TSH Receptor Gene Research Articles

Autoimmune Thyroid Disease Genes Identified in Non-Caucasians

Autoimmune thyroid diseases (AITDs), including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), are among the commonest autoimmune disorders, affecting approximately 2% - 5% of the population. Epidemiological data support strong genetic influences on the development of AITD. The identification of genes placing individuals at an increased risk for the development of AITD has been a slow process. However, over the last 20 years or so real progress has been made with the mapping of novel loci, via a number of different approaches. The first AITD gene discovered, Human Leucocyte Antigen (HLA)/Major Histocompatibility Complex (MHC), is associated with both GD and HT. Non-MHC genes that confer susceptibility to AITD can be classified into two groups: (1) immune-regulatory genes (e.g., CD40, CTLA-4, and PTPN22); (2) thyroid-specific genes—thyroglobulin and TSH receptor genes. These genes interact with environmental factors, such as infection, likely through epigenetic mechanisms to trigger disease. In this review, we will summarize the latest findings on AITD susceptibility genes in non-Caucasians.

Frequent TSH Receptor Genetic Alterations with Variable Signaling Impairment in a Large Series of Children with Nonautoimmune Isolated Hyperthyrotropinemia

Heterozygous mutations in the TSH receptor gene (TSHR) are associated with partial TSH resistance, characterized by isolated nonautoimmune hyperthyrotropinemia (NAHT). The prevalence and management of this condition is controversial. Our objective was to investigate the prevalence and clinical impact of TSHR alterations in a large series of pediatric patients with NAHT and to dissect their mechanism of action. For this prospective multicenter study, clinical data and samples were collected in the clinical units and conveyed to a centralized laboratory for analysis. Subjects included 153 unrelated patients with NAHT aged <18 yr. Exclusion criteria included thyroid dysgenesis or major associated congenital defects. Parameters of thyroid function, TSHR gene analysis, and TSHR functional assays were evaluated. The frequency of heterozygous nonpolymorphic TSHR variations was 11.8%. We identified seven previously unknown variations: a frameshift (p.Q33PfsX46), one intronic (g.IVS4+2A→G), and five novel missense (p.P162L, p.Y466C, p.I583T, p.I607T, and p.R609Q) variations. The missense variations variably affected TSHR membrane expression and G(s) and/or G(q/11) signaling. Several variations cosegregated with NAHT in the affected families. Parameters of thyroid function were similar between affected and unaffected family members. Nonpolymorphic alterations in the TSHR gene are commonly associated with isolated NAHT in young patients, thus configuring partial TSH resistance as the most frequent inheritable cause of isolated NAHT. The identification of TSHR defects may thus be helpful for a tailored management of subclinical hypothyroidism. We provide further evidence that besides the well-known defects in G(s) signaling, TSHR genetic alternations found in NAHT may frequently impair the G(q/11) pathway.

Two rare TSH receptor amino acid substitutions in toxic thyroid adenomas

Toxic adenoma and toxic multinodular goiter (TMNG) are common causes of hyperthyroidism in iodine-deficient regions, but they are relatively rare in iodine-sufficient regions, including Japan. Constitutive activating mutations of the thyroid stimulating hormone receptor (TSHR) gene and adenylate cyclase-stimulating G α protein (GNAS) gene are frequent in these thyrotoxic disorders. Here we report two cases of rare TSHR gene mutations in Japanese thyrotoxicosis patients. In Case 1, we observed multiple toxic nodules with thyrotoxicosis, and in Case 2, we detected a solitary toxic nodule in an 8-year-old girl. In both cases, ultrasonography showed thyroid nodules and scintigraphy revealed increased uptake. Total thyroidectomy was performed for Case 1 and a hemi-thyroidectomy was performed for Case 2. Genetic analysis of the resected tissues revealed an I568F mutation in Case 1 and a S281I mutation in the TSHR gene in Case 2. The I568F mutation was located in the second extracellular loop, and the S281I mutation was located in the N-terminal extracellular domain of the TSH receptor. In Case 1, the mutation was restricted to the largest nodule, and was not detected in other functioning nodules or non-nodule thyroid tissue. Bi-allelic expression of the TSHR gene was confirmed by reverse transcription-polymerase chain reaction in both tumors. Both the I568F and S281I mutations were studied previously in vitro, and were revealed to cause basal activation of the protein kinase A pathway. Case 1 represents the second reported case of an I568F mutation and Case 2 represents the third reported case of an S281I mutation.

