Alternative titles; symbols
HGNC Approved Gene Symbol: TSHR
SNOMEDCT: 1230272009, 703309000;
Cytogenetic location: 14q31.1 Genomic coordinates (GRCh38) : 14:80,955,621-81,146,306 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q31.1 | Hyperthyroidism, familial gestational | 603373 | Autosomal dominant | 3 |
| Hyperthyroidism, nonautoimmune | 609152 | Autosomal dominant | 3 | |
| Hypothyroidism, congenital, nongoitrous, 1 | 275200 | Autosomal recessive | 3 | |
| Thyroid adenoma, hyperfunctioning, somatic | 609152 | 3 | ||
| Thyroid carcinoma with thyrotoxicosis, somatic | 609152 | 3 |
Nagayama et al. (1989) isolated a TSHR cDNA from a human thyroid cDNA library. The deduced 764-amino acid protein has a molecular mass of 86.8 kD and contains a signal peptide, 7 transmembrane regions, 5 potential glycosylation sites, and a short intracytoplasmic region. The TSHR cDNA encoded a functional receptor that activated adenylate cyclase in response to TSH.
Libert et al. (1989) used a dog Tshr cDNA to isolate a human TSHR cDNA from a thyroid cDNA library. The cDNA encodes a deduced 744-amino acid protein with 90.3% homology to the dog protein. Two major 4.6- and 4.4-kb mRNA transcripts were identified, suggesting alternative splicing.
By analyzing several TSHR cDNA clones, Misrahi et al. (1990) determined that the mature TSHR polypeptide contains 743 amino acids with a calculated molecular mass of 84.5 kD. The putative TSH receptor has a 394-residue extracellular domain, a 266-residue transmembrane domain, and an 83-residue intracellular domain. The authors observed a high degree of homology with the luteinizing hormone/choriogonadotropin receptor (LHCGR; 152790).
Kakinuma and Nagayama (2002) found that the TSHR gene can express at least 5 alternatively spliced forms.
The TSH receptor differs from the LHCG receptor by the presence of 2 unique insertions of 8 and 50 amino acids in the extracellular domain. Wadsworth et al. (1990) showed that the 8-amino acid tract near the amino terminus of the TSH receptor is an important site of interaction with both TSH and autoantibodies against the TSH receptor (thyroid-stimulating immunoglobulins, TSI). Either deletion or substitution of this region abolished the interaction, whereas a deletion of the 50-amino acid tract had no effect.
Contiguous to the 5-prime end of the thyroid transcription factor-1 (TTF1; 600635) element upstream and within the TSHR promoter is an element on the noncoding strand with single-strand binding activity that is important for regulation of TSHR expression. Ohmori et al. (1996) identified a cDNA encoding a single-strand binding protein (SSBP), referred to as SSBP1, that forms a specific complex with this element on the noncoding strand of TSHR. SSBP1 is a ubiquitous transcription factor that contributes to TSHR maximal expression, and mutation analyses showed that a GXXXXG motif is important for the binding and enhancer function of SSBP1. The authors concluded that the common transcription factors regulate TSHR and major histocompatibility gene expression. They also concluded that SSBP1 is a member of a family of SSBPs that interact with RNA and with the promoter of retroviruses, and are important in RNA processing. Members of this family also can interact with c-myc (190080), a gene linked to growth and DNA replication.
The high sequence homology with the LHCG receptor, which is composed of a single polypeptide chain, led many to suppose a similar structure for the TSH receptor. However, Loosfelt et al. (1992) presented evidence for a heterodimeric structure of TSHR. The extracellular (hormone-binding) alpha subunit had an apparent molecular mass of 53 kD, whereas the membrane-spanning beta subunit seemed heterogeneous and had an apparent molecular mass of 33 to 42 kD. Human thyroid membranes contained 2.5 to 3 times as many beta subunits as alpha subunits; however, the 2 subunits probably derive from a single gene since a single reading frame was demonstrated by cDNA cloning and sequencing. The exact site of cleavage that results in the 2 subunits was difficult to define.
The TSH receptor is the antigen targeted by autoantibodies in Graves disease (275000). By PCR amplification of specific cDNA, Feliciello et al. (1993) demonstrated that mature TSH receptor mRNA is expressed in the retroorbital tissue of both healthy subjects and patients with Graves disease. Of other tissues and cells tested, only thyroid tissue expressed the TSHR mRNA. The findings provided a link between orbital involvement and thyroid disease in Graves disease.
Graves et al. (1999) used epitope-mapped monoclonal and polyclonal antibodies to TSHR as immunoblot probes to detect and characterize the molecular species of the receptor present in normal human thyroid tissue. In reduced membrane fractions, both full-length (uncleaved) holoreceptor and cleavage-derived subunits of the holoreceptor were detected. Uncleaved holoreceptor species included a nonglycosylated form of apparent molecular mass 85 kD and 2 glycosylated forms of approximately 110 and 120 kD. The membranes also contained several forms of cleavage-derived TSHR alpha and beta subunits. Alpha subunits were detected by antibodies to epitopes localized within the N-terminal end of the TSHR ectodomain and migrated diffusely between 45 and 55 kD, reflecting a differentially glycosylated status. Several species of beta subunit were present, the most abundant having apparent molecular masses of 50, 40, and 30 kD. The authors concluded that posttranslational processing of the TSHR occurs in human thyroid tissue and involves multiple cleavage sites.
Lazar et al. (1999) studied the expression of 4 thyroid-specific genes (sodium-iodide symporter (NIS, or SLC5A5; 601843), thyroid peroxidase (TPO; 274500), thyroglobulin (TG; 188450), and TSHR) as well as the gene encoding glucose transporter-1 (GLUT1, or SLC2A1; 138140) in 90 human thyroid tissues. Messenger RNAs were extracted from 43 thyroid carcinomas (38 papillary and 5 follicular), 24 cold adenomas, 5 Graves thyroid tissues, 8 toxic adenomas, and 5 hyperplastic thyroid tissues; 5 normal thyroid tissues were used as reference. A kinetic quantitative PCR method, based on the fluorescent TaqMan methodology and real-time measurement of fluorescence, was used. NIS expression was decreased in 40 of 43 (93%) thyroid carcinomas and in 20 of 24 (83%) cold adenomas; it was increased in toxic adenomas and Graves thyroid tissues. TPO expression was decreased in thyroid carcinomas but was normal in cold adenomas; it was increased in toxic adenomas and Graves thyroid tissues. TG expression was decreased in thyroid carcinomas but was normal in the other tissues. TSHR expression was normal in most tissues studied and was decreased in only some thyroid carcinomas. In thyroid cancer tissues, a positive relationship was found between the individual levels of expression of NIS, TPO, TG, and TSHR. No relationship was found with the age of the patient. Higher tumor stages (stages greater than I vs stage I) were associated with lower expression of NIS and TPO. Expression of the GLUT1 gene was increased in 1 of 24 (4%) adenomas and in 8 of 43 (19%) thyroid carcinomas. In 6 thyroid carcinoma patients, 131-I uptake was studied in vivo. NIS expression was low in all samples, and 3 patients with normal GLUT1 expression had 131-I uptake in metastases, whereas the other 3 patients with increased GLUT1 gene expression had no detectable 131-I uptake. The authors concluded that (1) reduced NIS gene expression occurs in most hypofunctioning benign and malignant thyroid tumors; (2) there is differential regulation of the expression of thyroid-specific genes; and (3) an increased expression of GLUT1 in some malignant tumors may suggest a role for glucose-derivative tracers to detect in vivo thyroid cancer metastases by positron-emission tomography scanning.
Chia et al. (2007) studied the diagnostic value of circulating TSHR mRNA for preoperative detection of differentiated thyroid cancer (DTC) in patients with thyroid nodules. Based on cytology/pathology, 88 patients had DTC and 119 had benign thyroid disease. The TSHR mRNA levels in cancer patients were significantly higher than in benign disease (P less than 0.0001). At a cutoff value of 1.02 ng/g total RNA, the TSHR mRNA correctly classified 78.7% of patients preoperatively (sensitivity = 72.0%; specificity = 82.5%). Chia et al. (2007) concluded that TSHR mRNA measured with fine needle aspirations enhances the preoperative detection of cancer in patients with thyroid nodules, reducing unnecessary surgeries, and immediate postoperative levels can predict residual/metastatic disease.
