Search

A tired 32-year-old woman complaining of tiredness was referred for work-up of a possible immune deficiency. She had a history of recurrent infections since birth, which usually responded to antibiotics within a few days. Her mother, a nurse, had reported that early charts had disappeared. Munchausen's by proxy was suspected for years. Careful anamnesis indicated possible recurrent fever. Serum IgD levels were high, which led us to suspect Hyper IgD Syndrome. Sequencing of the mevalonate kinase gene revealed 2 mutations, leading to amino acid substitutions: one already described (V3771) and R40W: never reported before. Mevalonate kinase activity was very low in the patient's peripheral blood cells. We used the "Poly Phen" prediction program successfully. Our experiments confirmed the diagnosis of mevalonate kinase deficiency. We used steroids to abort recurrent crises., Case Reports, Journal Article, SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a recently described genetic cause of hyponatremia in male infants. Whether this X-linked condition could be detected in the adult or also could affect women is unknown. A large five-generation family was identified in which the recently described arginine-vasopressin receptor type 2 (AVPR2) mutation that is responsible for NSIAD was segregated. The proband was a 74-yr-old patient who had a syndrome of inappropriate antidiuresis and whose hyponatremia resisted administration of two AVPR2 antagonists. The phenotype of family members who carry the mutation was investigated. Patients with normal serum sodium were subjected to a water-load test. The previously reported activating missense R137C mutation in the AVPR2 gene in three hemizygous male and four heterozygous female individuals was identified. Except in one woman, spontaneous episodes of hyponatremia or abnormal water-load test were identified in all patients with the mutation, whether male or female. Skewed X inactivation was evidenced in the blood of the asymptomatic woman, which is compatible with preferential inactivation of her mutated allele. NSIAD is not limited to male infants. The diagnosis also should be considered in both male and female adults., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

SCOPUS: le.j, FLWIN, info:eu-repo/semantics/published

Pulmonary arterial hypertension (PAH) is clinically characterized by a sustained elevation in mean pulmonary artery pressure leading to significant morbidity and mortality. The disorder is typically sporadic, and in such cases the term idiopathic PAH (IPAH) is used. However, cases that occur within families (familial PAH (FPAH)) display similar clinical and histopathological features, suggesting a common etiology. Heterozygous mutations of a type II member of the TGF-beta cell signaling superfamily known as BMPR2 on chromosome 2q33 have been identified in many kindreds with FPAH, yet display both reduced penetrance and sex bias. This report presents the compilation of data for 144 distinct mutations that alter the coding sequence of the BMPR2 gene identified in 210 independent PAH subjects. This large data set characterizes the extent of sequence variation and reveals that the majority (71%) of mutations in FPAH and IPAH comprise nonsense, frameshift, and splice-site defects, and gene rearrangements. These predict premature termination of the transcript with likely loss through the process of nonsense-mediated decay (NMD). A total of 44 missense mutations were identified that substitute amino acid residues at highly conserved sites within recognized functional domains of the mature receptor. We assess this category of mutations in the context of their heterogeneous effects on cell signaling when assayed by in vitro cell-based systems. Disease-causing mutation hot-spots within BMPR2 are summarized. Taken together, these observations are likely to aid in the development of targeted mutation detection strategies relevant for patient management. Finally, we examine the age- and sex-dependent reduced penetrance of BMPR2 mutations by reviewing bmpr2 animal models and the requirement for additional genetic and/or environmental modifiers of disease. In conclusion, these data provide compelling genetic evidence that haploinsufficiency is the predominant molecular mechanism u, Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: re.j, FLWIN, info:eu-repo/semantics/published

Isolated hypoparathyroidism is an uncommon metabolic disorder characterized by hypocalcemia and hyperphosphatemia, with absent or low levels of PTH. It may present as an apparently sporadic disorder or may be transmitted in families as a genetic trait. Mutations of the calcium-sensing receptor gene and of the preproPTH gene have been reported in occasional cases, and a mutation of the parathyroid-specific transcription factor GCMB gene has been reported in one familial case. We report a second family with isolated hypoparathyroidism and a GCMB mutation. The patients were two siblings from asymptomatic, first-cousin parents, indicating autosomal recessive inheritance. The mutation consisted of the substitution of a glycine residue with a serine at position 63 (G63S) in the DNA-binding GCM domain of GCMB. Functional studies in transfected cells showed that the mutation caused loss of GCMB function, as it abolished transactivation capacity, despite normal subcellular localization, protein stability, and DNA-binding specificity. Contrary to the previously reported family, our patients displayed low but clearly detectable levels of PTH in plasma. This residual hormone secretion probably results from a very small residual activity of the G63S mutant GCMB., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published