Molecular screening of the TSH receptor (TSHR) and thyroid peroxidase (TPO) genes in Korean patients with nonsyndromic congenital hypothyroidism

To investigate thyroid-stimulating hormone receptor (TSHR) and thyroid peroxidase (TPO) mutations in Korean patients with primary congenital hypothyroidism (CH). Congenital hypothyroidism is a common genetic disorder in which the majority of mutations occur in the TSHR and TPO genes. We examined the frequencies of TSHR and TPO mutations among Korean patients with primary CH. Furthermore, we explored the relationships between imaging findings and mutation status. A total of 193 paediatric patients with nonsyndromic CH were enrolled in the present study. Patients with decreased (99m) Tc uptake were screened for TSHR mutations using Sanger sequencing, and those with increased uptake were screened for TPO mutations. The relationships between scintigraphic and ultrasonographic findings and mutation status were analysed. Thirteen (16·5%) of 79 patients with decreased (99m) Tc uptake were found to harbour TSHR mutations including G132R, G245S, R450H, R519C and F525S. The R450H mutation was present in 13 (72·2%) of 18 disease alleles. Seven (10·3%) of 68 patients with increased (99m) Tc uptake harboured TPO mutations including R189Q, K439E, G493S, C808LfsX72, A863T, R875Hfs and P883S. The TSHR and TPO mutations were observed only in patients with normal to slightly enlarged thyroid glands. This study identified underlying TSHR and TPO mutations in Korean patients with CH and revealed a possible relationship between imaging findings and mutation status. In addition, the low rate of mutation positivity suggests significant genetic heterogeneity of CH in the Korean population.

TSH receptor extracellular region mutations in thyroid functioning nodules: further evidence for the functional role of this region in the receptor activation

IntroductionA causative role for activating mutations of the TSHreceptor (TSHR) has been demonstrated in the majority ofthyroid hyperfunctioning nodules, as well as for thefamilial and sporadic congenital nonautoimmune hyper-thyroidism [1, 2] and also the rare hyperfunctioning car-cinomas [3, 4]. More than 30 different amino acidsubstitutions have been described so far, and their char-acterization, together with in vitro mutagenesis studieshave been exploited for a structure–function analysis of thereceptor, leading to a structural model in which the areasinvolved in the binding to TSH or signal transduction havebeen depicted [5]. The emerging picture suggests theexistence of a molecular constraint which limits the con-stitutive activity of the receptor, removed by the interactionof TSH with the extracellular (EX) portion, but with animportant role played also by the transmembrane regions inthe dimerization process and the functional activation ofthe receptor [5, 6]. Herein we describe the discovery of twounusual heterozygous mutations occurring in two of seventhyroid functioning nodules detected as single nodules or ina multinodular goiter.Materials and methodsSpecimen of nodular tissues were collected and immedi-ately frozen after surgical removal from seven patients withsingle or multinodular hyperfunctioning goiter. Non-nod-ular normal tissue from the contralateral lobe was alsocollected. After RNA extraction and cDNA synthesis, PCRamplification of the exons 9 and 10 of the TSHR gene wasperformed as previously described [3, 4] and the amplifiedproducts sequenced with a BigDye Terminator version 3.1Cycle Sequencing kit in an automated 3130xl analyzer(both from Applied Biosystems, Foster City, CA, USA).The study protocol was approved by the local ethicscommittee.ResultsSequencing of TSH receptor gene in a small cohort ofseven patients with thyroid hyperfunctioning nodulesrevealed the presence, in two cases, of unusual somaticheterozygous mutations. The first was a deletion of D403