Kakinuma and Nagayama (2002) determined that the TSHR gene contains 13 exons.
Akamizu et al. (1990) mapped the TSHR gene to human chromosome 14 by study of somatic cell hybrid DNAs. By in situ hybridization, Rousseau-Merck et al. (1990) and Libert et al. (1990) regionalized the gene to 14q31.
Akamizu et al. (1990) mapped the mouse Tshr gene to chromosome 12 using linkage studies in interspecies backcross mice. Wilkie et al. (1993) also localized the mouse Tshr gene to chromosome 12.
Nonautoimmune Hyperthyroidism
Duprez et al. (1994) demonstrated heterozygous constitutively activating germline mutations in the TSHR gene (603372.0019; 603372.0020) in patients with hereditary nonautoimmune hyperthyroidism (609152). The functional in vitro characteristics of these 2 mutations were similar to those already described previously for autonomously functioning thyroid adenomas (Van Sande et al., 1995), and thus explained the development of thyroid hyperplasia and hyperthyroidism in the affected patients.
Paschke and Ludgate (1997) found reports of 4 infants with sporadic congenital hyperthyroidism occurring from a de novo germline mutation. In all cases, both parents were euthyroid. The authors noted that a number of gain-of-function mutations had been observed as somatic mutations in hyperfunctioning thyroid adenomas and in familial autosomal dominant hyperthyroidism. In their Figure 1, Paschke and Ludgate (1997) outlined the constitutively activating and inactivating mutations of the TSHR gene, as well as the location of somatic mutations found in thyroid carcinomas. At some locations, several different amino acid substitutions had been described. Most gain-of-function mutations were in exon 10.
Hypothyroidism, Congenital, Nongoitrous, 1
Alberti et al. (2002) sequenced the entire TSHR gene in a series of 10 unrelated patients with slight (6.6-14.9 mU/liter) to moderate (24-46 mU/liter) elevations of serum TSH, associated with normal free thyroid hormone concentrations, consistent with a diagnosis of thyrotropin resistance (CHNG1; 275200). Thyroid volume was normal in all patients, except 2 with modest hypoplasia. Autoimmune thyroid disease was excluded in all patients on the basis of clinical and biochemical parameters. Eight patients had at least 1 first-degree relative bearing the same biochemical picture. TSHR mutations were detected in 4 of 10 (40%) cases by analyzing DNA from peripheral leukocytes (see, e.g., 603372.0006; 603372.0029; 603372.0030; 603372.0031; 603372.0013). The authors concluded that partial resistance to TSH action is a frequent finding among patients with slight hyperthyrotropinemia of nonautoimmune origin, and that heterozygous germline mutations of TSHR may be associated with serum TSH values fluctuating above the upper limit of the normal range.
Calebiro et al. (2005) cotransfected COS-7 cells with wildtype TSHR and mutant receptors (C41S, 603372.0013; C600R, 603372.0029; L467P, 603372.0030) found in patients with autosomal dominant partial TSH resistance. Variable impairment of cAMP response to bovine TSH stimulation was observed, suggesting that inactive TSHR mutants may exert a dominant-negative effect on wildtype TSHR. By using chimeric constructs of wildtype or inactive TSHR mutants fused to different reporters, the authors documented an intracellular entrapment, mainly in the endoplasmic reticulum, and reduced maturation of wildtype TSHR in the presence of inactive TSHR mutants. Fluorescence resonance energy transfer and coimmunoprecipitation experiments supported the presence of oligomers formed by wildtype and mutant receptors in the endoplasmic reticulum. Calebiro et al. (2005) concluded that their findings provide an explanation for the dominant transmission of partial TSH resistance.
Familial Gestational Hyperthyroidism
Rodien et al. (1998) described a gain-of-function mutation of the TSHR gene (603372.0024) as the cause of familial gestational hyperthyroidism (603373). The mutation rendered the thyrotropin receptor hypersensitive to chorionic gonadotropin.
Hyperfunctioning Thyroid Adenoma and Thyroid Carcinoma with Thyrotoxicosis, Somatic
In 3 of 11 hyperfunctioning thyroid adenomas (see 609152), Parma et al. (1993) identified somatic mutations in the TSHR gene (603372.0002; 603372.0003). These mutations were restricted to tumor tissue.
By direct sequencing, Fuhrer et al. (1997) screened a consecutive series of 31 toxic thyroid nodules (TTNs) for mutations in exons 9 and 10 of the TSHR gene and in exons 7 to 10 of the Gs-alpha protein gene (GNAS1; 139320). Somatic TSHR mutations were identified in 15 of the 31 (48%) TTNs. The TSHR mutations were localized in the third intracellular loop (asp619 to gly, 603372.0002; ala623 to val; and a 27-bp deletion resulting in deletion of 9 amino acids at codons 613 to 621), the sixth transmembrane segment (phe631 to leu, 603372.0004; thr632 to ile; and asp633 to glu), the second extracellular loop (ile568 to thr), and the third extracellular loop (val656 to phe). One mutation, ser281 to asn, was found in the part of the extracellular domain encoded by exon 9. All of the identified TSHR mutations resulted in constitutive activity. No mutations were found in exons 7 to 10 of GNAS1. The authors concluded that constitutively activating TSHR mutations occur in 48% of TTNs, representing the most frequent molecular mechanism known to cause TTNs.
Russo et al. (1997) identified a somatic TSHR mutation (D633H; 603372.0008) in an autonomously functioning thyroid insular carcinoma that caused severe thyrotoxicosis.
Parma et al. (1997) investigated 33 different, autonomous hot nodules from 31 patients for the presence of somatic mutations in the TSHR and Gs-alpha genes. Twenty-seven mutations (82%) were found in the TSHR gene, affecting a total of 12 different residues or locations. All but 2 of the mutations studied had previously been identified as activating mutations. The authors identified the 2 novel mutations as a point mutation causing a leu629-to-phe substitution (L629F; 603372.0022), a deletion of 12 bases removing residues 658-661 (asn-ser-lys-ile) at the C-terminal portion of exoloop 3 (del658-661). Only 2 mutations (6%) were found in Gs-alpha genes. In 4 nodules, no mutation was detected. Five residues (ser281, ile486, ile568, phe631, and asp633) were found to be mutated in 3 or 4 different nodules, making them hotspots for activating mutations. The authors concluded that in a cohort of patients from a moderately iodine-deficient area, somatic mutations increasing the constitutive activity of TSHR are the major cause of autonomous thyroid adenomas.
Possible Association with Toxic Multinodular Goiter
Toxic multinodular goiter (TMNG) represents a frequent cause of endogenous hyperthyroidism, affecting 5 to 15% of such patients. To search for alterations of TSHR in autonomously functioning thyroid nodules (AFTN) and TMNG, Gabriel et al. (1999) used bidirectional, dye primer automated fluorescent DNA sequencing of the entire transmembrane domain and cytoplasmic tail of TSHR using DNA extracted from nodular regions of 24 patients with TMNG and 7 patients with AFTN. Eight of the 24 (33.3%) patients with TMNG were heterozygous for an asp727-to-glu polymorphism (D727E) in the cytoplasmic tail of TSHR. Three of the 24 (12.5%) patients with TMNG were heterozygous for a missense mutation, and 1 patient had multiple heterozygous mutations. Two patients had silent polymorphism of codons 460 and 618. The authors found no mutations in the transmembrane domain and cytoplasmic tail of TSHR in the 7 patients with AFTN, except for a silent polymorphism of codon 460 in 1. DNA fingerprinting of codon 727 using restriction enzyme NlaIII and genomic DNA confirmed the sequencing results in all cases, indicating that the sequence alterations were not somatic in nature. This technique was also used to examine peripheral blood genomic DNA from 52 normal individuals and 49 patients with Graves disease; 33.3% of TMNG (P of 0.019 vs normal subjects), 16.3% of Graves disease patients (p of 0.10 vs normal subjects), and 9.6% of normal individuals were heterozygous for the D727E polymorphism. Expression of the D727E variant in eukaryotic cells resulted in an exaggerated cAMP response to TSH stimulation compared with that of the wildtype TSHR. The authors concluded that the germline polymorphism D727E is associated with TMNG, and suggested that its presence is an important predisposing genetic factor in TMNG pathogenesis.