Letter, info:eu-repo/semantics/published

BACKGROUND AND STUDY AIMS: Chronic pancreatitis is considered to be a predisposing factor for pancreatic ductal adenocarcinoma (PAC). The purpose of this study was to examine the prognostic value of a finding of mutated (K- ras) gene in predicting the development of PAC in patients with chronic pancreatitis. PATIENTS AND METHODS: The pancreatic duct brushings of 146 patients with chronic pancreatitis were examined in order to identify K- ras gene mutations. A total of 112 patients were followed up (median duration 42 months) using clinical evaluation, serum CA19 - 9 levels, and imaging studies. RESULTS: One or more K- ras mutations were found in 57 of the 146 patients with chronic pancreatitis (39 %). Patients harboring K- ras mutations had a higher incidence of persistent alcohol consumption ( P = 0.041) and of prior rupture of the main pancreatic duct ( P = 0.040). A finding of nuclear atypia in brushing cytology was also more common in patients with K- ras mutation ( P = 0.048). Out of the 112 patients who were followed up, PAC occurred in four of the 44 patients who had a K- ras mutation, but in none of the 68 patients with the wild genotype ( P = 0.022). PAC occurred in three of the 25 patients who did not have pancreatic calcifications ( P = 0.034) and in four of the 54 patients who had demonstrated exocrine insufficiency, but in none of the 58 patients with preserved exocrine function ( P = 0.051). Using stepwise logistic regression, the absence of calcifications, the presence of exocrine insufficiency, and the presence of K- ras mutation were identified as independent predictive factors for cancer development in all patients with chronic pancreatitis. CONCLUSIONS: K- ras gene mutations occur in chronic pancreatitis and are associated with evolution towards PAC. The absence of pancreatic calcifications and the presence of exocrine insufficiency were identified as additional predictive factors for the development of PAC., Journal Article, info:eu-repo/semantics/published

AIM: To ascertain the prevalence of germline mutations in the TSH receptor gene as a cause of juvenile thyrotoxicosis (JT) in non-autoimmune patients. TSH receptor gene mutations are not seen in autoimmune-active patients. METHODS: In a nationwide study on JT, 123 patients were re-examined 10 y (range 4 to 21 y) after diagnosis. Two patients with toxic adenoma were excluded. In 25 patients, no TPO, TG or TSH-R antibodies were found. In 17 patients, DNA material was available for TSH receptor gene analysis. The entire TSH receptor gene was sequenced in five patients. TSH receptor "hot spots" for mutations in exon 9 and 10 were sequenced in the remaining 12 patients. RESULTS: A TSH receptor gene germline mutation was identified in only one patient of a total number of 121 patients with JT, of which 17 patients were presumed to have non-autoimmune JT by the lack of thyroid autoantibodies. CONCLUSION: In Denmark the prevalence of germline mutations in the TSH receptor gene is one in 121 patients with JT (0.8%; 95% CI: 0.02-4.6%) and one in 17 patients with presumed non-autoimmune JT (6%; 95% CI: 5.88% (0.15-28.69))., Journal Article, Research Support, Non-U.S. Gov't, FLWIN, info:eu-repo/semantics/published