Study on the Relationship Between TSHR Gene and Thyroid Diseases

Thyroid stimulating hormone receptor (TSHR) is thought to play a critical role in the pathogenesis of certain thyroid diseases, including Graves' disease (GD), multinodular thyroid goiter (MTG), and Hashimoto's thyroiditis (HT). In order to understand whether single nucleotide polymorphisms in the TSHR gene contribute to thyroid diseases, we have conducted a case-control study in which, we examined 8 TSHR gene single-nucleotide polymorphisms in introns 1, 4, 5, 6 and exons 7 and 8, respectively, among patients with thyroid diseases. These included one family with GD (3 patients and 9 healthy members); 60 patients with familiar thyroid diseases (30 with GD, 20 with MTG, and 10 with HT patients), 48 sporadic patients with GD and 96 healthy control individuals. Direct sequencing of all 10 exons and part of introns of TSHR gene, in these patients as well as healthy controls revealed eight polymorphisms. A novel polymorphism in exon 8 AGA(Arg) → CGA(Arg). However, there were no significant differences between patients and controls in the incidence of these polymorphisms. These results suggest that the polymorphisms (polymorphism in intron 1 at 81 bp upstream of exon 2; polymorphism in intron 4 at 135 bp upstream of exon 5; polymorphism in intron 4 at 365 bp upstream of exon 5; polymorphism in intron 5 at 69 bp upstream of exon 6; means polymorphism in intron 6 at 13 bp downstream of exon 6; polymorphism in intron 6 at 187 bp upstream of exon 7; E7+16: polymorphism in 16 bp of exon 7; polymorphism in 40 bp of exon 8) of the TSHR gene may not contribute to the pathogenesis of thyroid diseases.

Nonclassic TSH Resistance:TSHRMutation Carriers with Discrepantly High Thyroidal Iodine Uptake

Inactivating mutations in the TSH receptor gene (TSHR) cause TSH resistance. Most patients with TSH resistance have low to normal thyroidal radioiodine uptake (RAIU), which is consistent with the physiological knowledge that TSH stimulates iodine uptake. To date, only one TSHR mutation-carrying family with discrepantly high RAIU has been reported. We aimed to test whether TSHR mutation carriers with high RAIU are observed in a cohort of Japanese patients with congenital hypothyroidism (CH). Twenty-four Japanese CH patients with high RAIU were screened for TSHR mutations. The capacities of mutant TSHR to activate Gs- and Gq-coupled signaling pathways were evaluated in vitro. Two patients were found to have biallelic TSHR mutations: p.[T145I]+[R450H] in one and p.[R450H]+[I661fs] in the other. The two subjects had permanent CH with slightly high RAIU (41.8 and 43.0%, reference 8-40) but did not have goiter. One had a slightly high perchlorate discharge rate (10%, reference <10). Expression experiments revealed that T145I-TSHR retained partial ability to transduce both Gs- and Gq-coupled pathways, whereas I661fs-TSHR could transduce neither of them. R450H-TSHR had partial ability to transduce Gs-coupled signaling but had abrogated ability to transduce Gq-coupled signaling, indicating that coupling to Gq was dominantly affected. We show that 8% of Japanese CH patients with high RAIU (two in 24) has inactivating TSHR mutations. Expression of this apparently discrepant phenotype, which we term nonclassic TSH resistance, is presumably associated with the characteristic signaling property of the mutant TSHR, namely the Gq-dominant coupling defect.

Association of TSHR gene intron 1 polymorphisms with Graves′ disease

Objective To investigate the association between polymorphisms of thyroid-stimulating hormone receptor(TSHR)gene intron 1(rs179247, rs12101261)and Graves′ disease(GD)in the China Han population from Xuzhou city, Jiangsu Province. Methods Total 1 066 GD patients and 1 107 control subjects were recruited for genotyping by Taqman probe technique on Fluidigm EP1 platform. Meanwhile, serum concentrations of thyroid hormone and TSH receptor antibodies(TRAb)were determined. Results The rs179247_A, rs12101261_T were significantly associated with GD risk(OR=1.35, 95%CI 1.19-1.54, P=5.92×10-6; OR=1.32, 95%CI 1.16-1.50, P=2.22×10-5). Logistic regression identified that rs179247 was an independent susceptibility locus of GD. Serum TRAb concentration showed a significant difference(P=0.015)among rs179247_AA, AG, and GG genotypes. Conclusion rs179247 and rs12101261 in TSHR intron 1 are both associated with GD, and rs179247 may contribute risk to GD independently. The polymorphism is associated with TRAb, but not with serum concentration of thyroid hormones, age of onset, diffused thyroid goiter, ophthalmic signs, and relapse. Key words: Graves disease; TSHR gene intron 1; TSH receptor antibodies; Polymorphism, single nucleotide

Deletion of thyrotropin receptor residue Asp403 in a hyperfunctioning thyroid nodule provides insight into the role of the ectodomain in ligand-induced receptor activation.