Muhlberg et al. (2000) compared the D727E frequencies of 128 European Caucasian patients with toxic nonautoimmune thyroid disease (83 with toxic adenoma, 31 with toxic multinodular goiter, and 14 with disseminated autonomy) with those of 99 healthy controls and 108 patients with Graves disease. They found no significant differences in codon 727 polymorphism frequencies between patients with autonomously functioning thyroid disorders (13.3%) and the healthy control group (16.2%). Moreover, the subtypes of toxic nonautoimmune thyroid disease were not related to significant differences in codon 727 polymorphism frequencies compared with the healthy control group. There was no significant difference between the polymorphism frequency among patients with Graves disease (21.3%) and that of healthy controls. The authors concluded that there was no association between the D727E polymorphism of the TSHR and toxic thyroid adenomas or toxic multinodular goiter in their study population.
Tonacchera et al. (2000) searched for inactivating TSHR or Gs-alpha mutations in areas of toxic or functionally autonomous multinodular goiters that appeared hyperfunctioning at thyroid scintiscan but did not clearly correspond to definite nodules at physical or ultrasonographic examination. Activating TSHR mutations were detected in 14 of these 20 hyperfunctioning areas, whereas no mutation was identified in nonfunctioning nodules or areas contained in the same gland. No Gs-alpha mutation was found. The authors concluded that activating TSHR mutations are present in the majority of nonadenomatous hyperfunctioning nodules scattered throughout the gland in patients with toxic or functionally autonomous multinodular goiter.
Possible Association with Susceptibility to Graves Disease
Although Heldin et al. (1991) and Bahn et al. (1994) suggested that substitutions in the TSHR gene (D36H; 603372.0001 and pro52-to-thr; P52T) were associated with Graves disease (275000) and Graves ophthalmopathy, respectively, Simanainen et al. (1999) reported that the D36H and P52T substitutions were polymorphic variants with a frequency of approximately 5% and 7.3%, respectively. Simanainen et al. (1999) found no association between these 2 polymorphisms and Graves disease. Similarly, Kotsa et al. (1997) found no association between the TSHR P52T polymorphism and Graves disease among 180 patients with Graves disease. The variant allele was present in 8.3% of patients and 7.3% of controls.
For additional discussion of a possible association between variation in the TSHR gene and Graves disease, see 275000.
Reviews
Vassart et al. (1991) reviewed the molecular genetics of the thyrotropin receptor.
TSHR Mutation Database
Trulzsch et al. (1999) described a database of TSHR mutations. The desirability of such a database came from the growing number of mutations identified and the variety of clinical phenotypes associated with the different mutations: somatic constitutively activating mutations in toxic thyroid nodules (e.g., 603372.0002); constitutively activating germline mutations as the cause of sporadic (e.g., 603372.0004) and familial (e.g., 603372.0019) nonautoimmune autosomal dominant hyperthyroidism (609152); and inactivating mutations associated with inherited TSH resistance (275200) (e.g., 603372.0005).
Using an adenovirus-mediated mouse model of Graves disease, Chen et al. (2003) demonstrated that goiter and hyperthyroidism occurred to a significantly greater extent when the adenovirus expressed the free alpha subunit as opposed to a genetically modified TSHR that cleaves minimally into subunits (p less than 0.005). Chen et al. (2003) concluded that shed alpha subunits induce or amplify the immune response leading to hyperthyroidism in Graves disease.
Abe et al. (2003) generated Tshr-null mice by replacing exon 1 of Tshr with a GFP cassette. They detected intense GFP fluorescence in thyroid follicles. Western blot analysis showed a 50% decrease in Tshr expression in heterozygotes and no expression in Tshr-null mice. Tshr-null mice were runted and hypothyroid, and they died by age 10 weeks with severe osteoporosis and significant reduction of calvarial thickness. Profound osteoporosis and focal osteosclerosis were observed in heterozygotes. Confocal microscopy demonstrated expression of Tshr in bone cells. They found 3-fold increased expression of Tnf (191160) in the bone marrow of Tshr-null mice. Neutralizing anti-Tnf antibody inhibited enhanced osteoclastogenesis in Tshr-null bone marrow cell cultures, suggesting that TNF is a proosteoclastic signal mediating the effects of TSHR deletion. Abe et al. (2003) found that TSH activation of Tshr resulted in attenuated osteoclast formation by inhibiting Jnk (see 601158) and Nfkb (see 164011) signaling, resorption, and survival. They showed that TSH regulated osteoblast differentiation through a Runx2 (600211)- and osterix (SP7; 606633)-independent mechanism that involved downregulation of the prodifferentiation factors Lrp5 (603506) and Flk1 (KDR; 191306). Abe et al. (2003) concluded that TSH acts as a single molecular switch in the independent control of both bone formation and resorption. Hase et al. (2006) found that the increased osteoclastogenesis in homozygous and heterozygous Tshr-null mice was rescued with graded reductions in the dosage of the Tnf gene.
Rubin et al. (2010) described the use of massively parallel sequencing to identify selective sweeps of favorable alleles and candidate mutations that have had a prominent role in the domestication of chickens and their subsequent specialization into broiler (meat-producing) and layer (egg-producing) chickens. Rubin et al. (2010) generated 44.5-fold coverage of the chicken genome using pools of genomic DNA representing 8 different populations of domestic chickens as well as red jungle fowl (Gallus gallus), the major wild ancestor. Rubin et al. (2010) reported more than 7,000,000 SNPs, almost 1,300 deletions, and a number of putative selective sweeps. One of the most striking selective sweeps found in all domestic chickens occurred at the locus for thyroid-stimulating hormone receptor (TSHR), which has a pivotal role in metabolic regulation and photoperiod control of reproduction in vertebrates. Several of the selective sweeps detected in broilers overlapped genes associated with growth, including growth hormone receptor (600946), appetite, and metabolic regulation. Rubin et al. (2010) found little evidence that selection for loss-of-function mutations had a prominent role in chicken domestication, but they detected 2 deletions in coding sequences, including one in SH3RF2 (613377), that the authors considered functionally important.
In a 29-year-old patient with Graves disease (GRD1; 275000), Heldin et al. (1991) identified a somatic substitution in the TSHR gene in thyroid tissue: a G-to-C transversion, resulting in an asp36-to-his (D36H) substitution. DNA in tissues originating from all 3 germ layers showed only the germline receptor sequence. Whether the mutation was directly implicated in the pathogenesis of the patient's autoimmune thyroid disorder or had functional significance in relation to the hyperthyroidism was unclear.
In a review article, Paschke and Ludgate (1997) stated that the TSH receptor is a passive bystander in autoimmune hyperthyroidism, or Graves disease, and suggested that mutations in the TSHR gene are not involved in autoimmune disease pathogenesis.
Simanainen et al. (1999) reported that the D36H substitution was not associated with Graves disease and is a polymorphic variant, with a frequency of approximately 5%.
In 3 of 11 hyperfunctioning thyroid adenomas (see 609152), Parma et al. (1993) identified somatic mutations in the carboxy-terminal portion of a third cytoplasmic loop of the thyrotropin receptor. These mutations were restricted to tumor tissue and involved 2 different residues: asp619-to-gly (D619G) in 2 cases, and ala623-to-ile (A623I; 603372.0003) in 1. The mutant receptors conferred constitutive activation of adenylyl cyclase when tested by transfection in COS cells. Parma et al. (1993) concluded that G protein-coupled receptors are susceptible to constitutive activation by spontaneous somatic mutations and may therefore behave as protooncogenes.
For discussion of the ala623-to-ile (A623I) mutation in the TSHR gene that was found in compound heterozygous state in 3 of 11 hyperfunctioning thyroid adenomas (see 609152) by Parma et al. (1993), see 603372.0002.
In a boy with nonautoimmune congenital hyperthyroidism (609152), Kopp et al. (1995) identified a heterozygous T-to-C germline mutation in the TSHR gene, resulting in a phe631-to-leu (F631L) substitution. Functional studies showed that the F631L mutation resulted in constitutive activation of the receptor. The mother was euthyroid, and repeated tests for thyroid antibodies in both the mother and patient were always negative.
Fuhrer et al. (1997) identified the F631L mutation in a toxic thyroid adenoma (see 609152).
