| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
CLINICAL CASE SEMINAR |
Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (L.M., C.V., D.C., S.C., G.V.), Faculté de Médecine, Université Libre de Bruxelles, B-1070 Bruxelles, Belgium; Service de Génétique Médicale (B.G.), Hôpital Jean Bernard, 86021 Poitiers, France; Service de Génétique Médicale (C.R., J.P., M.A., G.V.), Hôpital Erasme, B-1070 Bruxelles, Belgium; and Hôpital Universitaire Dupuytren (A.L.R.), CHU 87042 Limoges, France
Address all correspondence and requests for reprints to: Gilbert Vassart, IRIBHM, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, B-1070 Bruxelles, Belgium. E-mail: gvassart{at}ulb.ac.be.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
On the other hand, thyroid dysembryogeneses constitute a heterogenous collection of situations characterized by defects in the normal development of the gland. They are classically subdivided into ectopy (
80% of the cases), agenesis (20% of the cases), and hypoplasia (5% of the cases) of the gland (7). Contrary to hormonogenesis defects, thyroid dysembryogeneses present mainly as sporadic cases. Despite the recent report of minor thyroid abnormalities in first relatives of patients with thyroid dysgenesis (8), the observation that monozygotic twins are consistently discordant (9, 7) excludes a simple Mendelian or multigenic mode of transmission for the majority of the cases. In a minority of the cases, however, mutations have been identified in patients with various forms of thyroid dysgenesis, affecting genes known to be implicated in the normal embryonic development of the gland. These include TITF1 (also known as NKX2.1 or T/EBP) (10, 11), TTF2 (also known as TITF2, FOXE1, or FKHL15) (12, 13), and PAX8 (14, 15, 16); these three transcription factors are expressed very early during thyroid development, and the implication of this in thyroid embryogenesis has been demonstrated unambiguously in knockout mouse models (17, 18, 19).
Homozygous TTF2 mutations are found in the Bamforth syndrome (20), which is characterized by thyroid agenesis, cleft palate, choanal atresia, and kinky hairs (12, 13). TITF1 has recently been found mutated, in the heterozygous state, in patients with mild thyroid dysfunction and choreoathetosis (10, 11).
For PAX8, contrary to the situation prevailing in knockout mice in which only homozygotes are affected, loss of function mutation of a single allele in humans is enough to cause thyroid hypoplasia (14, 15, 16), albeit with variable penetrance and expressivity (16). PAX8 is a paired domain-containing protein belonging to the Pax family of transcription factors. In addition to its role in thyroid development, PAX8 has been shown to regulate the expression of TG, TPO, and the sodium-iodide symporter (21, 22, 23) by binding to their promoter regions through its 128-amino acid paired domain.
So far, five mutations of PAX8 have been described in cases of congenital hypothyroidism (two sporadic and three familial cases) (14, 15, 16). All of these mutations are located in the paired domain, and four of them have been shown to hinder the DNA-binding activity of PAX8. Of the three familial cases, two show an autosomal dominant transmission of the disease. In the third family, there was a profound discrepancy between two related individuals bearing the same heterozygous mutation (16). One individual had an overt phenotype of congenital hypothyroidism with thyroid hypoplasia, whereas the other did not present any sign of hypothyroidism until early adulthood when mild hypothyroidism was diagnosed, with signs of autoimmunity (16).
In the present study, we report a novel loss of function mutation of the PAX8 gene in a family presenting with congenital hypothyroidism, which substitutes a highly conserved serine of the paired domain in position 54 for a glycine (S54G).
