Familial Nonautoimmune Hyperthyroidism Research Articles

Report of a family with three generations of undiagnosed familial nonautoimmune hyperthyroidism.

SummaryFamilial nonautoimmune hyperthyroidism (FNAH) is rare and occurs due to a constitutively activating thyroid-stimulating hormone receptor (TSHR) germline mutation. Forty-one families with FNAH have been reported so far. In the study, 17 of 41 families were not diagnosed with FNAH until three generations or more were described with hyperthyroidism. We report a case of FNAH diagnosed in the third generation. The index patient was diagnosed with hyperthyroidism at age 3. Large fluctuations in thyroid hormone levels occurred during anti-thyroid drug treatment, and he developed a goiter. The patient’s mother had similar history, requiring two surgical interventions and radioiodine treatment. The younger brother of the index patient did not experience large thyroid hormone level fluctuations, nor increased thyroid growth. A heterozygous TSHR c.1357A>G mutation, resulting in a M453V amino acid exchange, was detected in all three patients leading to FNAH diagnosis, with complete genotype–phenotype segregation. Based on Sorting intolerant from tolerant (SIFT) and PolyPhen2 scores of 0.01 and 0.99, respectively, an effect on protein function can be assumed. As illustrated by this family with FNAH, total thyr oidectomy is necessary for patients with nonautoimmune hyperthyroidism. Development of goiter is common, anti-thyroid drug treatment is often difficult, and remission of hyperthyroidism does not occur after discontinuation of anti-thyroid drug treatment. Thus, early diagnosis and appropriate treatment of FNAH is necessary to avoid predictable, unnecessary complications and further surgical interventions.Learning pointsIn the study, 19/42 cases of familial nonautoimmune hyperthyroidism (FNAH), including the reported case, were not diagnosed as FNAH until the third generation; this lead to suboptimal treatment and frequent relapses of nonautoimmune hyperthyroidism (NAH).Detection of thyroid-stimulating hormone receptor (TSHR) mutations in patients with suspected FNAH to confirm diagnosis is essential to ensure proper treatment for the patient and further affected family members.NAH will persist without proper treatment by total thyroidectomy.Symptoms and age of onset may vary between family membersAll family members with a TSHR germline mutation should be monitored with thyroid-stimulating hormone and for symptoms throughout their lives.

Familial Non-autoimmune Hyperthyroidism in Family Members Across Four Generations Due To a Novel Disease-causing Variant in The Thyrotropin Receptor Gene.

Activating disease-causing variants in the thyrotropin-receptor (TSHR) gene are associated with familial or sporadic congenital non-autoimmune hyperthyroidism. Familial non-autoimmune hyperthyroidism (FNAH) is a rare form of hyperthyroidism with 41 families reported so far in the TSHR gene mutation database. We present clinical and genetic features of 11 patients with FNAH across four generations of a Slovenian family. They all developed clinical features of hyperthyroidism but did not show characteristics of autoimmune hyperthyroidism. Members of the initially diagnosed generation were diagnosed as hyperthyrotic after they developed cardiac complications (rhythm disorders, thromboembolic events, cardiac insufficiency), while patients in the younger generations were diagnosed earlier, and consequently, early cardiovascular complications were less frequent. All patients had a novel heterozygous TSHR variant NP_ 000360.2: p.Met453Val (NM_000369.2: c.1357A>G) predicted to be pathogenic. Therefore, besides expending the mutational spectrum of the activating TSHR variants in FNAH, our experience with this multi-generation family confirms the need for early diagnosis and appropriate treatment of FNAH.