In 3 sisters, 2 of whom were found to have congenital hypothyroidism (CHNG1; 275200) on neonatal screening, Sunthornthepvarakul et al. (1995) identified compound heterozygosity for 2 mutations in the TSHR gene: the paternal allele had a 599T-A transversion, resulting in an ile167-to-asn (I167N) substitution, and the maternal allele had a 583C-G transversion, resulting in a pro162-to-ala (P162A) substitution (603372.0006). The mutant thyrotropin receptor inherited from the father had almost no biologic activity, and that inherited from the mother had reduced activity. The sisters were euthyroid, with normal serum concentrations of thyroid hormone but high concentrations of thyrotropin, indicating so-called partial thyrotropin resistance (also referred to as 'compensated hypothyroidism').
For discussion of the pro162-to-ala (P162A) mutation in the TSHR gene that was found in compound heterozygous state in patients with congenital hypothyroidism (CHNG1; 275200) by Sunthornthepvarakul et al. (1995), see 603372.0005.
In a patient with nonautoimmune hyperthyrotropinemia and a hypoplastic thyroid gland on ultrasound, Alberti et al. (2002) identified compound heterozygosity for 2 mutations in the TSHR gene: the P162A mutation and a cys600-to-arg (C600R; 603372.0029) substitution.
In a newborn with severe nonautoimmune hyperthyroidism (609152), de Roux et al. (1996) identified a heterozygous T-to-C transition in the TSHR gene, resulting in a met453-to-thr (M453T) substitution in the second transmembrane domain of the receptor. The mutation was absent in both parents, neither of whom had a history of thyroid disease. Functional expression analysis showed that the M453T mutation resulted in constitutive activation of adenylate cyclase without enhancement of phospholipase C activity.
Russo et al. (1997) reported a case of an insular thyroid carcinoma presenting as an autonomously functioning thyroid nodule and causing severe thyrotoxicosis (see 609152). The tumor was metastatic to a cervical lymph node and both lungs. An activating mutation of the TSHR gene was found in both the primary tumor and the lymph node metastasis. A G-to-C mutation, resulting in an asp633-to-his (D633H) substitution in the TSHR protein, was identified in the absence of changes in GSP (see 139320), RAS (see 190020), PTC/RET (164761), TRK (see 191315), MET (164860), or P53 (191170). Thus, an activating TSHR mutation was implicated as the cause of a hyperfunctioning thyroid carcinoma.
In a child with congenital hypothyroidism (CHNG1; 275200) found on neonatal screening who had markedly increased serum TSH concentrations and low normal thyroid hormone levels, Clifton-Bligh et al. (1997) identified compound heterozygosity for 2 mutations in the TSHR gene: a G-to-A transition, resulting in an arg109-to-gln (R109Q) substitution in the extracellular domain of the receptor, and a G-to-A transition, resulting in a premature termination codon at trp546 (W546X; 603372.0010) in the fourth transmembrane segment. Each parent was heterozygous for one mutation, and both parents had normal thyroid function. Cells transiently transfected with the R109Q mutant protein exhibited reduced membrane binding of radiolabeled TSH and impaired signal transduction in response to TSH. In contrast, the W546X mutant protein was nonfunctional, with negligible membrane radioligand binding. The authors concluded that a single normal TSHR allele is sufficient for normal thyroid function, but that the presence of 2 mutant alleles causes TSH resistance.
For discussion of the trp546-to-ter (W546X) mutation in the TSHR gene that was found in compound heterozygous state in a patient with congenital hypothyroidism (CHNG1; 275200) by Clifton-Bligh et al. (1997), see 603372.0009.
Jordan et al. (2003) reported 2 Welsh sibs with congenital hypothyroidism identified by neonatal screening. Both had normal-sized and placed glands but negative isotope uptake. Both sibs were homozygous for the W546X mutation in the fourth membrane spanning region of the TSHR protein. The euthyroid parents were heterozygous for the mutation and unrelated. Jordan et al. (2003) noted that the W546X had been described in 3 additional families (1 of them Welsh), suggesting that it may be a relatively common mutation. Jordan et al. (2003) genotyped 368 euthyroid Welsh individuals using single-nucleotide primer extension, and found 366 homozygous wildtype and 2 heterozygous for the mutation. Jordan et al. (2003) suggested that the W546X mutation may be a major contributor to hypothyroidism in the Welsh population.
In 4 unrelated French patients with congenital hypoparathyroidism (CHNG1; 275200) found by neonatal screening, de Roux et al. (1996) identified loss-of-function mutations in the TSHR gene. One patient was homozygous for a pro162-to-ala substitution (603372.0006). The 3 others were compound heterozygotes: gln324-to-ter/asp410-to-asn (603372.0012), cys41-to-ser (603372.0013)/phe525-to-leu (603372.0014), and cys390-to-trp (603372.0015)/trp546-to-ter (603372.0010). The patients showed so-called partial thyrotropin resistance, with increased plasma TSH concentrations and normal T3 and T4 concentrations. TSH levels were normal in the heterozygous parents. Expression of the various mutated receptors in transfected COS-7 cells demonstrated their impaired function. The cys390-to-trp substitution abolished high-affinity hormone binding; asp410-to-asn bound the hormone normally, but failed to activate adenylate cyclase; phe525-to-leu also markedly impaired adenylate cyclase activation, underlining the importance of the second intracellular loop in receptor signaling.
For discussion of the asp410-to-asn (D410N) mutation in the TSHR gene that was found in a patient with congenital hypoparathyroidism (CHNG1; 275200) by de Roux et al. (1996), see 603372.0011.
For discussion of the cys41-to-ser (C41S) mutation in the TSHR gene that was found in a patient with congenital hypoparathyroidism (CHNG1; 275200) by de Roux et al. (1996), see 603372.0011.
Alberti et al. (2002) identified heterozygosity for the C41S mutation in a male infant found to have congenital hypoparathyroidism on neonatal screening. His father, who was also heterozygous for the mutation, had a mildly elevated TSH level.
For discussion of the phe525-to-leu (F525L) mutation in the TSHR gene that was found in a patient with congenital hypoparathyroidism (CHNG1; 275200) by de Roux et al. (1996), see 603372.0011.
For discussion of the cys390-to-trp (C390W) mutation in the TSHR gene that was found in a patient with congenital hypoparathyroidism (CHNG1; 275200) by de Roux et al. (1996), see 603372.0011.
For discussion of the C390W mutation in the TSHR gene that was found in compound heterozygous state in a patient with congenital hypothyroidism with reduced thyroid volume by Biebermann et al. (1997), see 603372.0018. Biebermann et al. (1997) found that the C390W mutation resulted in decreased affinity of TSH for the TSHR.
In a brother and sister, born of consanguineous parents, with congenital hypothyroidism (CHNG1; 275200), Abramowicz et al. (1997) identified a homozygous mutation in the TSHR gene, resulting in an ala553-to-thr (A553T) substitution in the fourth transmembrane domain of the protein. The mutation was heterozygous in both parents and 2 unaffected sibs. The patients were initially diagnosed with thyroid agenesis, but cervical ultrasonography in both patients revealed a very hypoplastic thyroid gland. Functional analysis in transfected COS-7 cells showed that the mutation resulted in extremely low expression at the cell surface as compared with the wildtype receptor, in spite of an apparently normal intracellular synthesis. Blood thyroglobulin was unexpectedly elevated in the patients at the time of diagnosis; Abramowicz et al. (1997) speculated as to the possible explanation for this seemingly paradoxical finding.
Kopp et al. (1997) reported an infant with hyperthyroidism caused by a solitary adenoma (see 609152) harboring a somatic G-to-T transversion in the TSHR gene, resulting in a ser281-to-ile (S281I) substitution in the carboxy terminus of the extracellular domain. The mutation was found only in the adenomatous tissue and not in peripheral leukocytes of the patient or his parents. Functional expression studies showed that the S281I mutation resulted in increased basal cAMP levels and increased affinity for TSH.