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Patient II-1 (Fig. 1
), a male subject, was born in 1994 by caesarean section at 38 wk after an uneventful pregnancy. Caesarean section was performed for narrow pelvis. Birth weight was 3500 g; length was 50 cm; Apgar score was 10; and cranial circumference was 36 cm. The patient was diagnosed as hypothyroid in the frame of the neonatal screening program for congenital hypothyroidism. Initial TSH value obtained from the dried blood spot at d 5 was 131 µU/ml (upper limit, 25 µU/ml). Control values at d 7 were as follows: TSH, 336 µU/ml (normal values, 0.2–4 µU/ml); free T4, 5.7 pg/ml (normal values, 7–18 pg/ml) (7.3 pmol/liter; normal values, 9–23 pmol/liter); and TG, 57 ng/ml (normal values, 0–30 ng/ml). Thyroid 123I scintigraphy performed at d 8 before treatment was started showed a gland in normal position and of normal shape but with overall weak fixation. A diagnosis of dyshormonogenesis was tentatively made, and substitution therapy was started. The patient showed normal physical development; he is currently following regular schooling but is 1 yr behind. At 9 yr, under replacement therapy of 150 µg/d L-T4, he was 144 + 2 SD and weighed 46 kg. His free T4, free T3, and TSH values were 13.8 pg/ml (normal values, 7–16.3 pg/ml) (17.7 pmol/liter; normal values, 9–21 pmol/liter), 5.33 pg/ml (normal values, 2.3–4.2 pg/ml) (8.19 pmol/liter; normal values, 3–5.4 pmol/liter), and 9.31 µU/ml (normal values, 0.15–5 µU/ml), respectively. At 11.5 yr of age, the volume of his thyroid gland was 0.18 ml (normal values for this age, 2–3.3 ml) as measured by ultrasonography. Urinary calcium was also measured at this age and showed a calcium to creatinine ratio of 0.39 (normal values, 0.06–0.73).
|
Patient II-2, sister of patient II-1 (Fig. 1
) was born by caesarean section in 1999 after an uneventful pregnancy (weight at birth, 3590 g; length, 48 cm; cranial circumference, 36 cm; and Apgar score, 10). She was diagnosed with congenital hypothyroidism on the neonatal screening program (TSH spot test, 100.9 µU/ml). Confirmation was obtained at 7 d of age [TSH, 70.6 µU/ml; free T4, 14.2 pg/ml (18.2 pmol/liter)]. Thyroid echography at birth revealed an in-place thyroid. 123I scintigraphy, performed before substitution therapy was initiated, confirmed the presence of in-place thyroid tissue of normal size. Iodide trapping was 13.9% at 3 h and 24.7% at 24 h. A perchlorate discharge test was performed and considered positive (21.5 and 20.4% decrease at 30 and 150 min, respectively). Under substitution therapy (55 µg/d L-T4), she developed normally. At 3.5 yr, she was 96 cm and weighed 14,100 g. Intellectual development was normal despite relational problems. Her latest plasma TSH, free T3, and free T4 values were 50.46 µU/ml, 4.06 pg/ml (normal values, 2.3–4.2 pg/ml) (6.24 pmol/liter; normal values, 3–5.4 pmol/liter), and 13.3 pg/ml (normal values, 7–16.3 pg/ml) (17.1 pmol/liter; normal values, 9–21 pmol/liter), respectively. Renal echography showed two normal kidneys. Her thyroid gland had a volume of 0.34 ml (normal values for age 3.5 yr, 0.6–1.4 ml) as measured by ultrasonography. Urinary calcium was also measured and showed a calcium to creatinine ratio of 0.42, with normal values between 0.06 and 0.73.
Patient I-2, the mother of patients II-1 and II-2, does not show any thyroid problem. There is no consanguineous relationship with patient I-1. She is 150 cm in height and weighs 45 kg. In 1998, her plasma TSH was 1.15 µU/ml (normal values, 0.2–4 µU/ml), and her free T4 was 15 pg/ml (normal values, 8.5–18.5 pg/ml) (19.3 pmol/liter; normal values, 11–24 pmol/liter). A first pregnancy, after in vitro fertilization performed for oligospermia, ended by spontaneous abortion at 25 wk. Thereafter, patients II-1 and II-2 were born from spontaneous pregnancy and in vitro fertilization, respectively. Both deliveries were by caesarean section because of fetal disproportion.
Informed consent was obtained from the subjects, and all studies abided the standards of our institutional ethical committees.
