Biomedical subjects

S Costagliola

Publications and source records attributed to S Costagliola.

At least 19 recordsLinked to original sources

PubMed2005

Presence and absence of follicle-stimulating hormone receptor mutations provide some insights into spontaneous ovarian hyperstimulation syndrome physiopathology.

CONTEXT: Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening complication of ovarian stimulation treatments. Moreover, four mutations of the FSH receptor (FSHr) were recently described in patients presenting with spontaneous OHSS (sOHSS) of the first trimester of pregnancy with normal levels of human chorionic gonadotropin (hCG). OBJECTIVE: The objective of this study was to look for novel FSHr mutations in patients with sOHSS associated with different levels of hCG and TSH to 1) find new residues important for FSHr activation and specificity, and 2) better delineate the pathophysiology of the different presentations of sOHSS. DESIGN, INTERVENTION, AND PATIENTS: After blood sampling, we sequenced the FSHr from genomic leukocytes DNA from eight patients with sOHSS of the first or second trimester of pregnancy with normal or high hCG levels or with high TSH levels associated with severe hypothyroidism. SETTING: This study was performed at a university laboratory. MAIN OUTCOME MEASURE: The main outcome measure was FSHr sequencing and in vitro evaluation of the variation of cAMP production of FSHr mutants. RESULTS: A new mutation was found in the patient with sOHSS of the first trimester of pregnancy with a normal hCG level: I5.54(545)T, in transmembrane helix V of the FSHr. When tested functionally, this mutant displayed promiscuous activation by both hCG and TSH together with detectable constitutive activity. In contrast, no mutations were found in the FSHr from patients with high hCG or TSH levels, indicating that for those seven patients, sOHSS results from the natural promiscuous stimulation of a wild-type FSHr by very high concentrations of hCG or TSH. CONCLUSIONS: sOHSS can occur by at least three different pathophysiological mechanisms.

Adult↗

PubMed2005

Quantification of cells expressing the thyrotropin receptor in extraocular muscles in thyroid associated orbitopathy.

BACKGROUND/AIM: Thyroid associated orbitopathy (TAO) and Graves' disease (GD) have an autoimmune pathogenesis, possibly related to the thyrotropin receptor (TSHR). The aim of this study was to determine whether TSHR immunoreactivity is correlated with disease severity or serum TSHR antibody (TRAB) levels. METHODS: Orbital tissues from 30 patients with TAO were compared with those of 20 patients with strabismus and four with non-thyroid orbital inflammation. TSHR was detected by immunohistochemistry and TRAB were measured by radioreceptor assay. RESULTS: No TSHR immunoreactivity was detected in the 24 control orbital tissues, whereas in all TAO biopsies elongated fibroblast-like cells, expressing TSHR, were present. These cells were located between the muscle cells, which were separated by oedema in the acute phase but fibrous tissue in the chronic phase of disease. Semi-thin sections showed numerous mast cells present in the chronic phase and in close contact with adipocytes. The number of TSHR immunostained cells was high in early disease, decreased with disease duration, and was positively correlated with TRAB levels at the onset of TAO. CONCLUSION: TSHR immunoreactivity was demonstrated specifically in TAO orbits which highlights the importance of TRAB early in the pathogenesis.

Adult↗

PubMed2004

New insights into the pathophysiology of ovarian hyperstimulation syndrome. What makes the difference between spontaneous and iatrogenic syndrome?

The recent identification of mutations in the FSH receptor gene, which display an increased sensitivity to hCG and are responsible for the development of spontaneous ovarian hyperstimulation syndrome (OHSS), provides for the first time the molecular basis for the physiopathology of spontaneous OHSS. Based on these recent findings, this paper underlines the differences between spontaneous and iatrogenic OHSS and proposes a model to account for the different chronology between the two forms of the syndrome. In the iatrogenic form, the follicular recruitment and enlargement occur during ovarian stimulation with exogenous FSH, while in the spontaneous form, the follicular recruitment occurs later through the stimulation of the FSH receptor by pregnancy-derived hCG. In both forms, massive luteinization of enlarged stimulated ovaries ensues, inducing the release of vasoactive mediators, leading to the development of the symptoms of OHSS.

Female↗

PubMed2004

[Structure-function relations of glycoprotein hormone receptors and their medical applications].