In a female infant who was found by neonatal screening to have congenital hypothyroidism with reduced thyroid volume (CHNG1; 275200), Biebermann et al. (1997) identified compound heterozygosity for 2 mutations in exon 10 of the TSHR gene. The maternal allele contained both an 18-bp deletion (del1217-1234) and a 4-bp insertion, resulting in a frameshift and premature termination. Transfection studies showed that this truncated TSHR was trapped intracellularly and completely lacked cell surface expression. The paternal allele harbored the cys390-to-trp (C390W; 603372.0015) mutation. The C390W mutation resulted in a drastic loss of affinity and potency for TSH. In contrast to loss-of-function mutations of the TSHR that lead to euthyroid hyperthyrotropinemia, these 2 mutations led to persistent congenital hypothyroidism and defective organ development.
In affected members of a large kindred from northern France with autosomal dominant nonautoimmune hyperthyroidism (609152) originally reported by Thomas et al. (1982), Duprez et al. (1994) identified a heterozygous T-to-C transition in exon 10 of the TSHR gene, resulting in a val509-to-ala (V509A) substitution in the third transmembrane domain of the protein. Functional expression studies of the V509A mutation showed higher basal intracellular cAMP levels with high constitutive activation of the receptor. Duprez et al. (1994) noted that autosomal dominant nonautoimmune hyperthyroidism is the germline counterpart of hyperfunctioning thyroid adenomas (e.g., 603372.0017), in which different somatic mutations with similar functional characteristics have been demonstrated.
In affected members of a large pedigree from northern France with nonautoimmune autosomal dominant hyperthyroidism (609152), Duprez et al. (1994) identified a heterozygous G-to-A transition in exon 10 of the TSHR gene, resulting in a cys672-to-tyr (C672Y) substitution in the seventh transmembrane domain of the protein. Functional expression studies of the C672Y mutation showed higher basal intracellular cAMP levels with high constitutive activation of the receptor.
In a boy with nonautoimmune hyperthyroidism (609152), Holzapfel et al. (1997) identified a heterozygous G-to-A transition in the TSHR gene, resulting in a ser505-to-asn (S505N) substitution in the third transmembrane region of the protein. No other family members carried the mutation, indicating it was a de novo event. Transient expression of the TSHR S505N mutant in COS cells resulted in a constitutively activated cAMP cascade. The authors noted that patients with sporadic congenital nonautoimmune hyperthyroidism should be treated with early subtotal to near-total thyroid resection because of frequent relapses, and that postoperative radioiodine treatment should be considered for such patients.
In a 10-year-old boy and his 31-year-old mother with nonautoimmune hyperthyroidism (609152), Fuhrer et al. (1997) identified a heterozygous G-to-T transversion in the TSHR gene, resulting in a leu629-to-phe (L629F) substitution. There was no history of thyroid disease in the rest of the family. Transient expression of the mutated L629F TSHR construct confirmed constitutive activity of the TSHR.
Parma et al. (1997) identified the L629F mutation in a toxic hyperfunctioning thyroid adenoma (see 609152).
In a child with severe congenital hyperthyroidism (609152), Gruters et al. (1998) identified a heterozygous mutation in the TSHR gene, resulting in a ser281-to-asn (S281N) substitution in the extracellular domain of the protein. Functional studies of the S281N mutation revealed a marked increase in basal cAMP levels when the mutant receptor was expressed in COS-7 cells. No other family members had the mutation. The child's paternal aunt and paternal grandmother had hyperthyroidism and, like the proband, were heterozygous for an R528H mutation in exon 10 of the TSHR gene; however, functional expression of the R528H mutation did not result in constitutive activity, and the authors concluded that R528H is a polymorphism.
Rodien et al. (1998) described a woman and her mother who had recurrent gestational hyperthyroidism (603373). Both women were heterozygous for a mutation in the TSHR gene, resulting in a lys183-to-arg (K183R) substitution in the extracellular domain of the thyrotropin receptor. The mutant receptor was more sensitive than the wildtype receptor to chorionic gonadotropin, thus accounting for the occurrence of hyperthyroidism despite the presence of normal chorionic gonadotropin concentrations. Rodien et al. (1999) referred to this situation as promiscuity among the glycoprotein hormones.
In affected members of a Chinese family with nonautoimmune familial thyrotoxicosis (609152), Khoo et al. (1999) identified a heterozygous C-to-T transition in the TSHR gene, resulting in a pro639-to-ser (P639S) substitution. The 3 children in the family developed thyrotoxicosis during childhood, and the father was diagnosed as thyrotoxic at the age of 38 years. Two of the children and the father had mitral valve prolapse associated with mitral regurgitation. The authors concluded that there was a close temporal relationship between the onset of thyrotoxicosis and the diagnosis of mitral valvular disease in these patients.
Tonacchera et al. (2000) described a 22-year-old female patient with severe nonautoimmune hypothyroidism (CHNG1; 275200) and mental retardation. Genetic analysis identified a homozygous mutation in the TSHR gene, resulting in a thr477-to-ile (T477I) substitution in the first extracellular loop of the receptor of the TSHR protein. Serum T4 and T3 concentrations and thyroglobulin were below the sensitivity of the methods, with elevated serum TSH levels. A normally shaped hypoplastic gland was found by scintiscan to be located in the appropriate anatomic position in the neck. The gland did not respond after administration of bovine TSH in terms of 131-I uptake, serum thyroid hormones, and thyroglobulin secretion. The brother, one sister of the father (whose DNA was not available), the mother of the proposita, one sister, and the brother were heterozygous for the T477I allele. All of the heterozygotes were unaffected. After transfection in COS-7 cells, the mutant allele displayed an extremely low expression at the cell surface. This findings demonstrated a loss of function TSHR mutation associated with severe congenital hypothyroidism and absent circulating thyroglobulin due to TSH unresponsiveness.
Russo et al. (2000) reported 2 sibs, born of consanguineous parents, who had resistance to TSH and euthyroid hyperthyrotropinemia ('compensated hypothyroidism') (CHNG1; 275200). By direct sequencing of the TSHR gene, they identified a novel mutation in the TSHR gene, resulting in an arg310-to-cys (R310C) substitution in the extracellular domain of the protein. The mutation was homozygous in the 2 affected brothers; heterozygous in both parents, an uncle, and an unaffected brother; and absent in the other unaffected brother. When stably transfected in Chinese hamster ovary cells, the mutant allele showed loss of response to TSH in terms of cAMP stimulation. However, a constitutive activity in terms of basal cAMP production was detected in the mutant, compared with wildtype, TSHR. The authors concluded that the R310C TSHR mutant may determine both the TSH resistance and the clinical euthyroidism detected in this family.
Biebermann et al. (2001) reported a family in which 3 individuals had nonautoimmune hyperthyroidism (609152) caused by a heterozygous mutation in the TSHR gene, resulting in a gly431-to-ser (G431S) substitution in transmembrane domain-1 of the protein. The mutation was found in the investigated patient, his father, and the paternal grandmother. As observed in 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. The authors concluded that constitutively activating mutations can be found in the entire transmembrane domain region of the TSHR, indicating the important role of all parts of the transmembrane domain region for maintaining the inactive receptor conformation.
In a patient with nonautoimmune hyperthyrotropinemia and a hypoplastic thyroid gland on ultrasound (CHNG1; 275200), Alberti et al. (2002) identified compound heterozygosity for 2 mutations in the TSHR gene: a T-to-C transition in exon 10, resulting in a cys600-to-arg (C600R) substitution in the fifth transmembrane segment of the protein, and a pro162-to-ala (P162A; 603372.0006) substitution.
In a 5-year-old girl with nonautoimmune hyperthyrotropinemia (CHNG1; 275200) and her monozygotic twin, Alberti et al. (2002) detected a heterozygous T-to-C transition in exon 10 of the TSHR gene, resulting in a leu467-to-pro (L467P) substitution in the second transmembrane segment of the protein.
In a boy who presented with severe congenital hypothyroidism (CHNG1; 275200), the first child of nonconsanguineous French Canadian parents, Gagne et al. (1998) detected compound heterozygosity for 2 mutations in the TSHR gene: a deletion of 2 bases from codon 655, designated delAC655, in exon 10, and a splice site mutation, IVS6+3G-C (603372.0032), in intron 6. The deletion mutation was expected to cause premature termination of translation at codon 656 within the third extracellular loop of the receptor, resulting in a truncated protein lacking the last TM7 domain and the C-terminal tail. The splicing mutation was predicted to cause skipping of exon 6, resulting in the absence of one leucine-rich motif from the N-terminal hormone-binding domain of the receptor. Neck ultrasound revealed a very hypoplastic thyroid gland.