Thyroid dysgenesis is the most common cause of congenital hypothyroidism, a relatively frequent disease affecting 1 in 3000-4000 newborns. Whereas most cases are sporadic, mutations in transcription factors implicated in thyroid development have been shown to cause a minority of cases transmitted as monogenic Mendelian diseases. PAX8 is one of these transcription factors, and so far, five mutations have been identified in its paired domain in patients with thyroid dysgenesis. We have identified a novel mutation of PAX8, in the heterozygous state, in a father and his two children both presenting with congenital hypothyroidism associated with an in-place thyroid of normal size at birth. In addition, one of the affected siblings displayed unilateral kidney agenesis. The mutation substitutes a highly conserved serine in position 54 of the DNA-binding domain of the protein (S54G mutation) by a glycine. Functional analyses of the mutant protein (PAX8-S54G) demonstrated that it is unable to bind a specific cis-element of the thyroperoxidase gene promoter in EMSAs and that it has almost completely lost the ability to act in synergy with Titf1 to transactivate transcription from the thyroglobulin promoter/enhancer. These results indicate that loss of function mutations of the PAX8 gene may cause congenital hypothyroidism in the absence of thyroid hypoplasia., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

OBJECTIVE: Appetite-suppressant drug fenfluramine is implicated in primary pulmonary hypertension (PPH) but the molecular pathways that mediate this effect are unknown. A mouse model incriminates the serotonin 5-HT(2B) receptor but contrasts with other models where this receptor has been shown to mediate pulmonary arterial relaxation via nitric oxide production. METHODS: We analyzed the human 5-HT(2B) gene in 10 patients with appetite-suppressant drug-associated PPH. RESULTS: A mutation causing premature truncation of the protein product was found in one patient. The mutation was not found in 80 control subjects and no 5-HT(2B) mutation was found in 18 PPH patients not associated with appetite-suppressants. Functional analysis of the transfected receptor expressed either transiently in COS cells or stably in CHO cells demonstrated that the mutated receptor fails to activate the second messenger inositol-phosphates cascade and subsequent intracellular calcium release, in spite of normal expression at the cell membrane. The mutated receptor had no constitutive activity, and produced no dominant negative effect on the wild-type receptor. CONCLUSION: Loss of serotonin 5-HT(2B) receptor function may predispose to fenfluramine-associated PPH in man., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Created in 1987, the department of medical genetics finds its origins in molecular endocrinology research which had developed from the seventies at the Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM) of the Faculty of Medicine. After its fusion with the Center of Human Genetics of the ULB, in 1992, the department is composed of three units: the lab of molecular genetics and oncology, the lab of cytogenetics and a clinical genetics unit. One thousand consultations of genetic counseling and more than 15,000 molecular or cytogenetic diagnostic procedures are performed annually. The development of the clinical activities was paralleled by a very active research activity, resulting in a series of "firsts". Amongst the main results are: the identification of the first mutations responsible for congenital hypothyroidism; the molecular cloning of the TSH receptor and of a series of "orphan" G protein-coupled receptors; the identification of a novel neuropeptide, nociceptin, by the first example of "reverse pharmacology"; the identification of olfactory receptors on the sperm of mammals, including man; the identification in molecular terms of the mechanisms responsible for acquired and hereditary hyperthyroidisms; the identification of the chemokine receptor CCR5 as the major coreceptor of HIV-1, and of the prevalent mutation of CCR5 conferring resistance to HIV to about 1% of the European population., English Abstract, Journal Article, Review, info:eu-repo/semantics/published

OBJECTIVE: Constitutively activating mutations of the thyrotropin receptor (TSHR) have been found in the majority of autonomously functioning thyroid nodules (AFTNs) in European patients. The reported frequency of these mutations varies among reports but amounts to 50-80%. To date, only one such mutation responsible for AFTNs has been identified in the Japanese population and the pathogenic role of such mutations in Japanese AFTNs has been questioned. In the present study, we evaluated the frequency of activating mutations in the TSHR and G(alpha)s in 10 Japanese AFTNs. DESIGN: Genomic DNA was extracted from fresh frozen tissue. The TSHR and the almost entire sequence of the gene coding for the alpha subunit of Gs have been amplified and sequenced. RESULTS: In sequence analysis, four mutations in the TSHR (T632A, I486M, M453T and L512R) were found. To complete our analysis, we searched mutations in the gene coding for the alpha subunit of Gs, in the samples negative for TSHR mutations. In one case a mutation (R201H) affecting GTPase activity was found. CONCLUSIONS: If we focus on the solitary nodules, we obtain the same mutation proportion as in European patients (70%). The absence of TSHR and G(alpha)s mutations in a significant proportion of autonomous adenomas in multinodular goiters suggests that other causes may also play a role in the genesis of these lesions., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