The Thyrotropin receptor (TSHr), like the other members of glycoprotein hormone receptors (GPHR) family (LH/CG and FSH receptors), presents a bipartite structure, with a carboxyl-terminal serpentine region implicated in the transmission of the signal activation and a large extracellular domain (ECD) responsible of the hormone binding with a high affinity. This asks the question of the mechanism implicated in the intra-molecular transduction of the activating signal. The GPHR can be activated by a large diversity of mutations affecting also the ectodomain. Moreover, the TSH receptor can also be activated by autoantibodies from patients with Graves' disease, responsible for hyperthyroidism. The mechanisms implicated into the stimulation by the hormone binding, "gain of function" mutations or by autoantibody from patients with Graves' disease remain unknown. Our study is mainly focusing on the knowledge of these mechanisms of activation.

Animals↗

PubMed2003

Sphingolipid-cholesterol domains (lipid rafts) in normal human and dog thyroid follicular cells are not involved in thyrotropin receptor signaling.

Partition of signaling molecules in sphingolipid-cholesterol-enriched membrane domains, among which are the caveolae, may contribute to signal transduction efficiency. In normal thyroid, nothing is known about a putative TSH/cAMP cascade compartmentation in caveolae or other sphingolipid-cholesterol-enriched membrane domains. In this study we show for the first time that caveolae are present in the apical membrane of dog and human thyrocytes: caveolin-1 mRNA presence is demonstrated by Northern blotting in primary cultures and that of the caveolin-1 protein by immunohistochemistry performed on human thyroid tissue. The TSH receptor located in the basal membrane can therefore not be located in caveolae. We demonstrate for the first time by biochemical methods the existence of sphingolipid-cholesterol-enriched domains in human and dog thyroid follicular cells that contain caveolin, flotillin-2, and the insulin receptor. We assessed a possible sphingolipid-cholesterol-enriched domains compartmentation of the TSH receptor and the alpha- subunit of the heterotrimeric G(s) and G(q) proteins using two approaches: Western blotting on detergent-resistant membranes isolated from thyrocytes in primary cultures and the influence of 10 mm methyl-beta-cyclodextrin, a cholesterol chelator, on basal and stimulated cAMP accumulation in intact thyrocytes. The results from both types of experiments strongly suggest that the TSH/cAMP cascade in thyroid cells is not associated with sphingolipid-cholesterol-enriched membrane domains.

Animals↗

PubMed2003

Anion selectivity by the sodium iodide symporter.

The iodide transporter of the thyroid (NIS) has been cloned by the group of Carrasco. The NIS-mediated transport was studied by electrophysiological methods in NIS-expressing Xenopus oocytes. Using this method, the anion selectivity of NIS was different from that previously reported for thyroid cells, whereas perchlorate and perrhenate were found not transported. In this study we compared the properties of human NIS, stably transfected in COS-7 cells to those of the transport in a thyroid cell line, the FRTL5 cells, by measuring the transport directly. We measured the uptake of (125)I(-), (186)ReO(4)(-), and (99m)TcO(4)(-) and studied the effect on it of known competing anions, i.e. ClO(4)(-), SCN(-), ClO(3)(-), ReO(4)(-), and Br(-). We conclude that the properties of the NIS transporter account by themselves for the properties of the thyroid iodide transporter as described previously in thyroid slices. The order of affinity was: ClO(4)(-) > ReO(4)(-) > I(-) >/= SCN(-) > ClO(3)(-) > Br(-). NIS is also inhibited by dysidenin (as in dog thyroid).

Animals↗

PubMed2003

Correlation between the loss of thyroglobulin iodination and the expression of thyroid-specific proteins involved in iodine metabolism in thyroid carcinomas.