Alberti et al. (2002) identified this mutation, which they referred to as T655del (stop codon at position 656), in heterozygous state in a patient with nonautoimmune partial thyrotropin resistance (also referred to as 'compensated hypothyroidism').
For discussion of the splice site mutation in the TSHR gene (IVS6+3G-C) that was found in compound heterozygous state in a patient with severe congenital hypothyroidism (CHNG1; 275200) by Gagne et al. (1998), see 603372.0031.
Abe, E., Marians, R. C., Yu, W., Wu, X.-B., Ando, T., Li, Y., Iqbal, J., Eldeiry, L., Rajendren, G., Blair, H. C., Davies, T. F., Zaidi, M. TSH is a negative regulator of skeletal remodeling. Cell 115: 151-162, 2003. [PubMed: 14567913] [Full Text: https://doi.org/10.1016/s0092-8674(03)00771-2]
Abramowicz, M. J., Duprez, L., Parma, J., Vassart, G., Heinrichs, C. Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland. J. Clin. Invest. 99: 3018-3024, 1997. [PubMed: 9185526] [Full Text: https://doi.org/10.1172/JCI119497]
Akamizu, T., Ikuyama, S., Saji, M., Kosugi, S., Kozak, C., McBride, O. W., Kohn, L. D. Cloning, chromosomal assignment, and regulation of the rat thyrotropin receptor: expression of the gene is regulated by thyrotropin, agents that increase cAMP levels, and thyroid autoantibodies. Proc. Nat. Acad. Sci. 87: 5677-5681, 1990. [PubMed: 1696008] [Full Text: https://doi.org/10.1073/pnas.87.15.5677]
Alberti, L., Proverbio, M. C., Costagliola, S., Romoli, R., Boldrighini, B., Vigone, M. C., Weber, G., Chiumello, G., Beck-Peccoz, P., Persani, L. Germline mutations of TSH receptor gene as cause of nonautoimmune subclinical hypothyroidism. J. Clin. Endocr. Metab. 87: 2549-2555, 2002. [PubMed: 12050212] [Full Text: https://doi.org/10.1210/jcem.87.6.8536]
Bahn, R. S., Dutton, C. M., Heufelder, A. E., Sarkar, G. A genomic point mutation in the extracellular domain of the thyrotropin receptor in patients with Graves' ophthalmopathy. J. Clin. Endocr. Metab. 78: 256-260, 1994. [PubMed: 7508946] [Full Text: https://doi.org/10.1210/jcem.78.2.7508946]
Bahn, R. S., Heufelder, A. E., Dutton, C. M. A point mutation of the TSH receptor in retro-ocular fibroblasts from a patient with Graves' ophthalmopathy. (Abstract) J. Endocr. Invest. 16 (suppl. 2-6): 30 only, 1993.
Biebermann, H., Schoneberg, T., Hess, C., Germak, J., Gudermann, T., Gruters, A. The first activating TSH receptor mutation in transmembrane domain 1 identified in a family with nonautoimmune hyperthyroidism. J. Clin. Endocr. Metab. 86: 4429-4433, 2001. [PubMed: 11549687] [Full Text: https://doi.org/10.1210/jcem.86.9.7888]
Biebermann, H., Schoneberg, T., Krude, H., Schultz, G., Gudermann, T., Gruters, A. Mutations of the human thyrotropin receptor gene causing thyroid hypoplasia and persistent congenital hypothyroidism. J. Clin. Endocr. Metab. 82: 3471-3480, 1997. [PubMed: 9329388] [Full Text: https://doi.org/10.1210/jcem.82.10.4286]
Calebiro, D., de Filippis, T., Lucchi, S., Covino, C., Panigone, S., Beck-Peccoz, P., Dunlap, D., Persani, L. Intracellular entrapment of wild-type TSH receptor by oligomerization with mutants linked to dominant TSH resistance. Hum. Molec. Genet. 14: 2991-3002, 2005. [PubMed: 16135555] [Full Text: https://doi.org/10.1093/hmg/ddi329]
Chan, J. Y. C., Lerman, M. I., Prabhakar, B. S., Isozaki, O., Santisteban, P., Kuppers, R. C., Oates, E. L., Notkins, A. L., Kohn, L. D. Cloning and characterization of a cDNA that encodes a 70-kDa novel human thyroid autoantigen. J. Biol. Chem. 264: 3651-3654, 1989. [PubMed: 2917966]
Chen, C.-R., Pichurin, P., Nagayama, Y., Latrofa, F., Rapoport, B., McLachlan, S. M. The thyrotropin receptor autoantigen in Graves disease is the culprit as well as the victim. J. Clin. Invest. 111: 1897-1904, 2003. [PubMed: 12813025] [Full Text: https://doi.org/10.1172/JCI17069]
Chia, S.-Y., Milas, M., Reddy, S. K., Siperstein, A., Skugor, M., Brainard, J., Gupta, M. K. Thyroid-stimulating hormone receptor messenger ribonucleic acid measurement in blood as a marker for circulating thyroid cancer cells and its role in the preoperative diagnosis of thyroid cancer. J. Clin. Endocr. Metab. 92: 468-475, 2007. [PubMed: 17118994] [Full Text: https://doi.org/10.1210/jc.2006-2088]
Clifton-Bligh, R. J., Gregory, J. W., Ludgate, M., John, R., Persani, L., Asteria, C., Beck-Peccoz, P., Chatterjee, V. K. K. Two novel mutations in the thyrotropin (TSH) receptor gene in a child with resistance to TSH. J. Clin. Endocr. Metab. 82: 1094-1100, 1997. [PubMed: 9100579] [Full Text: https://doi.org/10.1210/jcem.82.4.3863]
de Roux, N., Misrahi, M., Brauner, R., Houang, M., Carel, J. C., Granier, M., le Bouc, Y., Ghinea, N., Boumedienne, A., Toublanc, J. E., Milgrom, E. Four families with loss of function mutations of the thyrotropin receptor. J. Clin. Endocr. Metab. 81: 4229-4235, 1996. [PubMed: 8954020] [Full Text: https://doi.org/10.1210/jcem.81.12.8954020]
de Roux, N., Polak, M., Couet, J., Leger, J., Czernichow, P., Milgrom, E., Misrahi, M. A neomutation of the thyroid-stimulating hormone receptor in a severe neonatal hyperthyroidism. J. Clin. Endocr. Metab. 81: 2023-2026, 1996. [PubMed: 8964822] [Full Text: https://doi.org/10.1210/jcem.81.6.8964822]
Dechairo, B. M., Zabaneh, D., Collins, J., Brand, O., Dawson, G. J., Green, A. P., Mackay, I., Franklyn, J. A., Connell, J. M., Wass, J. A. H., Wiersinga, W. M., Hegedus, L., Brix, T., Robinson, B. G., Hunt, P. J., Weetman, A. P., Carey, A. H., Gough, S. C. Association of the TSHR gene with Graves' disease: the first disease-specific locus. Europ. J. Hum. Genet. 13: 1223-1230, 2005. [PubMed: 16106256] [Full Text: https://doi.org/10.1038/sj.ejhg.5201485]
Duprez, L., Parma, J., Van Sande, J., Allgeier, A., Leclere, J., Schvartz, C., Delisle, M.-J., Decoulx, M., Orgiazzi, J., Dumont, J., Vassart, G. Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism. Nature Genet. 7: 396-401, 1994. [PubMed: 7920658] [Full Text: https://doi.org/10.1038/ng0794-396]
Feliciello, A., Porcellini, A., Ciullo, I., Bonavolonta, G., Avvedimento, E. V., Fenzi, G. Expression of thyrotropin-receptor mRNA in healthy and Graves' disease retro-orbital tissue. Lancet 342: 337-338, 1993. [PubMed: 8101586] [Full Text: https://doi.org/10.1016/0140-6736(93)91475-2]
Fuhrer, D., Holzapfel, H.-P., Wonerow, P., Scherbaum, W. A., Paschke, R. Somatic mutations in the thyrotropin receptor gene and not in the Gs-alpha protein gene in 31 toxic thyroid nodules. J. Clin. Endocr. Metab. 82: 3885-3891, 1997. [PubMed: 9360556] [Full Text: https://doi.org/10.1210/jcem.82.11.4382]
Fuhrer, D., Wonerow, P., Willgerodt, H., Paschke, R. Identification of a new thyrotropin receptor germline mutation (leu629phe) in a family with neonatal onset of autosomal dominant nonautoimmune hyperthyroidism. J. Clin. Endocr. Metab. 82: 4234-4238, 1997. [PubMed: 9398746] [Full Text: https://doi.org/10.1210/jcem.82.12.4405]
Gabriel, E. M., Bergert, E. R., Grant, C. S., van Heerden, J. A., Thompson, G. B., Morris, J. C. Germline polymorphism of codon 727 of human thyroid-stimulating hormone receptor is associated with toxic multinodular goiter. J. Clin. Endocr. Metab. 84: 3328-3335, 1999. [PubMed: 10487707] [Full Text: https://doi.org/10.1210/jcem.84.9.5966]
Gagne, N., Parma, J., Deal, C., Vassart, G., Van Vliet, G. Apparent congenital athyreosis contrasting with normal plasma thyroglobulin levels and associated with inactivating mutations in the thyrotropin receptor gene: are athyreosis and ectopic thyroid distinct entities? J. Clin. Endocr. Metab. 83: 1771-1775, 1998. [PubMed: 9589691] [Full Text: https://doi.org/10.1210/jcem.83.5.4771]