Somatic mutations of the TSH receptor (TSHR) gene are the main cause of autonomously functioning thyroid nodules. Except for mutations in ectodomain residue S281, all of the numerous reported activating mutations are in the TSHR membrane-spanning region. Here, we describe a patient with a toxic adenoma with a novel heterozygous somatic mutation caused by deletion of ectodomain residue Asp403 (Del-D403). Subsequent in vitro functional studies of the Del-D403 TSHR mutation demonstrated greatly increased ligand-independent constitutive activity, 8-fold above that of the wild-type TSHR. TSH stimulation had little further effect, indicating that the mutation produced near maximal activation of the receptor. In summary, we report only the second TSHR ectodomain activating mutation (and the first ectodomain deletion mutation) responsible for development of a thyroid toxic adenoma. Because Del-D403 causes near maximal activation, our finding provides novel insight into TSHR structure and function; residue D403 is more likely to be involved in the ligand-mediated activating pathway than in the ectodomain inverse agonist property.

The Coexistence of a Novel Inactivating Mutant Thyrotropin Receptor Allele with Two Thyroid Peroxidase Mutations: A Genotype-Phenotype Correlation

TSH receptor (TSHR) and thyroid peroxidase (TPO) gene mutations occur independently. This is the first report of their coexistence in the same individuals. The objective of the study was to evaluate the genotype-phenotype correlations when mutations in both genes are present alone or together in the same individual. Thirty subjects from an extended Arab kindred underwent clinical investigation and molecular studies of the mutant TSHRs. A novel mutant TSHR was identified, involving four nucleotides at three sites on the same allele, c.267G>T (L89L), c.269/270AG>CT (Q90P), and c.790C>T (P264S). In addition, two known TPO gene mutations, G493S and R540X, were identified. Thirteen heterozygotes for the mutant TSHR allele had mild hyperthyrotropinemia. In nine of theses, the coexistence of a TPO mutation in one allele did not magnify the hyperthyrotropinemia. Homozygotes for the mutant TSHR and a compound heterozygote for the TPO mutations presented frank hypothyroidism. In vitro studies showed increasing loss of function for Q90P less than P264S less than Q90P/P264S TSHR mutants, the latter being that expressed in the subjects under investigation. The two interchangeably used WT TSHR vectors, L87 and V87, although functionally identical, differed in structure and function in the presence of the Q90P mutation. TSHR and TPO gene mutations were identified alone and together in individuals of a consanguineous kindred. Homozygotes for the TSHR and a compound heterozygote for the TPO mutations were hypothyroid. The mild hyperthyrotropinemia of heterozygotes for the mutant TSHR allele was not aggravated by the coexistence of a TPO defect in one allele.

Current questions of thyroid diseases in childhood

In recent years our knowledge on thyroid diseases in childhood has been increased. Several forms of congenital hypothyroidism (dysgenesis, dyshormongenesis, thyrotropin resistance and some central forms) are consequences of gene mutations. Maternal hypothyroxinemia due to severe iodine deficiency leads to early neurological damage and congenital hypothyroidism. Neonatal screening of congenital hypothyroidism and early treatment with l-thyroxin ensure good prognosis. Differential diagnosis of the various forms of congenital hypothyroidism in newborns is not an easy task. The need for treatment of transient hypothyroxinemia is still controversial. Diagnosis of juvenile lymphocytic thyroiditis can be ascertained by the clinical status, ultrasound examination, detection of anti-peroxydase antibodies, evaluation of thyroid function, and fine needle aspiration cytology. L-thyroxin therapy is recommended in cases of subclinical and manifest hypothyroidism. The transient form of the rare newborn hyperthyroidism is the consequence of maternal Graves-Basedow disease. It can be a sever condition and its permanent form is caused by TSH-receptor gene mutation. In the pathogenesis of autonomic thyroid adenoma mutations of the TSH-receptor and the alpha subunit of the stimulatory G-protein are involved. Treatment of Graves-Basedow disease in childhood is a debated question. The first choice is medical treatment with antithyroid and beta-blocking drugs. However, remission rate is low under this therapy, and the disease is characterised by frequent relapses. For this reason, the necessity of definitive therapy frequently arises. In Europe subtotal thyroidectomy is used as second choice of therapy, but clinical experience in the United States showed that radioiodine treatment is a safe and effective therapy for children and adolescents. Iodine deficient goitre in childhood is a form of iodine deficiency disorder. It is the consequence of adaptation to iodine deficiency. It can be treated by iodine or/and l-thyroxin, and its development can be prevented by iodinated salt. In childhood, thyroid nodule needs for a detailed investigation because of the possibility of thyroid cancer. Medullar thyroid carcinoma indicates genetic screening in the patients and their family, and the presence of disease-causing RET-proto-oncogene mutation confirms the need for total thyroidectomy already in childhood.