Progress in biotechnology has provided useful tools for tracing proteins involved in thyroid hormone synthesis in vivo. Mono- or polyclonal antibodies are now available to detect on histological sections the Na(+)/I(-) symporter (NIS) at the basolateral pole of the cell, the putative iodide channel (pendrin) at the apical plasma membrane, thyroperoxidase (TPO), and members of the NADPH-oxidase family, thyroid oxidase 1 and 2 (ThOXs), part of the H(2)O(2)-generating system. The aim of this study was to correlate thyroglobulin (Tg) iodination with the presence of these proteins. Tg, T(4)-containing Tg, NIS, pendrin, TPO, ThOXs, and TSH receptor (TSHr) were detected by immunohistochemistry on tissue sections of normal thyroids and various benign and malignant thyroid disorders. Tg was present in all cases. T(4)-containing Tg was found in the adenomas, except in Hurthle cell adenomas. It was never detected in carcinomas. NIS was reduced in all types of carcinomas, whereas it was detected in noncancerous tissues. Pendrin was not expressed in carcinomas, except in follicular carcinomas, where weak staining persisted. TPO expression was present in insular, follicular carcinomas and in follicular variants of papillary carcinomas, but in a reduced percentage of cells. It was below the level of detection in papillary carcinomas. The H(2)O(2)-generating system, ThOXs, was found in all carcinomas and was even increased in papillary carcinomas. Its staining was apical in normal thyroids, whereas it was cytoplasmic in carcinomas. The TSHr was expressed in all cases, but the intensity of the staining was decreased in insular carcinomas. In conclusion, our work shows that all types of carcinomas lose the capacity to synthesize T(4)-rich, iodinated Tg. In follicular carcinomas, this might be due to a defect in iodide transport at the basolateral pole of the cell. In papillary carcinomas, this defect seems to be coupled to an altered apical transport of iodide and probably TPO activity. The TSHr persists in virtually all cases.

Biomarkers↗

PubMed2003

Kinetics of thyrotropin-stimulating hormone (TSH) and thyroid-stimulating antibody binding and action on the TSH receptor in intact TSH receptor-expressing CHO cells.

The kinetics of TSH binding and the effects of TSH and thyroid-stimulating antibody (TSAb) on cAMP accumulation have been measured in TSH receptor-expressing CHO cells (CHO-TSHR cells). The parallel kinetics of TSH binding to its receptor and of cell cAMP concentration after the addition and withdrawal of TSH show that in the case of this receptor, signal generation and concentration are at all times proportional to occupancy. In physiological ionic medium, TSAb, but not TSH, action is slowed and in some cases almost nonexistent. The kinetics of cAMP disappearance after washout of TSAb is also slower. cAMP accumulation is faster for Fabs than for the TSAb from which they derive. Analysis of the data suggest that 1) serum TSAb are oligoclonal antibodies sets, at low concentrations, with a high affinity for the TSH receptor; 2) ionic interactions are involved in the action of TSAb on the TSH receptor; and 3) TSAb activation of the TSH receptor is at least a two-step process. Among others, a possible explanation is that the full activation of the receptor requires the binding of two or more different antibody molecules on different sites of the same TSH receptor. This analysis provides a benchmark for studies of experimentally induced monoclonal antibodies activating the TSH receptor.

Animals↗

PubMed2003

Activating mutations of TSH receptor.

Mechanisms of activation of G protein-coupled receptor by the agonist, are supposed to rely on release from structural constraints, then allowing the "relaxed" receptor to activate the G protein. By analogy with experimental works on alpha1b adrenergic receptor, showing that mutations could result in constitutive activation of the receptor, it was hypothezised, that similar but spontaneous somatic mutations of the Thyrotropin-receptor could be the cause of thyroid toxic adenomas. This hypothesis has been confirmed. Furthermore, the rare cases of familial non autoimmune hyperthyroidism have been shown to be caused by germline mutations of Thyrotropin receptor, as well as the cases of non autoimmune neonatal hyperthyroidism. Beside the constitutive activation of the Thyrotropin-receptor a case of sensitization of the Thyrotropin-receptor to hCG by a mutation in the extracellular domain has been identified as the cause of familial gestational hyperthyroidism. All those mutation studies have been helpful in understanding the mechanisms of activation of glycoproteic hormones. A first model had been proposed, according to datas obtained from these mutations. In this model, the extracellular domain of the receptor exerts an inhibitory action on the transmembrane domain, and this interaction has to be disrupted to allow for activation of the receptor. However, recent experimental datas suggest that interaction between extracellular domain and transmembrane domain are more complex than just inhibitory, and that upon activation, the extracellular domain may convert from an inhibitory structure to an activating one.

Adenoma↗

PubMed2002

Generation of a mouse monoclonal TSH receptor antibody with stimulating activity.