OBJECTIVE: The cyclic AMP (cAMP) cascade is the main regulatory pathway in thyrocytes. Whilst activating mutations in the TSH receptor or in the Gs alpha-subunit, which increase cAMP levels, have been shown to be responsible for 80% of the autonomous adenomas, no such mutations have been observed in the other types of thyroid tumors, suggesting that other mechanisms exist. The discovery of Epac ('exchange nucleotide protein directly activated by cAMP'), a novel cAMP-binding protein, which is strongly expressed in the thyroid, raised the possibility of a role for this protein in the generation of the unexplained cold thyroid follicular adenomas. Thus, we investigated whether activating mutations in either Epac or Rap (the downstream target of Epac) could be responsible for the generation of these thyroid nodules. DESIGN: Epac and Rap1 (Rap1A and Rap1B) cDNAs were sequenced in 10 patients. The sequencing of the cDNAs was realized on both strands in the cold nodule and the juxtanodular tissue of each patient. RESULTS: No mutations in either Epac or Rap1 cDNAs were found. For five patients, a polymorphism in Epac at codon 332 (Gly--Ser) was observed. CONCLUSIONS: In this report, we show that the cAMP--Epac--Rap1 signaling pathway in the thyroid gland does not play a major role in the generation of cold thyroid follicular adenomas, since no mutations in either Epac or Rap1 could be observed in the 10 nodules studied., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Journal Article, Research Support, Non-U.S. Gov't, FLWIN, info:eu-repo/semantics/published

Haemoglobinopathies are the most frequent genetic diseases in the world. The estimated frequency of carriers in the world is of 200 millions while there is about 300.000 births per year of major forms of haemoglobinopathies. The neonatal screening of haemoglobinopathies performed at the Hospital Erasme on around 80% of births in Brussels since 1994 has demonstrated that the frequency of carriers of an abnormal haemoglobin is around 1.5% while more than 1/2.000 newborns has a major haemoglobinopathy. A strategy must be adopted to manage the haemoglobinopathies in Brussels., English Abstract, Journal Article, Review, info:eu-repo/semantics/published

Most of the time congenital hypothyroidism appears as a sporadic disease. In addition to the rare defects in hormonosynthesis associated with goiters, the causes of congenital hypothyroidism include agenesis and ectopy of the thyroid gland. The study of some familial cases has allowed the identification of a few genes responsible for congenital hypothyroidism. We report here a familial case of congenital hypothyroidism, transmitted as a recessive trait, and caused by a homozygous mutation in the thyrotropin receptor (TSH-R). The initial diagnosis of thyroid agenesis, based on the absence of tracer uptake on scintiscan, was incorrect, because ultrasound examination identified severely hypoplastic thyroid tissue in the cervical region., Case Reports, Journal Article, info:eu-repo/semantics/published