Cutting Edge: The Etiology of Autoimmune Thyroid Diseases

Significant progress has been made in our understanding of the mechanisms leading to autoimmune thyroid diseases (AITD). For the first time, we are beginning to unravel these mechanisms at the molecular level. AITD, including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are common autoimmune diseases affecting the thyroid. They have a complex etiology that involves genetic and environmental influences. Seven genes have been shown to contribute to the etiology of AITD. The first AITD gene discovered, HLA-DR3, is associated with both GD and HT. More recently, this association was dissected at the molecular level when it was shown that substitution of the neutral amino acids Ala or Gln with arginine at position beta 74 in the HLA-DR peptide binding pocket is the specific sequence change causing AITD. Non-MHC genes that confer susceptibility to AITD can be classified into two groups: (1) immune-regulatory genes (e.g., CD40, CTLA-4, and PTPN22); (2) thyroid-specific genes-thyroglobulin and TSH receptor genes. These genes interact with environmental factors, such as infection, likely through epigenetic mechanisms to trigger disease. In this review, we summarize the latest findings on disease susceptibility and modulation by environmental factors.

Molecular description of non-autoimmune hyperthyroidism at a neonate caused by a new thyrotropin receptor germline mutation

BackgroundConstitutively activating germline mutations in the thyrotropin receptor (TSHR) gene result in non-autoimmune hyperthyroidism and can be transmitted as a dominant trait or occur sporadically. These mutations are mostly located in the serpentine part of this G-protein coupled receptor.MethodsSequencing exon 9 and 10 of the thyrotropin receptor gene in a two months old patient identified a mutation which was functionally characterized after transient transfection into COS-7 cells. Cell surface localization was investigated by an ELISA approach and for signalling properties we measured cAMP by alpha screen technology for Gs/adenylyl cyclase activation and use a reporter gene assay for determination of Gq/11 phospholipase C-β activation.ResultsWe detected a heterozygous mutation in the first extracellular loop of the TSHR gene leading to an exchange of an isoleucine residue for asparagine at amino acid position 486 (I486N). Cell surface localization was reduced to 51% of wild-type TSHR. Functional characterization of the mutant receptor revealed constitutive activation of the Gs/adenylyl cyclase pathway, in contrast basal activity of the Gq/11 pathway was comparable to the wild-type. The bovine TSH-induced cAMP accumulation was slightly reduced, but IP3 signaling was impaired.ConclusionWe identified a new TSHR germline mutation (I486N) in a neonate with non-autoimmune sporadic hyperthyroidism. The mutation is located at the extracellular loop 1 and exhibits an increase in basal cAMP accumulation, but unexpectedly impairs the capability for TSH induced Gq mediated signaling. The TSHR homology model suggests isoleucine 486 as a potential key-player for induction of signal transduction by an interplay with further activation sensitive extracellular parts.

A Family with Congenital Hypothyroidism Caused by a Combination of Loss-of-Function Mutations in the Thyrotropin Receptor and Adenylate Cyclase-Stimulating G Alpha-Protein Subunit Genes