Graves, P., Pritsker, A., Davies, T. F. Post-translational processing of the natural human thyrotropin receptor: demonstration of more than two cleavage sites. J. Clin. Endocr. Metab. 84: 2177-2181, 1999. [PubMed: 10372728] [Full Text: https://doi.org/10.1210/jcem.84.6.5795]
Gruters, A., Schoneberg, T., Biebermann, H., Krude, H., Kron, H. P., Dralle, H., Gudermann, T. Severe congenital hyperthyroidism caused by a germ-line neo mutation in the extracellular portion of the thyrotropin receptor. J. Clin. Endocr. Metab. 83: 1431-1436, 1998. [PubMed: 9589634] [Full Text: https://doi.org/10.1210/jcem.83.5.4776]
Hase, H., Ando, T., Eldeiry, L., Brebene, A., Peng, Y., Liu, L., Amano, H., Davies, T. F., Sun, L., Zaidi, M., Abe, E. TNF-alpha mediates the skeletal effects of thyroid-stimulating hormone. Proc. Nat. Acad. Sci. 103: 12849-12854, 2006. [PubMed: 16908863] [Full Text: https://doi.org/10.1073/pnas.0600427103]
Heldin, N.-E., Gustavsson, B., Westermark, K., Westermark, B. A somatic point mutation in a putative ligand binding domain of the TSH receptor in a patient with autoimmune hyperthyroidism. J. Clin. Endocr. Metab. 73: 1374-1376, 1991. [PubMed: 1955520] [Full Text: https://doi.org/10.1210/jcem-73-6-1374]
Hiratani, H., Bowden, D. W., Ikegami, S., Shirasawa, S., Shimizu, A., Iwatani, Y., Akamizu, T. Multiple SNPs in intron 7 of thyrotropin receptor are associated with Graves' disease. J. Clin. Endocr. Metab. 90: 2898-2903, 2005. [PubMed: 15741259] [Full Text: https://doi.org/10.1210/jc.2004-2148]
Holzapfel, H.-P., Wonerow, P., von Petrykowski, W., Henschen, M., Scherbaum, W. A., Paschke, R. Sporadic congenital hyperthyroidism due to a spontaneous germline mutation in the thyrotropin receptor gene. J. Clin. Endocr. Metab. 82: 3879-3884, 1997. [PubMed: 9360555] [Full Text: https://doi.org/10.1210/jcem.82.11.4378]
Jordan, N., Williams, N., Gregory, J. W., Evans, C., Owen, M., Ludgate, M. The W546X mutation of the thyrotropin receptor gene: potential major contributor to thyroid dysfunction in a Caucasian population. J. Clin. Endocr. Metab. 88: 1002-1005, 2003. [PubMed: 12629076] [Full Text: https://doi.org/10.1210/jc.2002-021301]
Kakinuma, A., Nagayama, Y. Multiple messenger ribonucleic acid transcripts and revised gene organization of the human TSH receptor. Endocr. J. 49: 175-180, 2002. [PubMed: 12081236] [Full Text: https://doi.org/10.1507/endocrj.49.175]
Khoo, D. H. C., Parma, J., Rajasoorya, C., Ho, S. C., Vassart, G. A germline mutation of the thyrotropin receptor gene associated with thyrotoxicosis and mitral valve prolapse in a Chinese family. J. Clin. Endocr. Metab. 84: 1459-1462, 1999. [PubMed: 10199795] [Full Text: https://doi.org/10.1210/jcem.84.4.5620]
Kopp, P., Muirhead, S., Jourdain, N., Gu, W.-X., Jameson, J. L., Rodd, C. Congenital hyperthyroidism caused by a solitary toxic adenoma harboring a novel somatic mutation (serine281-isoleucine) in the extracellular domain of the thyrotropin receptor. J. Clin. Invest. 100: 1634-1639, 1997. [PubMed: 9294132] [Full Text: https://doi.org/10.1172/JCI119687]
Kopp, P., van Sande, J., Parma, J., Duprez, L., Gerber, H., Joss, E., Jameson, J. L., Dumont, J. E., Vassart, G. Congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene. New Eng. J. Med. 332: 150-154, 1995. [PubMed: 7800007] [Full Text: https://doi.org/10.1056/NEJM199501193320304]
Kotsa, K. D., Watson, P. F., Weetman, A. P. No association between a thyrotropin receptor gene polymorphism and Graves' disease in the female population. Thyroid 7: 31-33, 1997. [PubMed: 9086566] [Full Text: https://doi.org/10.1089/thy.1997.7.31]
Lazar, V., Bidart, J.-M., Caillou, B., Mahe, C., Lacroix, L., Filetti, S., Schlumberger, M. Expression of the Na(+)/I(-) symporter gene in human thyroid tumors: a comparison study with other thyroid-specific genes. J. Clin. Endocr. Metab. 84: 3228-3234, 1999. [PubMed: 10487692] [Full Text: https://doi.org/10.1210/jcem.84.9.5996]
Libert, F., Lefort, A., Gerard, C., Parmentier, M., Perret, J., Ludgate, M., Dumont, J. E., Vassart, G. Cloning, sequencing and expression of the human thyrotropin (TSH) receptor: evidence for binding of autoantibodies. Biochem. Biophys. Res. Commun. 165: 1250-1255, 1989. [PubMed: 2610690] [Full Text: https://doi.org/10.1016/0006-291x(89)92736-8]
Libert, F., Passage, E., Lefort, A., Vassart, G., Mattei, M.-G. Localization of human thyrotropin receptor gene to chromosome region 14q31 by in situ hybridization. Cytogenet. Cell Genet. 54: 82-83, 1990. [PubMed: 2249482] [Full Text: https://doi.org/10.1159/000132964]
Loosfelt, H., Pichon, C., Jolivet, A., Misrahi, M., Caillou, B., Jamous, M., Vannier, B., Milgrom, E. Two-subunit structure of the human thyrotropin receptor. Proc. Nat. Acad. Sci. 89: 3765-3769, 1992. [PubMed: 1570295] [Full Text: https://doi.org/10.1073/pnas.89.9.3765]
Misrahi, M., Loosfelt, H., Atger, M., Sar, S., Guiochon-Mantel, A., Milgrom, E. Cloning, sequencing and expression of human TSH receptor. Biochem. Biophys. Res. Commun. 166: 394-403, 1990. [PubMed: 2302212] [Full Text: https://doi.org/10.1016/0006-291x(90)91958-u]
Muhlberg, T., Herrmann, K., Joba, W., Kirchberger, M., Heberling, H.-J., Heufelder, A. E. Lack of association of nonautoimmune hyperfunctioning thyroid disorders and a germline polymorphism of codon 727 of the human thyrotropin receptor in a European Caucasian population. J. Clin. Endocr. Metab. 85: 2640-2643, 2000. [PubMed: 10946859] [Full Text: https://doi.org/10.1210/jcem.85.8.6704]
Murakami, M., Mori, M. Identification of immunogenic regions in human thyrotropin receptor for immunoglobulin G of patients with Graves' disease. Biochem. Biophys. Res. Commun. 171: 512-518, 1990. [PubMed: 1697467] [Full Text: https://doi.org/10.1016/0006-291x(90)91423-p]
Nagayama, Y., Kaufman, K. D., Seto, P., Rapoport, B. Molecular cloning, sequence and functional expression of the cDNA for the human thyrotropin receptor. Biochem. Biophys. Res. Commun. 165: 1184-1190, 1989. [PubMed: 2558651] [Full Text: https://doi.org/10.1016/0006-291x(89)92727-7]
Ohmori, M., Ohta, M., Shimura, H., Shimura, Y., Suzuki, K., Kohn, L. D. Cloning of the single strand DNA-binding protein important for maximal expression and thyrotropin (TSH)-induced negative regulation of the TSH receptor. Molec. Endocr. 10: 1407-1424, 1996. [PubMed: 8923467] [Full Text: https://doi.org/10.1210/mend.10.11.8923467]
Parma, J., Duprez, L., Van Sande, J., Cochaux, P., Gervy, C., Mockel, J., Dumont, J., Vassart, G. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 365: 649-651, 1993. [PubMed: 8413627] [Full Text: https://doi.org/10.1038/365649a0]
Parma, J., Duprez, L., Van Sande, J., Hermans, J., Rocmans, P., Van Vliet, G., Costagliola, S., Rodien, P., Dumont, J. E., Vassart, G. Diversity and prevalence of somatic mutations in the thyrotropin receptor and Gs-alpha genes as a cause of toxic thyroid adenomas. J. Clin. Endocr. Metab. 82: 2695-2701, 1997. [PubMed: 9253356] [Full Text: https://doi.org/10.1210/jcem.82.8.4144]
Paschke, R., Ludgate, M. The thyrotropin receptor in thyroid diseases. New Eng. J. Med. 337: 1675-1681, 1997. [PubMed: 9385128] [Full Text: https://doi.org/10.1056/NEJM199712043372307]
Rodien, P., Bremont, C., Luton, J.-P., Raffin-Sanson, M.-L., Parma, J., Duprez, L., Vassart, G. De la promiscuite chez les hormones glycoproteiques: hyperthyroidie gestationnelle familiale par mutation du recepteur de la TSH. Med. Sci. 15: 713-717, 1999.