info:eu-repo/semantics/published

The increase in thyroid carcinoma post-Chernobyl has been largely confined to a specific subtype of papillary carcinoma (solid/follicular). This subtype is observed predominantly in children under 10 in unirradiated populations, but maintains a high frequency in those aged 10-15 from those areas exposed to fallout from the Chernobyl accident. The aim of this study was to link morphology with molecular biology. We examined 106 papillary carcinomas from children under the age of 15 at operation. All were examined for rearrangements of the RET oncogene by reverse transcription polymerase chain reaction (RT-PCR); a subset of these cases were also examined for mutations of the three ras oncogenes, exon 10 of the thyroid stimulating hormone receptor, associated more usually with a follicular rather than papillary morphology, and exons 5, 6, 7 and 8 of the p53 gene, commonly involved in undifferentiated thyroid carcinoma. Rearrangements of the REToncogene were found in 44% of papillary carcinomas in which we studied fresh material; none of the tumours examined showed mutation in any of the other genes. The two rearrangements resulting from inversion of part of chromosome 10 (PTC1 and PTC3) accounted for the majority of RET rearrangements identified, with PTC1 being associated with papillary carcinomas of the classic and diffuse sclerosing variants and PTC3 with the solid/follicular variant., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Autologous transplantation using peripheral blood stem cells (PBSCs) collected after chemotherapy, followed by growth factor administration (ASCT), is increasingly used in the treatment of non-Hodgkin's lymphoma (NHL). However, quantitative data regarding contaminating malignant cells in the harvests are still scarce. We prospectively investigated 37 diffuse large-cell lymphomas (DLCLs) in complete remission (CR) that were treated according to multicentric protocols at our centre. DNA was extracted from the diagnostic lymph node. The complementarity-determining region (CDR) III was sequenced and a patient-specific oligomer synthesized. Contamination was evaluated semiquantitatively by polymerase chain reaction (PCR) and was confirmed by a limiting dilution analysis. PBSCs collected at regeneration after administration of granulocyte colony-stimulating factor (G-CSF), steady-state bone marrow (BM) and peripheral blood samples at CR were compared. DNA was available in 37 patients, from which 22 rearrangements could be sequenced. Patients (n = 15) who had both the required follow-up samples and a suitable clonal marker were investigated. In two cases, the patient-specific PCR assay set up at diagnosis later gave false-negative results in samples in which clonal DNA was still detectable by other sets of primers. PBSC contamination was highly variable: 7 out of 15 patients showed a PBSC/BM ratio of NHL cells greater than 1 log, whereas 8 out of 15 patients showed no difference and could vary from one apheresis to another. Eight ASCTs were performed, five of which used highly contaminated PBSCs: four patients relapsed early, three with disseminated lymphoma. Thus, 50% of DLCLs in CR seem to mobilize significantly malignant cells at regeneration under G-CSF. Considering the higher numbers of cells reinfused, this translates into a much higher number of lymphoma cells reinfused when compared with autologous bone marrow transplantation (ABMT). However, their clonogenic poten, Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, FLWIN, info:eu-repo/semantics/published

We report a Belgian girl born in 1983 with isolated thyrotropin (TSH) deficiency. Hypothyroidism without goiter was diagnosed at the age of 2 months, with extremely low total thyroxine (T4) at 0.3 microg/dL (4 nmol/L; N[normal]: 5.6-11.4 microg/dL). Basal TSH, only moderately elevated at 14.8 mU/L (N: 0-5.3; competitive radioimmunoassay, RIA), increased to 18.2 mU/L after thyrotropin-releasing hormone (TRH) stimulation, whereas prolactin increased normally. At age 15 years, after withdrawal of levothyroxine (LT4) therapy for 6 weeks, TRH stimulation slightly increased serum TSH using two immunometric assays, from less than 0.03 to 0.07 and from 0.2 to 0.3 (a monoclonal and polyclonal antibody), and from 1.9 to 4.1 mU/L using a polyclonal TSH antibody and iodinated recombinant TSH. Sequencing of the TSH-beta subunit gene revealed a homozygous single nucleotide deletion in codon 105 producing a frame shift that results in a truncated TSH-beta with nonhomologous 9 carboxyterminal amino acids and a loss of the 5 terminal residues. This mutation was previously reported in one Brazilian and two German families. The abnormal, and presumably biologically inactive, TSH can be detected in serum using appropriate antibodies. Its relatively small amount in serum is due to either reduced secretion or rapid degradation. The occurrence of the same mutation in three families of different ethnic origin suggests that this mutation may be prevalent in the population. Common ancestry or de novo mutations in a hot spot cannot be excluded. Finally, we must be aware that neonatal screening of congenital hypothyroidism based on blood spot TSH measurement will not detect this rare but severe genetic defect., Case Reports, Journal Article, Research Support, U.S. Gov't, P.H.S., info:eu-repo/semantics/published