Resistance to thyrotropin (TSH) causes congenital hypothyroidism (CH). TSH receptor (TSHR) and adenylate cyclase-stimulating G alpha protein subunit (GNAS) loss-of-function mutations cause TSH resistance. We describe a family with TSH resistance and CH bearing a combination of inactivating mutations in TSHR and GNAS genes. We describe studies to determine the molecular mechanisms involved in TSH resistance in this family. DNA sequencing to identify TSHR and GNAS gene mutations was performed. In vitro effects of the mutations on cAMP production and TSH binding were investigated in COS7 cells. cAMP production was evaluated by transfecting a cAMP response element (CRE)-luciferase reporter with pSVL-TSHR and pSVK3-GNAS vectors. For binding studies, cells transfected with pSVL-TSHR vectors were incubated with iodine-125 bovine TSH ((125)IbTSH). Family members with and without CH were heterozygous for the TSHR mutant p.E34K or the GNAS mutant c.750_751insA (=GNASMut). The propositus had CH and he was heterozygous for TSHR p.E34K; his mother, also heterozygous for TSHR p.E34K, did not have CH. The euthyroid propositus' wife was heterozygous for GNASMut. The propositus' two daughters had CH, one was heterozygous for GNASMut and the other a compound heterezygous for TSHR p.E34K and GNASMut. Albright's hereditary osteodystrophy phenotype was present in those with GNASMut mutation but only the daughters had pseudohypoparathyroidism type 1a. Cells transfected with TSHRE34K had lower TSH affinity and less CRE-luciferase response than cells transfected with TSHR wild-type (WT). Cells transfected with GNASMut did not stimulate CRE-luciferase activity, but when cells were transfected with GNASMut plus GNASWT, a similar response to GNASWT alone was observed. The combination of TSHRWT and GNASWT showed higher CRE-luciferase response than TSHRWT and TSHRE34K with either GNASWT or GNASWT plus GNASMut. CH was caused by loss-of-function mutations in TSHR and/or GNAS. The absence of CH in the propositus' mother argues against a role for TSHR p.E34K being the only cause of CH. The minimal thyroidal phenotypic differences between the sisters with pseudohypoparathyroidism type 1a and TSH resistance, both heterozygous for GNAS c.750_751insA but only one bearing the TSHR p.E34K mutant, suggest that the main cause for CH was preferential expression of the mutated maternal GNAS allele in the thyroid gland.

Thyroid Stimulating Hormone Receptor (TSHR) Intron 1 Variants Are Major Risk Factors for Graves' Disease in Three European Caucasian Cohorts

BackgroundThe thyroid stimulating hormone receptor (TSHR) gene is an established susceptibility locus for Graves' disease (GD), with recent studies refining association to two single nucleotide polymorphisms (SNPs), rs179247 and rs12101255, within TSHR intron 1.Methodology and Principal FindingsWe aimed to validate association of rs179247 and rs12101255 in Polish and UK Caucasian GD case-control subjects, determine the mode of inheritance and to see if association correlates with specific GD clinical manifestations. We investigated three case-control populations; 558 GD patients and 520 controls from Warsaw, Poland, 196 GD patients and 198 controls from Gliwice, Poland and 2504 GD patients from the UK National collection and 2784 controls from the 1958 British Birth cohort. Both rs179247 (P = 1.2×10−2–6.2×10−15, OR = 1.38–1.45) and rs12101255 (P = 1.0×10−4–3.68×10−21, OR = 1.47–1.87) exhibited strong association with GD in all three cohorts. Logistic regression suggested association of rs179247 is secondary to rs12101255 in all cohorts. Inheritance modeling suggested a co-dominant mode of inheritance in all cohorts. Genotype-phenotype correlations provided no clear evidence of association with any specific clinical characteristics.ConclusionsWe have validated association of TSHR intron 1 SNPs with GD in three independent European cohorts and have demonstrated that the aetiological variant within the TSHR is likely to be in strong linkage disequilibrium with rs12101255. Fine mapping is now required to determine the exact location of the aetiological DNA variants within the TSHR.

Sporadic Nonautoimmune Neonatal Hyperthyroidism Due to A623V Germline Mutation in the Thyrotropin Receptor Gene-Case Report

Neonatal hyperthyroidism is a rare disorder and occurs in two forms. An autoimmune form is associated with maternal Graves' disease, resulting from transplacental passage of maternal thyroid−stimulating antibodies and a nonautoimmune form is caused by gain of function mutations in the thyrotropin receptor (TSHR) gene. Thyrotoxicosis caused by germline mutations in the TSHR gene may lead to a variety of clinical consequences. To date, 55 activating mutations of the TSHR gene have been documented. Fourteen cases with sporadic activating TSHR germline mutations have been described. Here we report a male infant with nonautoimmune hyperthyroidism due to an activating germline TSHR mutation (A623V), whose clinical picture started in the newborn period with severe hyperthyroidism. His parents did not have the same mutation. This mutation had been previously detected as a somatic mutation in patients with toxic adenomas. This is the first report of a sporadic case of nonautoimmune congenital hyperthyroidism associated with A623V mutation.Conflict of interest:None declared.

Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations

Three syndromes affecting the thyroid gland are described in the literature separately: familial nonautoimmune hyperthyroidism, sporadic congenital nonautoimmune hyperthyroidism, and autonomous adenomas. Recent studies have shown that these three syndromes are caused by similar activating mutations of the TSH receptor gene (TSHR), and that the consequences of these mutations on the physiology and gene expression of the thyroid are qualitatively, but not quantitatively, similar. The three syndromes and two suggested unrecognized variants are in fact facets of the same disease, genetic hyperthyroidism due to TSHR mutations, the expression of which depends on the intensity of activation, its timing, and on the number of affected cells.

Reduced fertility with impairment of early-stage embryos observed in mice lacking Lgr4 in epithelial tissues

Lgr4 is one of the genes identified as novel G protein-coupled receptor genes designated Lgr4-Lgr8, with high homology with FSH receptor, LH receptor, and TSH receptor genes, but studies of Lgr4-mutant mice have suggested that Lgr4 has essential functions in development. This is the first report describing the relationship between the functions of Lgr4 and female reproductive systems.

Genetic Susceptibility to Autoimmune Thyroid Disease: Past, Present, and Future

Autoimmune thyroid diseases (AITD), including Graves' disease and Hashimoto's thyroiditis, arise due to complex interactions between environmental and genetic factors. There are sound data coming from epidemiological, family, and twin studies demonstrating a strong genetic influence on the development of AITD. In this review we summarize the new findings on the genetic susceptibility to AITD focusing on emerging mechanisms of susceptibility. Candidate gene analysis, whole-genome linkage screening, genome-wide association studies, and whole-genome sequencing are the major technologies that have advanced this field, leading to the identification of at least seven genes whose variants have been associated with AITD. One of the major ones is the HLA-DR gene locus. Recently, it was shown that substitution of the neutral amino acids Ala or Gln with arginine at position beta 74 in the HLA-DR peptide-binding pocket is key to the etiology of both Graves' disease and Hashimoto's thyroiditis. Several other genes have also been shown to confer susceptibility to AITD. These can be classified into two groups: (i) immune regulatory genes (cytotoxic T lymphocyte-associated protein 4, CD40, protein tyrosine phosphatase-22, and CD25) and (ii) thyroid-specific genes (thyroglobulin and thyrotropin receptor genes). The influence of individual genes on the development of AITD when assessed in a population appears to be weaker than would be expected from the data showing strong genetic susceptibility to AITD. Two possible mechanisms explaining this discrepancy are gene-gene interactions and subset effects. Significant progress has been made in our understanding of the immunogenetic mechanisms leading to thyroid autoimmunity. For the first time we are beginning to unravel these mechanisms at the molecular level. It is hoped that these new data will be translated into novel therapies and prevention strategies in AITD, such as costimulatory blockade.

The Genetics of the Thyroid Stimulating Hormone Receptor: History and Relevance

The thyroid stimulating hormone receptor (TSHR) is the key regulator of thyrocyte function. The gene for the TSHR on chromosome 14q31 has been implicated as coding for the major autoantigen in the autoimmune hyperthyroidism of Graves' disease (GD) to which T cells and autoantibodies are directed. The TSHR is a seven-transmembrane domain receptor that undergoes complex posttranslational processing. In this brief review, we look at the genetics of this important autoantigen and its influence on a variety of tissue functions in addition to its role in the induction of GD. There is convincing evidence that the TSH receptor gene confers increased susceptibility for GD, but not Hashimoto's thyroiditis. GD is associated with polymorphisms in the intron 1 gene region. How such noncoding nucleotide changes influence disease susceptibility remains uncertain, but is likely to involve TSHR splicing variants and/or microRNAs arising from this gene region. Whether such influences are confined to the thyroid gland or whether they influence cell function in the many extrathyroidal sites of TSHR expression remains unknown.