Direct sequencing
DNA was extracted from peripheral blood sampled on EDTA by standard methods. Part of the promoter region of PAX8 along with exons 3, 6, 7, and 8 were subjected to direct sequencing in patient II-1. Specific primers were used to amplify these regions, as previously described (14, 15). For the promoter, PCR was performed in the PE 2400 equipment (PE Applied Biosystems, Foster City, CA) in 20 µl with 200 ng genomic DNA and 1U Amplitaq Gold (PE Applied Biosystems) in 1x buffer II supplemented with 1 mM MgCl2, 200 µM deoxynucleotide triphosphate, and 2 pmol of the primers. The following conditions were used: initial denaturation at 95 C for 12 min, then 30 cycles at 95 C for 1 min, 52 C for 1 min, and 72 C for 1 min. For exons 3, 6, 7, and 8, PCR was performed in 20 µl of 1 U Taq DNA polymerase (Life Technologies, Inc., Merelbeke, Belgium) with 200 ng genomic DNA, supplemented with 200 µM deoxynucleotide triphosphate, 3 pmol of the primers, with MgCl2 concentrations varying from 1–2 mM, and 0–10% dimethylsulfoxide in the PE 2400 equipment. The PCR conditions were as described earlier, except for the annealing temperature, which was as described previously (14). PCR products were purified with the Qiaquick PCR purification kit (QIAGEN, Westburg, The Netherlands) and sequenced using the ABI PRISM Dye Terminator cycle sequencing Ready Reaction kit (PE Applied Biosystems). After identification of the mutation in patient II-1, direct sequencing of exon 3 was performed on DNA from patients I-1 and II-2.
Plasmids
Human PAX8a cDNA was amplified from Human Thyroid Gland Marathon-Ready cDNA library (Clontech Laboratories, Inc., Palo Alto, CA) using 5'-ATATGGTACCATGCCGCACAACTCCATC-3' and 5'-ATATCTAGACTACAGATGGTCAAAGGC-3' primers. The PCR product was cloned in pCDNA3 using the KpnI and XbaI restriction sites introduced in the primers to obtain PAX8WT-pCDNA3. The S54G mutant was obtained by direct mutagenesis using 5'-ACATCTCTCGCCAGCTCCGCGTCGGCCATGGCTGCG-3' and 5'-ACGCGGAGCTGGCGAGAGATGTCGCAGGGCCTTACACCC-3' primers, as described previously (24). The PCR product was digested with DpnI (New England Biolabs, Inc., Beverly, MA) to eliminate template Dam-methylated DNA, whereas the PCR-synthesized (unmethylated) molecules remained intact. The entire PAX8-S54G cDNA was sequenced and subcloned in a new pCDNA3 vector to avoid interfering with PCR-generated mutations.
The murine Titf1 gene was obtained by restriction from a bacterial artificial chromosome clone containing the genomic region spanning its locus. It was then subcloned in the pCDNA3 vector using the NotI and EcoRI restriction sites flanking the gene.
Protein production and Western blot analysis
Wild-type and mutated PAX8 cDNA constructs were transcribed and translated using the TnT Quick Coupled Transcription/Translation System from Promega Corporation (Madison, WI). A separate transcription/translation reaction was performed without plasmid DNA as a control for nonspecific binding in the EMSA (see Fig. 4). Five microliters of transcription/translation products were mixed with 20 µl of Laemmli buffer and boiled for 2 min. Two and 5 µl of each sample were loaded on a 10% SDS-PAGE. Western blotting of immunoreactive PAX8 was performed as previously described (15).
|
EMSAs were performed to assess whether the human PAX8-S54G mutant was still able to bind one of its target DNA sequences. Synthetic oligonucleotide CT was produced by annealing 5'-TGATGCCCACTCAAGCTTAGACAG-3' and 5'-CTGTCTAAGCTTGAGTGGGCATC3' primers and labeling with 32P-deoxy-ATP (20 pmol for 100 ng of oligonucleotide CT) 25 min at 4 C using Klenow large-fragment DNA polymerase. Two microliters of the transcription/translation products were incubated 30 min at room temperature in a binding buffer composed of 20 mM Tris-Cl (pH 7.5), 10% glycerol, 1 mM dithiothreitol, 25 mM KCl, 1.25 mM BSA, and 0.5 µg/ml salmon sperm DNA and with approximately 5000 cpm of the radiolabeled probe in a final volume of 20 µl. The reaction mixtures were then analyzed by PAGE at 8 C using a 10% polyacrylamide gel in a 0.5x Tris borate buffer (45 mM Tris borate and 1 mM EDTA). The gels were exposed to Super RX film from Fuji Photo Film USA, Inc. (Edison, NJ).