A Case of Familial Nonautoimmune Hyperthyroidism During Pregnancy

Familial nonautoimmune hyperthyroidism (FNAH) is a rare disease. To date there are few, if any, reports of pregnancies in women with FNAH. Our objective here is to present such a case. Free thyroxine (free T4), free triiodothyronine (free T3), thyroid-stimulating hormone (TSH), and antibodies related to the thyroid were measured. Fetal thyroid function indicators including thyroid volume and ossification were checked using ultrasound. Thyroid-stimulating hormone receptor (TSHR) gene analyses were performed. The patient was a 30-year-old woman with no past medical history. She was introduced to our hospital in the fifth gestational week for pregnancy care because her family history revealed that her mother had nonautoimmune hyperthyroidism with a TSHR-activating germ-line mutation (Asn406Ser). The serum free T4 was 1.88 ng/dL (normal, 0.62 to 1.19 ng/dL), free T3 was 3.27 pg/mL (normal, 2.55 to 3.88 pg/mL), TSH was 0.02 μIU/mL (normal, 0.007 to 3.619 μIU/mL), and TSHR was negative which were considered to be consistent with mild primary hyperthyroidism. Serum free T4, free T3, and TSH concentrations were monitored every 4 to 6 weeks with a peak free T4 of 2.23 ng/dL noted at gestational week 9. The patient had no signs related to hyperthyroidism throughout pregnancy. The patient delivered a 3,518 g girl at 40 weeks of gestation. Genetic analysis of her TSHR gene showed heterozygous Asn406Ser mutation. The offspring did not show any signs of prenatal hyperthyroidism, and thyroid function at day 6 after delivery revealed a free T4 of 2.41 ng/dL (normal, 1.83 to 2.91 ng/dL) and a TSH of 3.55 μIU/mL (normal, 0.51 to 4.57 μIU/mL). Women with FNAH and mild thyrotoxicosis prior to pregnancy may have continuous hyperthyroidism with additional change due to the series of human chorionic gonadotropin secretion during pregnancy.

Case Reports of Familial Non-autoimmune Hyperthyroidism in Two Malaysian Families due to Germline-activating Mutations in the Thyrotropin Receptor Gene

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2012 European Thyroid Association Guidelines for the management of familial and persistant sporadic non-autoimmune hyperthyroidism caused by thyroid-stimulating hormone receptor germline mutations

2012 European Thyroid Association Guidelines for the management of familial and persistant sporadic non-autoimmune hyperthyroidism caused by thyroid-stimulating hormone receptor germline mutations

Lack of association between autonomously functioning thyroid nodules and germline polymorphisms of the thyrotropin receptor and Gαs genes in a mild to moderate iodine-deficient Caucasian population.

Mutations of the thyrotropin receptor (TSHR) and/or Gαs gene have been found in a number of, but not all, autonomously functioning thyroid nodules (AFTNs). Recently, in a 15-year-old girl with a hyperfunctioning papillary thyroid carcinoma, we found two somatic and germline single nucleotide polymorphisms (SNPs): a SNP of the TSHR gene (exon 7, codon 187) and a SNP of Gαs gene (exon 8, codon 185). The same silent SNP of the TSHR gene had been reported in patients with AFTN or familial non-autoimmune hyperthyroidism. No further data about the prevalence of the two SNPs in AFTNs as well as in the general population are available in the literature. To clarify the possible role of these SNPs in predisposing to AFTN. Germline DNA was extracted from blood leukocytes of 115 patients with AFTNs (43 males and 72 females, aged 31-85 years, mean ± SD = 64 ± 13) and 100 sex-matched healthy individuals from the same geographic area, which is marginally iodine deficient. The genotype distribution of the two SNPs was investigated by restriction fragment length polymorphism-polymerase chain reaction. The prevalence of the two SNPs in our study population was low and not different to that found in healthy individuals: 8 % of patients vs. 9 % of controls were heterozygous for the TSHR SNP and 4 % patients vs. 6 % controls were heterozygous for the Gαs SNP. One patient harbored both SNPs. These results suggest that these two SNPs do not confer susceptibility for the development of AFTN.

A Japanese family with familial nonautoimmune hyperthyroidism with a novel mutation (Asn406Ser) in extracellular domain of thyrotrophin receptor

A Japanese family with familial nonautoimmune hyperthyroidism with a novel mutation (Asn406Ser) in extracellular domain of thyrotrophin receptor

Late Manifestation of Subclinical Hyperthyroidism After Goitrogenesis in an Index Patient with a N670S TSH Receptor Germline Mutation Masquerading as TSH Receptor Antibody Negative Graves’ Disease