Rodien, P., Bremont, C., Raffin Sanson, M.-L., Parma, J., Van Sande, J., Costagliola, S., Luton, J.-P., Vassart, G., Duprez, L. Familial gestational hyperthyroidism caused by a mutant thyrotropin receptor hypersensitive to human chorionic gonadotropin. New Eng. J. Med. 339: 1823-1826, 1998. [PubMed: 9854118] [Full Text: https://doi.org/10.1056/NEJM199812173392505]
Rousseau-Merck, M. F., Misrahi, M., Loosfelt, H., Atger, M., Milgrom, E., Berger, R. Assignment of the human thyroid stimulating hormone receptor (TSHR) gene to chromosome 14q31. Genomics 8: 233-236, 1990. [PubMed: 2249847] [Full Text: https://doi.org/10.1016/0888-7543(90)90276-z]
Rubin, C.-J., Zody, M. C., Eriksson, J., Meadows, J. R. S., Sherwood, E., Webster, M. T., Jiang, L., Ingman, M., Sharpe, T., Ka, S., Hallbook, F., Besnier, F., Carlborg, O., Bed'hom, B., Tixier-Boichard, M., Jensen, P., Siegel, P., Lindblad-Toh, K., Andersson, L. Whole-genome resequencing reveals loci under selection during chicken domestication. Nature 464: 587-591, 2010. [PubMed: 20220755] [Full Text: https://doi.org/10.1038/nature08832]
Russo, D., Betterle, C., Arturi, F., Chiefari, E., Girelli, M. E., Filetti, S. A novel mutation in the thyrotropin (TSH) receptor gene causing loss of TSH binding but constitutive receptor activation in a family with resistance to TSH. J. Clin. Endocr. Metab. 85: 4238-4242, 2000. [PubMed: 11095460] [Full Text: https://doi.org/10.1210/jcem.85.11.6985]
Russo, D., Tumino, S., Arturi, F., Vigneri, P., Grasso, G., Pontecorvi, A., Filetti, S., Belfiore, A. Detection of an activating mutation of the thyrotropin receptor in a case of an autonomously hyperfunctioning thyroid insular carcinoma. J. Clin. Endocr. Metab. 82: 735-738, 1997. [PubMed: 9062474] [Full Text: https://doi.org/10.1210/jcem.82.3.3838]
Simanainen, J., Kinch, A., Westermark, K., Winsa, B., Bengtsson, M., Schuppert, F., Westermark, B., Heldin, N.-E. Analysis of mutations in exon 1 of the human thyrotropin receptor gene: high frequency of the D36H and P52T polymorphic variants. Thyroid 9: 7-11, 1999. [PubMed: 10037069] [Full Text: https://doi.org/10.1089/thy.1999.9.7]
Sunthornthepvarakul, T., Gottschalk, M. E., Hayashi, Y., Refetoff, S. Resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene. New Eng. J. Med. 332: 155-160, 1995. [PubMed: 7528344] [Full Text: https://doi.org/10.1056/NEJM199501193320305]
Thomas, J. L., Leclere, J., Hartemann, P., Duheille, J., Orgiazzi, J., Petersen, M., Janot, C., Guedenet, J.-C. Familial hyperthyroidism without evidence of autoimmunity. Acta Endocr. 100: 512-518, 1982. [PubMed: 7124278] [Full Text: https://doi.org/10.1530/acta.0.1000512]
Tonacchera, M., Agretti, P., Chiovato, L., Rosellini, V., Ceccarini, G., Perri, A., Viacava, P., Naccarato, A. G., Miccoli, P., Pinchera, A., Vitti, P. Activating thyrotropin receptor mutations are present in nonadenomatous hyperfunctioning nodules of toxic or autonomous multinodular goiter. J. Clin. Endocr. Metab. 85: 2270-2274, 2000. [PubMed: 10852462] [Full Text: https://doi.org/10.1210/jcem.85.6.6634]
Tonacchera, M., Agretti, P., Pinchera, A., Rosellini, V., Perri, A., Collecchi, P., Vitti, P., Chiovato, L. Congenital hypothyroidism with impaired thyroid response to thyrotropin (TSH) and absent circulating thyroglobulin: evidence for a new inactivating mutation of the TSH receptor gene. J. Clin. Endocr. Metab. 85: 1001-1008, 2000. [PubMed: 10720030] [Full Text: https://doi.org/10.1210/jcem.85.3.6460]
Trulzsch, B., Nebel, T., Paschke, R. The thyrotropin receptor mutation database. (Editorial) Thyroid 9: 521-522, 1999. [PubMed: 10411112] [Full Text: https://doi.org/10.1089/thy.1999.9.521]
Van Sande, J., Parma, J., Tonacchera, M., Swillens, S., Dumont, J., Vassart, G. Genetic basis of endocrine disease: Somatic and germline mutations of the TSH receptor gene in thyroid diseases. J. Clin. Endocr. Metab. 80: 2577-2585, 1995. [PubMed: 7673398] [Full Text: https://doi.org/10.1210/jcem.80.9.7673398]
Vassart, G., Parmentier, M., Libert, F., Dumont, J. Molecular genetics of the thyrotropin receptor. Trends Endocr. Metab. 2: 151-156, 1991.
Wadsworth, H. L., Chazenbalk, G. D., Nagayama, Y., Russo, D., Rapoport, B. An insertion in the human thyrotropin receptor critical for high affinity hormone binding. Science 249: 1423-1425, 1990. [PubMed: 2169649] [Full Text: https://doi.org/10.1126/science.2169649]
Wilkie, T. M., Chen, Y., Gilbert, D. J., Moore, K. J., Yu, L., Simon, M. I., Copeland, N. G., Jenkins, N. A. Identification, chromosomal location, and genome organization of mammalian G-protein-coupled receptors. Genomics 18: 175-184, 1993. [PubMed: 8288218] [Full Text: https://doi.org/10.1006/geno.1993.1452]