Functional assay
The promoter/enhancer of the TG gene was cloned in pSEAP2basic (BD Biosciences, Palo Alto, CA) using KpnI and XhoI restriction sites to obtain a vector encoding a secreted thermoresistant form of alkaline phosphatase (SEAP) under the control of the TG promoter (hTGprom-SEAP). Because a synergism in the activity can be observed between PAX8 and TITF1 (25), we cotransfected HeLa cells with pCDNA3 vectors containing wild-type or mutant PAX8 and Titf1 cDNA, along with the reporter vector, using Metafectene (Biontex Laboratories GmbH, Munich, Germany) following the manufacturer’s instructions.
HeLa cells were grown in DMEM (Life Technologies, Inc.) supplemented with 10% fetal bovine serum. Cells were plated in 30-mm diameter culture dishes at 3 x 105 cells per dish 24 h before transfection. They were tranfected with 1 µg of hTGprom-SEAP, 100 ng of TitF1 in pCDNA3, and 100 ng of wild-type PAX8 (PAX8WT) or PAX8-S54G in pCDNA3 and the amount of total DNA was adjusted to 2 µg with empty vector. The medium was changed 6 h after transfection, and the SEAP activity of 15 µl of culture medium was assayed using the Great EscAPe SEAP Detection Kit (BD Biosciences) 48 h after transfection, following the manufacturer’s instructions.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
). I-1, the father, who was born before implementation of the neonatal screening program, was diagnosed when he was 3 yr old. In addition to hypothyroidism, he has agenesis of the right kidney and displays tubular hypercalciuria. Both his son and daughter were found to be hypothyroid upon neonatal screening and were tentatively diagnosed with congenital dyshormonogenesis on the basis of normal-sized glands (for both of them) and suggestive perchlorate discharge test (for patient II-2). Despite this, the apparent autosomal dominant transmission of the disease prompted investigation of the PAX8 gene.
The three patients were shown to carry an A to G transition, in the heterozygous state, in exon 3 of the PAX8 gene (Fig. 2). This results in the substitution of a highly conserved serine (codon AGC) at position 54 of the protein by a glycine (codon GGC, PAX8-S54G mutant).
|
). Both proteins were produced in equivalent amounts, indicating that the amino acid substitution does not cause destabilization of mutant PAX8, at least in vitro. As shown on Fig. 4, in vitro-produced PAX8WT bound readily to the probe (Fig. 4A, lanes 11–15). Binding was specifically competed for by excess of cold probe (Fig. 4B, lane 15) but not with increasing amounts of salmon sperm DNA (up to 100 µg/ml vs. 30 ng/ml of probe; Fig. 4A, lanes 11–15). Despite being added in the same concentration as the wild type, no shift in electrophoretic mobility of the probe could be observed using PAX8-S54G.
|
). This synergism was highly diminished when Titf1 was cotransfected with the mutant PAX8-S54G.
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
). Serine 54 is the homolog of serine 46 in the crystal structure of the PAX6 paired domain, located between the second and the third 
-helixes of the amino-terminal homeodomain-like motif. This particular residue participates in a Van der Waals interaction with a thymidine of base pair 7 of the recognition site and makes contact with the backbone of the DNA molecule through a hydrogen bond (26). A study of the structural properties of the PAX6 equivalent of another PAX8 mutant (L62R) showed that the modified paired domain fails to undergo the so-called induced fit in the presence of a specific DNA molecule, which allows the transcription factor to interact properly with its target (27). These findings provide a convincing molecular basis to the observed loss of DNA-binding activity of the PAX8-S54G mutant. The present observation adds to the notion that heterozygous loss of function mutations of PAX8 are responsible for congenital hypothyroidism of varying degrees of intensity (16). In addition, it indicates that PAX8 mutations may lead to confusion between dyshormonogenesis and dysgenesis. The propositus (patient II-1) may be considered as a typical case of congenital hypothyroidism with persistently elevated TSH levels and low free T4. The presence at birth of a normally located thyroid gland with decreased iodide trapping, at scintigraphy, initially suggested the diagnosis of dyshormonogenesis. Dyshormonogenesis was also the initial diagnosis made for patient II-2, the sister of the propositus. It was based on the scintigraphy and on a perchlorate discharge test interpreted as positive. The father of the propositus seemed to have a milder form of the disease. Although TSH and free T4 values and scintigraphy at birth are not available for him, the fact that delaying diagnosis and treatment until 3 yr of age did not result in severe mental retardation suggests that he was not profoundly hypothyroid in infancy. It is likely that during the first 3 yr of life, his thyroid gland underwent involution or, at least, did not follow a normal development, which would account for his becoming overtly hypothyroid. This hypothesis is supported by the evolution of thyroid sizes in patients II-1 and II-2, which range from normal at birth to hypoplastic in later years.