A Balb/c mouse was subjected to genetic immunization with a cDNA construct encoding the human thyrotropin receptor (TSHr). The immune response of the mouse resulted in the production of immunoglobulins recognizing the TSHr in three different assays: (1) flow immunocytometry (FACS) with CHO cells expressing the receptor; (2) receptor-dependent stimulation of cAMP production in the same cell line; and (3) competition with labeled TSH for binding to the receptor. One thousand hybridomas were generated from the spleen of the mouse and their supernatants were screened. A single monoclonal, IRI-SAb1, scored positive in all three assays and was studied further. It stimulated 13-fold cAMP production in TSHr-expressing CHO cells, with an EC50 in the low nanomolar range. When compared with bovine TSH, IRI-SAb1 behaved as a partial agonist. Contrary to the expectation from the characteristic of autoantibodies of Graves' patients, IRI-SAb1 recognized a linear epitope, which was localized in a segment encompassing the first 281 residues of the receptor.

Animals↗

PubMed2002

Tyrosine sulfation is required for agonist recognition by glycoprotein hormone receptors.

The glycoprotein hormone receptors (thyrotrophin receptor, TSHr; luteinizing hormone/chorionic gonadotrophin receptor, LH/CGr; follicle-stimulating hormone receptor, FSHr) constitute a subfamily of rhodopsin-like G protein-coupled receptors (GPCRs) with a long N-terminal extracellular extension responsible for high-affinity hormone binding. These ectodomains contain two cysteine clusters flanking nine leucine-rich repeats (LRR), a motif found in several protein families involved in protein-protein interactions. Similar to the situation described recently in CCR5, we demonstrate here that the TSHr, as it is present at the cell surface, is sulfated on tyrosines in a motif located downstream of the C-terminal cysteine cluster. Sulfation of one of the two tyrosines in the motif is mandatory for high-affinity binding of TSH and activation of the receptor. Site-directed mutagenesis experiments indicate that the motif, which is conserved in all members of the glycoprotein hormone receptor family, seems to play a similar role in the LH/CG and FSH receptors.

Amino Acid Sequence↗

PubMed2002

Structural changes in the angiofollicular units between active and hypofunctioning follicles align with differences in the epithelial expression of newly discovered proteins involved in iodine transport and organification.

In animals, as well as in humans, the thyroid gland is made of active follicles, with cuboidal cells and hypofunctioning follicles, with flattened cells. In this study, the functional status of human follicles was dissected out, based on immunohistochemical detection of TSH receptor, Na(+)/I(-) symporter, pendrin, thyroperoxidase (TPO), thyroid oxidases (ThOXs), and T(4)-containing iodinated Tg (Tg-I). To ascertain that angiofollicular units exist in the human, we studied the microvascular bed of each follicle, in correlation with detection of vascular endothelial growth factor (VEGF), of nitric oxide synthase III, and of endothelin in normal and goitrous thyroids. In hypofunctioning follicles, pendrin, TPO, and ThOXs were not detected, and there was no Tg-I in the colloid. At the opposite, in active follicles, pendrin, TPO, and ThOXs were detected in thyrocytes, and Tg-I was present in the colloid. In normal and goitrous thyroids, the capillary networks surrounding active follicles were larger than those surrounding hypofunctioning follicles. Immunoreactivity for nitric oxide synthase III and endothelin was solely detected in active follicles. Only a few follicles in normal thyroids were immunostained for VEGF, regardless of their functional status. In multinodular goiters, VEGF was detected in contact with the extracellular matrix at the basal pole of the cells. In conclusion, the present study endorses the likelihood of angiofollicular units in the human thyroids. Vascular changes are related to the functional status of thyrocytes.

Biological Transport↗

PubMed2002

Evidence for thyrotropin receptor immunoreactivity in pretibial connective tissue from patients with thyroid-associated dermopathy.