In 27 families with familial non-autoimmune hyperthyroidism (FNAH) reported up to date, the onset of hyperthyroidism varies from 18 months to 60 years. Also the manifestation of goitres is variable in these families. A 74-year-old woman first presented at the age of 69 years with tachyarrhythmia and hypertension. After initial treatment of her hypertension and oral anticoagulation for her intermittent atrial fibrillation, a thyroid workup revealed a suppressed TSH and normal fT3 and fT4. TPO, TSH receptor (TSHR), and thyroglobulin antibodies were negative. Thyroid ultrasound revealed a thyroid volume of 102 ml with several nodules with diameters of up to 2.6 cm right and up to 1.8 cm left. Scintigraphy showed a homogeneous Technetium-99 m ((99 m)Tc) uptake of 1.27%. She was subsequently treated with 1 GBq radioiodine ((131)I). At the age of 74, her thyroid function was normal and her thyroid volume decreased to 90 ml. Because of the diffuse (99 m)Tc uptake and the negative TPO, TSHR, and thyroglobulin antibodies, genetic analysis of her TSHR gene was performed, in spite of her negative family history for hyperthyroidism. Sequencing revealed a N670S TSHR germline mutation. Previous in vitro characterisation of this TSHR mutation suggests a weak constitutive activity, yet the experimental data are ambiguous. This case illustrates the necessity to analyse patients with hyperthyroidism accompanied by diffuse (99 m)Tc uptake and negative TPO, TSHR, and thyroglobulin antibodies for TSHR germline mutations. Moreover, it demonstrates that TSHR germline mutations may first lead to longstanding nodular goitrogenesis before the late manifestation of subclinical hyperthyroidism.

Sporadic congenital nonautoimmune hyperthyroidism caused by P639S mutation in thyrotropin receptor gene

Germline mutations of thyrotropin receptor (TSHR) gene determining a constitutive activation of the receptor were identified as a molecular cause of familial or sporadic congenital nonautoimmune hyperthyroidism (OMIM: 609152) (Nat Genet 7:396-401, 1994; N Engl J Med 332:150-154, 1995; Acta Endocrinol (Copenh) 100:512-518, 1982). We report the case of an Italian child subjected to the first clinical investigation at 24months for an increased growth velocity; biochemical investigation showed high FT4 and FT3 serum values and undetectable thyrotropin in the absence of anti-thyroid antibodies; the thyroid gland was normal at ultrasound examination. Treatment with methimazole was started at the age of 30months when her growth velocity was high and the bone age was advanced. DNA was extracted from her parents', brother's, and the patient's blood. Exons 9 and 10 of the TSHR gene were amplified by polymerase chain reaction and subjected to direct sequencing. In proband, a heterozygous substitution of cytosine to thymine determining a proline to serine change at position 639 (P639S) of the TSHR was detected while the parents and brothers of the propositus, all euthyroid, showed only the wild-type sequence of the TSHR gene. This mutation was previously described as somatic in patients affected by hyperfunctioning thyroid nodules and as germline in a single Chinese family affected by thyrotoxicosis and mitral valve prolapse. This constitutively activating mutation is able to activate both the cyclic AMP and the inositol phosphate metabolic pathways when expressed in a heterologous system. In conclusion, we describe the first case of sporadic congenital nonautoimmune hyperthyroidism caused by de novo germinal P639S mutation of TSHR.

Shared Sporadic and Somatic Thyrotropin Receptor Mutations Display More ActiveIn VitroActivities than Familial Thyrotropin Receptor Mutations

Germline thyrotropin receptor (TSHR) mutations are associated with sporadic congenital nonautoimmune hyperthyroidism and familial nonautoimmune hyperthyroidism. Somatic TSHR mutations are associated with toxic thyroid nodules (TTNs). The objective of the study was to define a relation of the clinical appearance and the in vitro activity (IVA) of the TSHR mutations described by several authors for these thyroid disorders. We analyzed the IVAs published as linear regression analysis (LRA) of the constitutive activity as a function of the TSHR expression and the basal cyclic adenosine monophosphate (cAMP) values to determine differences between exclusively somatic, exclusively familial, and shared sporadic and somatic TSHR-mutations. Further, we investigated correlations of the LRAs/basal cAMP values with clinical activity characteristics (CACs) of TTNs, such as largest diameter of the TTN and the age of the patient at thyroid surgery. Shared sporadic and somatic mutations showed higher median LRA (14.5) and higher median basal cAMP values (fivefold) than exclusively familial mutations (6.1, p = 0.0002; 2.9-fold, p < 0.0001, respectively). Moreover, mutations shared between sporadic congenital nonautoimmune hyperthyroidism and toxic thyroid nodules (TTNs) showed higher median LRA/basal cAMP values (p < 0.0001) than exclusively somatic mutations in TTNs (5.1; 3.89-fold, respectively). Exclusively somatic mutations and exclusively familial mutations showed no significant difference in their median LRA values (p = 0.786) but a significant difference for basal cAMP values (p = 0.0006). The two examined CACs showed no correlation with the IVA characterized by LRA/basal cAMP values or with the presence or absence of a TSHR-mutation. This systematic analysis of published constitutively activating TSHR-mutations, their CACs, and their IVA provides evidence for higher IVA of shared sporadic and somatic TSHR mutations as compared with familial TSHR mutations. CACs of somatic TSHR mutations in TTNs did not have a clear association with the IVA as characterized by LRA or basal cAMP values.