Up to now, loss of function mutations of the PAX8 gene were considered mainly to cause thyroid hypoplasia, with one description of cystic rudiments (14, 15, 16). The autosomal dominant transmission is well established, with variability in expressivity accounting for the observed dispersion for the onset of hypothyroidism (7, 28). The present cases indicate that some PAX8 mutations may be compatible with close to normal morphological development of the gland, but with impaired function suggestive of defective iodide organification and the inability to grow normally postnatally. It has been amply demonstrated that, in addition to their role in thyroid development, PAX8, TITF1, and TTF2 are implicated in the transcriptional control of several thyroid-specific genes (29, 30). Among these, TPO has been shown to be particularly dependent on PAX8 for efficient transcription (23). It may thus be hypothesized that, under condition of strong stimulation by TSH, some defective PAX8 alleles, like the present S54G mutant, would still be compatible with the development of a gland of normal location and size. Congenital hypothyroidism, in these cases, would be secondary to impaired TPO gene expression leading to defective iodide organification. The disease would thus correspond to a mixed situation, with some characteristics of thyroid dysgenesis (the inability to grow a goiter under strong stimulation by TSH) and others typical of dyshormonogenesis (partial organification defect). As such, it is reminiscent of the phenotype displayed by mice homozygous for null mutations of the TSH receptor, which display normal embryonic development of the gland but impaired growth and differentiation of their thyroid after birth (31). These two situations differentiate clearly from ectopy, in which thyroid rudiments incapable of growing adequately even under strong TSH stimulation do display increased uptake. Interestingly, transient organification defect has also been described in some of these cases (32).
The renal phenotype displayed by patient I-1, characterized by unilateral kidney agenesis and hypercalciuria, deserves special mention. In addition to thyroid, PAX8 is strongly expressed in the kidney during development, together with PAX2. Whereas homozygous Pax8–/– knockout mice show no kidney abnormality, cooperation between Pax8 and Pax2 for normal kidney development has recently been demonstrated from experiments with double knockout mice (33). Pax2+/– Pax8–/– mice fail completely to develop a metanephros, whereas Pax2+/– Pax8+/+ or Pax2+/– Pax8+/– mice display only 40 or 75% reduction in metanephros development, respectively (33). Although there is no evidence for the implication of PAX8 or PAX2 in hypercalciuria, one case of unilateral kidney agenesis associated with PAX8 mutation has been reported (34) but never published. Isolated unilateral kidney agenesis (or aplasia) (35) occurs with a frequency of 1 in 1300 newborns. It is difficult, although tempting, to relate the renal phenotype of the patient with his PAX8 gene mutation. Monoallelic expression of either the normal or the mutant allele may vary between individuals and between tissues (36, 37). This might explain both the variable expressivity displayed by heterozygous PAX8 mutations in man and the sporadic association of unilateral kidney agenesis. Besides, in the absence of data concerning the whole panel of developmental and differentiation-specific genes under the control of PAX8, we can only suggest that some PAX8 mutants might differentially affect transcription of the two categories of genes in relation with differences in their precise target DNA sequences.
|
Footnotes |
|---|
L.M. and B.G. contributed equally to this work.
Abbreviations: PAX8WT, Wild-type PAX8; SEAP, secreted thermoresistant form of alkaline phosphatase; TG, thyroglobulin; TPO, thyroperoxidase.
Received February 2, 2004.
