, nucleotide 2114 was a C rather than a T
(M705T), and nucleotide 3110 was a C rather than A (K1037T).
Linkage of RTH to NCoA-1 in this family could not be completed due to
the inability to genotype the proposita despite repeated attempts.
Based on the haplotypes of the two children (II-1 and II-2), it is
likely that the analyses would have not been informative. However, we
were able to exclude a mutation in the coding sequence of NCoA-1 in
this family by direct sequencing of the proposita’s cDNA. NCoR,
NCoA-3, and RXR show possible linkage to the RTH phenotype, as all
affected individuals (I-2, II-1, and II-2) share a common allele.
Unfortunately, we also encountered technical difficulties with the
genotyping of RXR using markers D1S1677and ATA38A05.
Family Mal
Pedigree analysis revealed that the RTH phenotype in family Mal is
inherited dominantly. Linkage analyses exclude the involvement of NCoR,
NCoA-1, NCoA-3, and RXR in the expression of the RTH phenotype. The
haplotypes derived from the combination of three markers (SMRT-A5281G,
GATA5H03, and GATA41E12) also exclude SMRT involvement. Note that there
is a recombination of the maternal allele in subject II-3, which is not
unexpected given the distance of 9.4 cM between markers GATA5H03 and
GATA41E12.
Family Mch
The mode of inheritance of RTH in family Mch cannot be determined from the pedigree, because only one family member is affected. The involvement of NCoR and SMRT was excluded assuming the syndrome is dominantly inherited, as the proposita transmitted both alleles to each of her unaffected children. In addition, the proposita shares common NCoR alleles with three unaffected siblings (II-4, II-5, and II-8). Involvement of NCoR and SMRT was excluded should the inheritance be recessive (compound heterozygous),5 because the proposita has the same haplotype as two unaffected siblings (II-4 and II-8).
Linkage analysis excludes the involvement of NCoA-1 regardless of whether inheritance was dominant or recessive based on shared alleles between the proposita and an unaffected sibling (II-5). However, linkage cannot be excluded if the proposita had a neomutation of NCoA-1, because she passed the same allele to both of her children. Nevertheless, sequencing of NCoA-1 cDNA from the proposita showed no abnormalities. Linkage of RTH to NCoA-3 is also excluded if the inheritance mode is dominant, because the proposita passed each of her two alleles to her unaffected children. However, if the syndrome is recessively inherited, linkage to NCoA-3 cannot be ruled out, because none of the normal siblings shares the haplotype of the proposita.
The presence of a fifth allele for NCoA-3 in generation II of the family, which is unique in the proposita, is suggestive of nonpaternity or a mutation. As both parents are deceased, their haplotypes could only be deduced from data derived from their progeny, and therefore, establishing paternity is not simple. In light of this, we typed 8 additional highly polymorphic markers, bringing the total number studied to 13. Only one, identified in the haplotype of NCoA-1, had a transmission pattern suggesting nonpaternity in the proposita (II-6). In simulation studies in which a half-sibling is generated in a pedigree of five full siblings, more than 20% of replicates had none or only 1 incompatibility. This proportion increased as the marker was assumed to be less informative. Thus, we have little power to determine whether the incompatible type at D20S423 in subject II-6 is due to nonpaternity or a mutation. This result has little effect on the overall interpretation of data. Indeed, assuming nonpaternity, linkage of a dominantly inherited phenotype to NCoR, SMRT, and NCoA-3 can still be excluded based on the haplotype of her 2 unaffected children alone, as indicated above. A recombinant allele in subject II-5 for the 2 NCoA-3 markers, located 6.1 cM apart, is not unusual.
The haplotypes of markers for RXR cannot be deduced unequivocally.
One parental allele inherited by the proposita depends on whether one
of her alleles inherited from the other parent was a recombinant (see
Fig. 3). In either event, linkage cannot be excluded. Unfortunately,
typing with marker ATA38A05 could not be accomplished.
Family Msn
Linkage of the RTH phenotype to all four cofactors and RXR was
excluded in this family, assuming a dominant mode of inheritance.
However, if the proposita had a neomutation, we cannot exclude NCoA-3
involvement, because she gave the same allele to all four of her
phenotypically normal children. If RTH in this family were recessively
inherited, the linkage data exclude NCoA-1 and RXR involvement, but
not NCoR or NCoA-3, because the unaffected siblings (II-3 and II-2) do
not share the same haplotype with the proposita. The results of linkage
analysis for SMRT were not informative for a recessive inheritance,
because both alleles of the father of the proposita (I-1) have an
identical haplotype, making it impossible to determine whether the
proposita shares the same haplotype with her unaffected sister,
II-3.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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)
in the expression of the RTH phenotype in eight subjects with no
mutations in the TRß gene. These subjects belong to four unrelated
families in which, in addition to TRß gene sequencing, linkage
analyses have excluded the involvement of the TRß gene in two (Msn
and Mch) and the TR gene in all four (15, 16). The phenotype of
these subjects was not different from that of individuals with RTH due
to TRß gene mutations (15, 16, 17, 18). The dominant inheritance in the majority of cases with RTH is due to interference of the mutant TRßs with the functions of the wild-type TRs. This DNE requires that the mutant TRs 1) bind to DNA at promoter sequences of target genes (34), 2) homodimerize (35) and heterodimerize with RXR (36), 3) interact with corepressors (22), and 4) recruit coactivators (14, 25).