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.

Detection of combined genomic variants in a Jordanian family with familial non-autoimmune hyperthyroidism

Five patients, four brothers and their paternal aunt, presented with a history of overt hyperthyroidism and goiter. Hyperthyroidism in this family was remarkable for its poor response to carbimazole (30-50 mg/d). The thyroid ultrasound showed a diffusely enlarged gland in all the affected members, and thyroid stimulating antibodies (TSAB) were negative. Screening for germline mutations in thyroid stimulating hormone (TSH) receptor (TSHR) gene was performed by direct sequencing of genomic DNA extracted from peripheral blood leukocytes of all family members. The sequence analysis of all TSHR gene exons and intron borders revealed two genomic variants. The first was a single nucleotide polymorphism (SNP) within exon seven (Asn187Asn), whereas the other was located in intron seven (IVS7+68TG). All affected members, two asymptomatic brothers with sub-clinical hyperthyroidism, and their father were heterozygous for those two genomic variants. Anti-thyroid drug treatment for several months successfully relieved symptoms in one subject, whereas the remaining patients required total thyroidectomy to control their disease. This is the first Jordanian family with familial non-autoimmune hyperthyroidism, with mutations affecting the TSHR gene.

Thyroid Gene Expression in Familial Nonautoimmune Hyperthyroidism Shows Common Characteristics with Hyperfunctioning Autonomous Adenomas

Dominant activating mutations of the TSH receptor are the cause of familial nonautoimmune hyperthyroidism (FNAH) (inherited mutations affecting the whole gland since embryogenesis) and the majority of hyperfunctioning autonomous adenomas (AAs) (somatic mutations affecting only one cell later in the adulthood). The objective of the study was defining the functional and molecular phenotypes of FNAH and comparing them with the ones of AA. Functional phenotypes were determined in vitro and molecular phenotypes by hybridization on microarray slides. Nine patients with FNAH were investigated, six for functional in vitro study of the tissue and five for gene expression. Iodide metabolism, H(2)O(2), cAMP, and inositol phosphate generation in FNAH slices stimulated or not with TSH were normal. The mitogenic response of cultured FNAH thyrocytes to TSH was normal but more sensitive to the hormone. Gene expression profiles of FNAH and AAs showed that among 474 genes significantly regulated in FNAH, 93% were similarly regulated in AAs. Besides, 783 genes were regulated only in AAs. Bioinformatic analysis pointed out common down-regulations of genes involved in immune response, cell/cell and cell/matrix adhesions, and apoptosis. Pathways up-regulated only in AAs mainly involve diverse biosyntheses. These results are consonant with the larger growth of AAs than FNAH tissues. Whether hereditary or somatic after birth, activating mutations of the TSH receptor have the same qualitative consequences on the thyroid cell phenotype, but somatic mutations in AAs have a much stronger effect than FNAH mutations. Both are variants of one disease: genetic hyperthyroidism.