Pretibial myxedema (PTM), mainly characterized by the accumulation of glycosaminoglycans in the dermis and subcutaneous tissue, is an extrathyroidal manifestation of autoimmune Graves' disease (GD), almost always associated with Graves' ophthalmopathy (GO). The thyrotropin receptor (TSH-R) has been proposed as the common target antigen in GD, GO and PTM, with evidence for receptor transcripts and/or protein in these locations. The aim of this study has been to investigate whether receptor protein is present in the pretibial tissues. Skin biopsies were obtained from two patients with PTM and two normal subjects without thyroid disease. A portion of each sample was fixed to produce semi-thin sections for Toluidine Blue or Periodic Acid Schiff (PAS) staining. The remainder was snap frozen to generate cryostat sections for immunohistochemical analysis using three monoclonal antibodies against TSH-R. In the skin from the two patients suffering from PTM, the dermis was infiltrated by inflammatory cells (lymphocytes, B cells, macrophages, mast cells) and adipocytes. The collagen fibers were dissociated by edema and by the accumulation of a PAS-positive material. Immunodetection of TSH-R produced positive staining on cells localized in the dermis, beneath the epidermis or close to the hypodermis. These cells were elongated and resembled fibroblasts. No immunoreactivity was observed in the dermis from control patients without thyroid disease. In conclusion, we have evidence for TSH-R immunoreactivity in the pretibium of patients with GD, GO and PTM. Further studies are needed to unambiguously identify the positive cells and determine whether the reactivity is due to the receptor itself or to a cross-reacting protein.

Aged↗

PubMed2001

Purification and characterization of a soluble bioactive amino-terminal extracellular domain of the human thyrotropin receptor.

The amino-terminal ectodomain of the human TSH receptor has been expressed at the surface of CHO cells as a glycosylphosphatidylinositol-anchored molecule containing a 10-residue histidine tag close to its C terminus. The soluble ectodomain could be released from the cells by treatment with a glycosylphosphatidylinositol-phospholipase C and purified to apparent homogeneity by cobalt-Sepharose chromatography. Two nanomoles of material was obtained, which was suitable for analysis by mass spectrometry. This allowed the identification of four out of the six potential N-glycosylation sites as being effectively glycosylated. A proportion of the purified soluble ectodomain displayed specific binding of (125)I-labeled TSH, allowing for the first time performance of classical saturation binding experiments. Two classes of high-affinity binding sites were identified: site A, K(d) 0.014 nM; site B, K(d) 0.83 nM. The significance of site A, whose affinity is much higher than for the holoreceptor at the surface of intact cells, remains to be clarified. The purified ectodomain was capable of inhibiting efficiently the thyroid stimulating activity of immunoglobulins from patients with Graves' disease. It allowed computation of the amounts of these immunoglobulins in patient's serum, giving values up to 10 microg/mL. Contrary to all currently available assays, the soluble ectodomain of the TSH receptor purified in a functionally competent conformation allows direct studies of its interactions with TSH and autoantibodies and opens the way to structural studies.

Amino Acid Sequence↗

PubMed2001

A conserved Asn in transmembrane helix 7 is an on/off switch in the activation of the thyrotropin receptor.

The thyrotropin (TSH) receptor is an interesting model to study G protein-coupled receptor activation as many point mutations can significantly increase its basal activity. Here, we identified a molecular interaction between Asp(633) in transmembrane helix 6 (TM6) and Asn(674) in TM7 of the TSHr that is crucial to maintain the inactive state through conformational constraint of the Asn. We show that these residues are perfectly conserved in the glycohormone receptor family, except in one case, where they are exchanged, suggesting a direct interaction. Molecular modeling of the TSHr, based on the high resolution structure of rhodopsin, strongly favors this hypothesis. Our approach combining site-directed mutagenesis with molecular modeling shows that mutations disrupting this interaction, like the D633A mutation in TM6, lead to high constitutive activation. The strongly activating N674D (TM7) mutation, which in our modeling breaks the TM6-TM7 link, is reverted to wild type-like behavior by an additional D633N mutation (TM6), which would restore this link. Moreover, we show that the Asn of TM7 (conserved in most G protein-coupled receptors) is mandatory for ligand-induced cAMP accumulation, suggesting an active role of this residue in activation. In the TSHr, the conformation of this Asn residue of TM7 would be constrained, in the inactive state, by its Asp partner in TM6.

Animals↗

PubMed2001

Role of complex asparagine-linked oligosaccharides in the expression of a functional thyrotropin receptor.