Although in most instances the severity of RTH correlates with
the degree of T3 binding impairment of the mutant
TRß (37, 38), discrepancies appear to be due to a strong DNE caused
by abnormal interactions with DNA, coactivators, corepressors or RXR.
For example, the mutant TRß R243Q/W, located in the hinge region of
the receptor, binds T3 poorly when complexed to
DNA despite normal T3 binding in solution (21, 39). As a consequence, dissociation of NCoR and recruitment of NCoA are
markedly impaired. Yoh et al. (22) reported 11 TRß
mutations with impaired ability to dissociate from corepressors, 2 of
which (
430M and 432G), exhibited unusually strong interaction
with SMRT. Moreover, introduction of an amino acid substitution that
abolished corepressor association with TR greatly diminished the DNE of
the natural TRß mutants (22, 23). In other instances, impaired
interaction of mutant TRs with coactivators played a role in the
manifestation of DNE. Natural and artificial mutations in the AF2
region of TRß showed poor interaction with coactivators (NCoA-1 and
RIP140), despite normal or near-normal T3-binding
affinity (25). Nagaya et al. (36) demonstrated that an
artificial mutation in one of the hydrophobic heptad repeats of the
putative receptor dimerization domain (L428R) impaired
heterodimerization of TR and RXR. Furthermore, when L428R was
introduced in mutant TRßs causing RTH, the DNE of the TRß mutant
was eliminated. From these findings, it can be deduced that abnormal
corepressors that fail to dissociate from TRs, defective coactivators
that do not associate with TR upon T3 binding, or
abnormal RXR that heterodimerize with TRs but cannot initiate
trans-activation or have increased affinity for the
corepressors could cause dominantly inherited RTH in the absence of TR
defects.
Of the two families (Mma and Mal) with dominantly inherited RTH
reported herein, we were able to exclude in one (Mal), by sequencing
and linkage analysis, the involvement of all four cofactors and RXR.
In the other family (Mma), the role of NCoA-1 was excluded. Moreover,
85% of the SMRT cDNA-coding sequence was normal. However, the
possibility of RTH linkage to NCoR, NCoA-3, and RXR could be neither
excluded nor proven because of the limited number of family
members.
In two families the mode of inheritance could not be determined by
pedigree analysis, because only one subject of each family was
affected. Assuming autosomal dominant inheritance, the involvement of
all four cofactors could be excluded in both families, as well as
RXR in family Msn. However, if the proposita of family Msn had a
neomutation, the involvement of NCoA-3 cannot be excluded. If the
inheritance mode were recessive, only NCoA-1 can be excluded in both
families. We cannot exclude the involvement of NCoA-3 and RXR in
family Mch and that of NCoR, SMRT, and NCoA-3 in family Msn.
Although based on pedigree analysis and theoretical considerations, abnormal cofactors or RXRs are likely to cause dominantly inherited RTH, we cannot exclude recessive (compound heterozygous) inheritance in family Msn, given phenotypically normal, nonconsanguineous parents. However, it is equally possible that the occurrence of RTH in subjects with normal parents and siblings represents putative neomutation in a gene, with dominant manifestation. Together with family Mma and 2 other families we previously reported (15, 16), the occurrence of a neomutation in 4 of these 6 families is much higher than the 13% prevalence of the neomutation in RTH caused by TRß mutations (5, 40). Moreover, there appears to be a reduced penetrance of the RTH phenotype in these families, because only 5 of 22 children born to affected parents are affected. This reduced penetrance, possibly due to reduced survival of embryos, may in part be responsible for the apparently high rate of neomutations.
Given our failure to demonstrate putative defects in 5 proteins intimately involved in the expression of TR-mediated thyroid hormone action, what are the alternative possibilities? Recent studies have uncovered sets of 10–20 mammalian proteins that integrate the effects of transcriptional activators of the polymerase II machinery akin to the yeast mediator complex. These protein complexes (SMCC/TRAP, ARC, DRIP, and NAT), isolated by different approaches, are the same or very similar polypeptides (41). Although they interact with a number of nuclear receptors, some, such as TRAP220, interacts directly with TR (42). The constantly increasing number of molecules recognized to be involved in the thyroid hormone-mediated activation of gene transcription has enhanced the complexity of the candidate gene approach in identification of the cause of RTH in subjects without TR gene defects.
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Acknowledgments |
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Footnotes |
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2 P.M.S. and S.P. contributed equally and should both be considered
second authors.
3 Present address: Children’s Hospital, Johannes Gutenberg
University, D55101 Mainz, Germany.
4 Present address: Department of Endocrinology, Hospital de
Clínicas, Federal University, Paraná,
Brazil.
5 Throughout this communication, the use of the
term recessive applies to compound heterozygous.
Received March 8, 2000.
Revised June 27, 2000.
Accepted July 3, 2000.
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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
cofactor. J Clin Endocrinol Metab. 81:4196–4203.[Abstract]
-deficient mouse. J Clin Invest. 106:73–79.[Medline]
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