A New Silent Germline Mutation of the TSH Receptor: Coexpression in a Hyperthyroid Family Member with a Second Activating Somatic Mutation

Up to date, three thyroid-stimulating hormone receptor (TSHR) germline variants have been reported for which no functional consequences have been detected by in vitro characterizations. However, familial nonautoimmune hyperthyroidism and hot nodules are clearly associated with constitutively activating TSHR germline mutations. We describe a family with a new TSHR germline mutation that is associated with euthyroidism in 13 family members and hyperthyroidism in 1 family member. Mutation analysis of the TSHR gene was performed by denaturing gradient gel electrophoresis. TSHR constructs were characterized by determination of cell surface expression, 3'-5'-cyclic adenosine monophosphate (cAMP) accumulation, and constitutive cAMP activity. A novel TSHR germline mutation (N372T) was found in a man who presented with thyrotoxicosis. The mutation was also detected in 13 family members, all of whom were euthyroid. Interestingly, an additional constitutively active somatic mutation (S281N) was identified on the second parental TSHR allele of the hyperthyroid index patient. Linear regression analysis showed a lack of constitutive activity for N372T. Moreover, coexpression studies of N372T with S281N did not reveal any evidence for a functional influence of N372T on the constitutively active mutation (CAM). N372T is unlikely to cause altered thyroid function. This is consistent with the finding that only the index patient with the additional somatic mutation S281N was hyperthyroid.

A novel TSHR gene mutation (Ile691Phe) in a Chinese family causing autosomal dominant non-autoimmune hyperthyroidism

Familial non-autoimmune hyperthyroidism is a rare autosomal dominant genetic disease resulting from activating mutations in the thyroid-stimulating hormone receptor (TSHR) gene. In this work a Chinese family with autosomal dominant non-autoimmune hyperthyroidism across four generations was collected. The strongest evidence for linkage in this study occurred on chromosome 14q24.2-31.3. By mutation scan of the TSHR gene located within the region of interest, a heterozygote substitution (A > T) at position 2071 of the TSHR was found, changing isoleucine 691 to phenylalanine. Our study identified the first germline mutation in the intracellular C-terminal domain of TSHR.

A New Case of Familial Nonautoimmune Hyperthyroidism Caused by the M463V Mutation in the TSH Receptor with Anticipation of the Disease Across Generations: A Possible Role of Iodine Supplementation

Hereditary (familial) nonautoimmune hyperthyroidism (FNAH) is caused by activating thyroid-stimulating hormone (thyrotropin) receptor (TSHR) germline mutations. We describe a family with recurrent thyrotoxicosis and goiter across three generations, including an 8-year-old girl. Sequences of the TSHR gene in the index patient, her father, her paternal grandmother, and a paternal uncle demonstrated the presence of an identical germline TSHR mutation. The mutation was heterozygous and determined the substitution of valine for methionine (codon 463; ATG-->GTG) in the second transmembrane domain of the TSHR in all the affected patients, but in none of the unaffected family members. We compared the clinical presentation of FNAH in the family reported by us with the other cases harboring the same mutation reported in the literature. This analysis revealed high variability in the phenotypical expression of the disease. In the family reported by us, we also observed a clear anticipation of the onset of the disease across generations, and we discussed whether such a phenomenon can be the consequence of the increased iodine supplementation in the area where the family lives.

Familial non-autoimmune hyperthyroidism due to a novel TSHR germline mutation (Ile568Val)

A 16 yr. old girl presented with a 4 month history of overt hyperthyroidism and goitre. She had a strong family history of recurrent hyperthyroidism affecting both her father and her paternal grandmother. The grandmother had undergone partial thyroidectomy at age 25 for toxic multinodular goitre and had suffered 3 relapses of hyperthyroidism, which were poorly controlled by further sugery and antithyroid medication. The father underwent thyroid surgery at 34 yr. and had a first relapse of hyperthyroidism at 38 yr., for which he received RIT. At 43 yr. he has subclinical hyperthyroidism. Hyperthyroidism in the girl was remarkable for its poor response to methimazole (40–60mg/d). Thyroid ultrasound showed a diffusely enlarged gland with normal echogeneity. TSAB and TPO-Ab were negative. Molecular analysis of genomic DNA extracted from peripheral blood leucocytes showed a TSHR germline mutation in codon 568 with a novel amino acid exchange of valine for isoleucine in the girl and her father. Only the wild-type TSHR sequence was found in the mother. Constitutively activating properties have previously been described for the Ile568Thr mutation, located in the 2nd extracellular TSHR loop. As a consequence of the molecular findings, the girl will undergo total thyroidectomy in October 2004. This is the second Saxonian family with autosomal-dominant non-autoimmune hyperthyroidism, adding to a total of 13 families and 11 individuals with activating TSHR germline mutations world-wide. Functional characterization of the novel Ile568Val TSHR germline mutation is in progress. We suggest that the condition may indeed be more frequent than hitherto thought and that consequent assessment of a family history in children as well as adults with thyroid autonomy will contribute to ensure correct diagnosis and adequate treatment of patients with activating TSHR germline mutations.