To evaluate the functional role of complex asparagine-linked oligosaccharides of the human thyrotropin receptor (TSHR), a Chinese hamster ovary cell line (JP09) and a K562 cell line (K562-TSHR) expressing this receptor were treated with deoxymannojirimycin (dMM), a mannosidase I inhibitor. dMM blocks the formation of complex-type structures and leads to the formation of high-mannose-type structures. Treatment of cells with dMM led to a decrease in the number of thyrotropin (TSH)-binding sites at the cell surface. Detection of the TSHR at the cell surface using a monoclonal antibody directed against the A subunit showed that this decrease was not due to a decrease in the number of TSHRs expressed at the cell surface. However the recognition of TSHR by a monoclonal antibody directed against the C peptide was greatly decreased. On immunoblotting, after deglycosylation using peptide N-glycanase F, the A subunit was visualized as a doublet (36 and 41 kDa). In control cells the species of higher molecular mass was more abundant whereas after dMM treatment the species of lower molecular mass became more abundant. This difference in molecular mass between the two peptides is compatible with the removal of the C peptide. In conclusion, the results show that inhibition of complex-type structure formation leads to (i) an incapacity for TSHR to bind TSH, without affecting its intracellular transport and (ii) an increase of TSHR susceptibility to proteases that remove the C peptide. We then hypothesized that removal of the C peptide could contribute to the formation of a non-functional TSHR.

1-Deoxynojirimycin↗

PubMed2001

Effects of mutations involving the highly conserved S281HCC motif in the extracellular domain of the thyrotropin (TSH) receptor on TSH binding and constitutive activity.

A model has been proposed in which, in the absence of TSH, the extracellular domain of the TSH receptor would exert a silencing effect on the serpentine domain involved in activation of the G(alpha)(s) protein. Mutation of S281 in the ectodomain is supposed to release this constraint, thereby causing receptor activation. This defines S281 and its neighbors as a segment important in intramolecular signal transduction. The functional importance of this segment was explored by site-directed mutagenesis experiments involving S281, as well as the two cysteine residues (C283, C284) present immediately downstream. S281 was mutated to N, T, G, and A in this study, and the functional characteristics of the mutants were compared. We found that S281N, S281T, and S281G display stronger constitutive activity than S281A mutant, suggesting that increase in constitutive activity is related to the extent of disruption of the local structure of the ectodomain. C283 and C284, the two consecutive cysteines that are highly conserved in glycoprotein hormone receptors, were mutated to serine, either alone (S281HSC or S281HCS) or in combination (S281HSS) and were studied in two different TSH receptor backgrounds. The mutated cysteine ectodomains were either linked to a glycosylphosphatidylinositol anchor or the serpentine domain of the wild-type holoreceptor. Glycosylphosphatidylinositol-anchored ectodomain receptors showed good cell surface expression in CHO cells, but only S281HCS was able to bind TSH specifically, illustrating the importance of C283, or the putative disulphide bond, in maintaining the conformation of the ligand binding site. In contrast, cysteine mutants on an extracellular domain-holoreceptor background displayed severely impaired membrane targeting and were poorly expressed in COS cells. However, basal cAMP production, normalized to expression at the plasma membrane, indicated significant increase in constitutive activity of all three mutants, compared with the wild-type receptor. Altogether, these findings support a model in which the ectodomain would act as a silencer of the basal activity of the serpentine portion of the receptor.

Amino Acid Sequence↗

PubMed2001

Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8.

Congenital hypothyroidism (CH) is a relatively frequent and potentially severe disease. It is classically subdivided into: 1) thyroid dysgenesis (TD), a defect in the organogenesis of the gland leading to hypoplastic, ectopic, or absent thyroid gland; or 2) thyroid dyshormonogenesis, a defect in one of the biochemical mechanisms responsible for thyroid hormone synthesis. Most cases of TD are sporadic, although familial occurrences have occasionally been described. Recently, several genes have been implicated in a small proportion of TD, but, in the majority of the cases, the etiology remains unknown. PAX8 is a transcription factor involved in thyroid development. So far, three loss-of-function mutations of PAX8 have been described, two in sporadic cases and one in familial thyroid hypoplasia. Here, we describe a novel mutation of PAX8 causing autosomal dominant transmission of CH with thyroid hypoplasia. The mutation consists of the substitution of a tyrosine for cysteine 57 in the paired domain of PAX8. When tested in cotransfection experiments with a thyroid peroxidasse promoter construct, the mutant allele was unable to exert its normal transactivation effect on transcription. Our results give further evidence that, contrary to the situation in knockout mice, haplo-insufficiency of PAX8 is a cause of CH in humans.

Adult↗