Intensification using peripheral blood stem cells collected after chemotherapy followed by growth factors is being increasingly investigated as an alternative to conventional chemotherapy for mantle cell non-Hodgkin lymphoma. We investigated 14 grades III-IV, t(11;14)-positive cases for contamination of PBSC collected after a polychemotherapy regimen followed by G-CSF. Patients were first treated with a polychemotherapy regimen. There were four CR, seven PR, two refractory and one early death. Seven patients have been transplanted, in whom PBSC were mobilized, using either cyclophosphamide/VP16 or Dexa-BEAM followed by G-CSF. For all patients, whether actually autografted or not, PB cells were tested at the time of regeneration on G-CSF after the first polychemotherapy or after the mobilizing regimen. PCR evaluation of contamination was performed first by a semi-quantitative approach, using serial dilutions of initial DNA, then confirmed using a limiting-dilution analysis. Two patients were not informative (one early death and one without an available molecular marker). PB cells collected at regeneration contained at least one log more lymphoma cells than steady-state blood or marrow, apart from in two cases. Moreover, where a mobilizing treatment diminished tumor burden in the patient, at the same time it increased PB contamination in most cases. We conclude that advanced mantle cell NHL appears to be largely resistant to significant in vivo purging by conventional chemotherapy. Where treatment brings benefits by reducing tumor load, it may at the same time negate it by mobilizing malignant cells into the collections used to intensify. Although the clonogenic potential of this massive infiltration is unknown (only gene marking studies could provide a definitive answer regarding the source of relapses), strategies aimed at reducing the level of contamination in the graft should be considered when designing future protocols., Journal Article, info:eu-repo/semantics/published

Growth and function of the thyroid and adrenal glands are maintained and controlled by thyrotropin (TSH) and adrenocorticotrophic hormone (ACTH), respectively. The action of these trophic hormones requires the presence of functional TSH and ACTH receptors. We describe a large inbred Bedouin kindred in which profound congenital hypothyroidism and hypoadrenocortisolism occurred alone or together in eight family members belonging to four nuclear families. The high serum TSH and ACTH levels in the presence of normal or hypoplastic thyroid glands and low glucocorticoid, but not mineralocorticoid concentrations, are characteristic of resistance to TSH and ACTH. Linkage analysis, using specific polymorphic markers, excluded the involvement of the ACTH receptor but not thyrotropin receptor (TSHR). A novel point mutation was identified in exon 10 of the TSHR that replaces the normal cytosine in nucleotide 2024 with a thymidine. As a result the normal arginine in codon 609 (CGA) is replaced with a stop codon (TGA). This mutation produces a truncated TSHR lacking the third intracellular and extracellular loops, the sixth and seventh transmembrane segments, and the intracytoplasmic tail. The presence of hypothyroidism did not affect the timing, severity, and manner of clinical manifestation of hypoadrenocortisolism., Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., info:eu-repo/semantics/published

Activating mutations of the TSH receptor (TSH-R) have been reported to result in toxic adenomas, multinodular goiters, sporadic neonatal hyperthyroidism, and familial autosomal dominant nonautoimmune hyperthyroidism. To date, all descriptions of such mutations, whether somatic or genomic, have been confined to the Caucasian population. We describe a Chinese family in whom a germline proline to serine substitution in position 639 resulted in familial thyrotoxicosis. This constitutively activating mutation has been previously described in a hyperfunctioning thyroid nodule. The three children in this family developed thyrotoxicosis during childhood; their father was diagnosed as thyrotoxic at the age of 38 yr. Two of the children and the father had mitral valve prolapse (MVP) associated with mitral regurgitation. There was a close temporal relationship between the onset of thyrotoxicosis and the diagnosis of mitral valvular disease in these patients. An increased prevalence of MVP has been reported in Graves' disease and chronic lymphocytic thyroiditis, but the pathophysiological mechanisms linking MVP and autoimmune thyroid disease are still not understood. This is the first report of an association between activating TSH-R mutations and MVP. We postulate that TSH-R activation may increase the clinical expression of MVP in genetically predisposed individuals., Case Reports, Journal Article, info:eu-repo/semantics/published

Gain of function and loss of function mutations of the TSH receptor have been implicated in the pathogenesis of various thyroid diseases. Gain of function mutations, when somatic, are the first cause of autonomous nodules; when germline, they are responsible for hereditary non-autoimmune toxic thyroid hyperplasia and for some cases of sporadic congenital hyperthyroidism. A subset of mutations modifying the receptor selectivity have recently been found to be involved in the pathogenesis of familial gestational hyperthyroidism. These mutations are of great interest for understanding the mechanism of receptor activation. Loss of function mutations of the TSH receptor are responsible for different phenotypes ranging from asymptomatic resistance to TSH to overt congenital hypothyroidism., Journal Article, Research Support, Non-U.S. Gov't, Review, info:eu-repo/semantics/published