Hyperthyroïdie néonatale sévère, révélatrice d’une maladie de basedow maternelle

Two of every thousand pregnancies are complicated by Graves' disease. Diagnosis is suggested by maternal disorders (tachycardia, exophthalmia, weight loss.) or fetal disorders (tachycardia, intra-uterine growth retardation, preterm birth.). Due to transfer into the fetal compartment of maternal antibodies which stimulate the fetal thyroid by binding to the thyroid thyrotropin (TSH) receptor, only 1% of children born to these mothers are described as having hyperthyroidism. Neonatal thyrotoxicosis disappears with clearance of the maternal antibodies; clinical signs usually disappear during the first four Months of life. The most frequent neonatal clinical signs of thyrotoxicosis are tachycardia, goiter, hyperexcitability, poor weight gain, hepatosplenomegaly, stare and eyelid retraction. Diagnosis is based on determination of the blood level of triiodothyronine (T3), thyroxine (T4) and TSH. To confirm the nature of hyperthyroidism, thyroid-stimulating immunoglobulins (TSI) should be assayed. The kinetics of TSI provides a guide for therapeutic adaptation and disappearance of TSI is a sign of recovery. Rare cases of familial non-autoimmune hyperthyroidism have been shown to be caused by germline mutation of the thyrotropin receptor. We report a case of severe neonatal hyperthyroidism which led to the diagnosis of maternal Graves' disease.

The spectrum of thyroid diseases in childhood and its evolution during transition to adulthood: natural history, diagnosis, differential diagnosis and management.

In this contribution, we review current knowledge on the pathogenesis, diagnosis and differential diagnosis of thyroid disorders in childhood and adolescence, as well as present an update on therapy methods and management guidelines for these disorders. This overview is conceptually divided into two parts, one focusing on thyroid functional disorders, i.e. conditions leading to hyper- and hypothyroidism, and another one pertinent to structural abnormalities of the thyroid gland, i.e. nodular disorders and thyroid cancer. Currently, congenital hypothyroidism is diagnosed in a much more timely fashion rather than in the past, rendering hypothyroidism-related mental retardation and developmental deficits very rare in newborns and children and, hence, diminishing significantly its public health impact. At the same time, considerable advances have occurred in our understanding of the molecular basis of several genetic conditions affecting the thyroid gland in childhood, such as familial non-autoimmune hyperthyroidism, as well as of the pathways leading to thyroid neoplasia.

The First Activating TSH Receptor Mutation in Transmembrane Domain 1 Identified in a Family with Nonautoimmune Hyperthyroidism

Sporadic and familial nonautoimmune hyperthyroidism are very rarely occurring diseases. Within the last years constitutively activating TSH receptor mutations were identified as one possible pathomechanism. Except for S281N in the extracellular N-terminal domain, all other germline mutations are located in the transmembrane domains 2, 3, 5, 6, and 7 of the TSH receptor, whereas no mutation was reported in transmembrane domains 1 and 4 to date. Here we report the first family with a constitutively active TSHR mutation in transmembrane domain 1 resulting in a substitution of the conserved Gly431 for Ser. This mutation was found in the investigated patient, his father, and the paternal grandmother. As known from other familial cases of nonautoimmune hyperthyroidism, the age of onset of the disease was variable, ranging from early childhood in the patient and his father to adolescence in the grandmother. Functional characterization of this mutation showed a constitutive activation of the Gs/adenylyl cyclase system. Moreover, this germline mutation also activates the Gq/11/phospholipase C pathway. The importance of Gly431 for receptor quiescence is supported further by introduction of other mutations at this position, all leading to constitutive receptor activity. Our data show now that constitutively activating mutations can be found in the entire transmembrane domain region of the TSH receptor, indicating the important role of all parts of the transmembrane domain region for maintaining the inactive receptor conformation.