Accepted June 3, 2004.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  A. Carre, G. Szinnai, M. Castanet, S. Sura-Trueba, E. Tron, I. Broutin-L'Hermite, P. Barat, C. Goizet, D. Lacombe, M.-L. Moutard, et al. Five new TTF1/NKX2.1 mutations in brain-lung-thyroid syndrome: rescue by PAX8 synergism in one case Hum. Mol. Genet., June 15, 2009; 18(12): 2266 - 2276. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hashemipour, S. Hovsepian, R. Kelishadi, R. Iranpour, R. Hadian, S. Haghighi, A. Gharapetian, M. Talaei, and M. Amini Permanent and transient congenital hypothyroidism in Isfahan-Iran J Med Screen, March 1, 2009; 16(1): 11 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Codutti, H. van Ingen, C. Vascotto, F. Fogolari, A. Corazza, G. Tell, F. Quadrifoglio, P. Viglino, R. Boelens, and G. Esposito The Solution Structure of DNA-free Pax-8 Paired Box Domain Accounts for Redox Regulation of Transcriptional Activity in the Pax Protein Family J. Biol. Chem., November 28, 2008; 283(48): 33321 - 33328. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Deladoey, N. Pfarr, J.-M. Vuissoz, J. Parma, G. Vassart, S. Biesterfeld, J. Pohlenz, and G. Van Vliet Pseudodominant Inheritance of Goitrous Congenital Hypothyroidism Caused by TPO Mutations: Molecular and in Silico Studies J. Clin. Endocrinol. Metab., February 1, 2008; 93(2): 627 - 633. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Al Taji, H. Biebermann, Z. Limanova, O. Hnikova, J. Zikmund, C. Dame, A. Gruters, J. Lebl, and H. Krude Screening for mutations in transcription factors in a Czech cohort of 170 patients with congenital and early-onset hypothyroidism: identification of a novel PAX8 mutation in dominantly inherited early-onset non-autoimmune hypothyroidism Eur. J. Endocrinol., May 1, 2007; 156(5): 521 - 529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Mittag, E. Winterhager, K. Bauer, and R. Grummer Congenital Hypothyroid Female Pax8-Deficient Mice Are Infertile Despite Thyroid Hormone Replacement Therapy Endocrinology, February 1, 2007; 148(2): 719 - 725. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Varela, C. M. Rivolta, S. A. Esperante, L. Gruneiro-Papendieck, A. Chiesa, and H. M. Targovnik Three Mutations (p.Q36H, p.G418fsX482, and g.IVS19-2A>C) in the Dual Oxidase 2 Gene Responsible for Congenital Goiter and Iodide Organification Defect Clin. Chem., February 1, 2006; 52(2): 182 - 191. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Medda, A. Olivieri, M. A. Stazi, M. E Grandolfo, C. Fazzini, M. Baserga, M. Burroni, E. Cacciari, F. Calaciura, A. Cassio, et al. Risk factors for congenital hypothyroidism: results of a population case-control study (1997-2003) Eur. J. Endocrinol., December 1, 2005; 153(6): 765 - 773. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Vassart and J. E. Dumont Thyroid Dysgenesis: Multigenic or Epigenetic ... or Both? Endocrinology, December 1, 2005; 146(12): 5035 - 5037. [Full Text] [PDF]
|
|
|
|
|
|
E. Amendola, P. De Luca, P. E. Macchia, D. Terracciano, A. Rosica, G. Chiappetta, S. Kimura, A. Mansouri, A. Affuso, C. Arra, et al. A Mouse Model Demonstrates a Multigenic Origin of Congenital Hypothyroidism Endocrinology, December 1, 2005; 146(12): 5038 - 5047. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Grasberger, U. Ringkananont, P. LeFrancois, M. Abramowicz, G. Vassart, and S. Refetoff Thyroid Transcription Factor 1 Rescues PAX8/p300 Synergism Impaired by a Natural PAX8 Paired Domain Mutation with Dominant Negative Activity Mol. Endocrinol., July 1, 2005; 19(7): 1779 - 1791. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S M Park and V K K Chatterjee Genetics of congenital hypothyroidism J. Med. Genet., May 1, 2005; 42(5): 379 - 389. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
