TSHR_HUMAN
Source:
hRBCD
; ID:
IPI00028642
PM19886704
PM23856902
Marked as 'Integral membrane protein'
Confidence:
medium (present in either hRBCD or BSc_CH or PM22954596)
Search PubMed for
(RBC AND this entry)
Gene names:
TSHR
, LGR3
Protein names and data:
TSHR_HUMAN
, Thyrotropin receptor
, Thyroid-stimulating hormone receptor; TSH-R; Flags: Precursor
Lenght: 764 a.a.
Mass: 86830 Da
fasta formatted sequence
Function:
Receptor for thyrothropin. Plays a central role in controlling thyroid cell metabolism. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Also acts as a receptor for thyrostimulin (GPA2+GPB5).
Disease:
( OMIM:
275200
603372
603373
609152
)
Note=Defects in TSHR are found in patients affected by hyperthyroidism with different etiologies. Somatic, constitutively activating TSHR mutations and/or constitutively activating G(s)alpha mutations have been identified in toxic thyroid nodules (TTNs) that are the predominant cause of hyperthyroidism in iodine deficient areas. These mutations lead to TSH independent activation of the cAMP cascade resulting in thyroid growth and hormone production. TSHR mutations are found in autonomously functioning thyroid nodules (AFTN), toxic multinodular goiter (TMNG) and hyperfunctioning thyroid adenomas (HTA). TMNG encompasses a spectrum of different clinical entities, ranging from a single hyperfunctioning nodule within an enlarged thyroid, to multiple hyperfunctioning areas scattered throughout the gland. HTA are discrete encapsulated neoplasms characterized by TSH- independent autonomous growth, hypersecretion of thyroid hormones, and TSH suppression. Defects in TSHR are also a cause of thyroid neoplasms (papillary and follicular cancers). Note=Autoantibodies against TSHR are directly responsible for the pathogenesis and hyperthyroidism of Graves disease. Antibody interaction with TSHR results in an uncontrolled receptor stimulation. Hypothyroidism, congenital, non-goitrous, 1 (CHNG1) [MIM:275200]: A non-autoimmune condition characterized by resistance to thyroid-stimulating hormone (TSH) leading to increased levels of plasma TSH and low levels of thyroid hormone. It presents variable severity depending on the completeness of the defect. Most patients are euthyroid and asymptomatic, with a normal sized thyroid gland. Only a subset of patients develop hypothyroidism and present a hypoplastic thyroid gland. Note=The disease is caused by mutations affecting the gene represented in this entry. Familial gestational hyperthyroidism (HTFG) [MIM:603373]: A condition characterized by abnormally high levels of serum thyroid hormones occurring during early pregnancy. Note=The disease is caused by mutations affecting the gene represented in this entry. Hyperthyroidism, non-autoimmune (HTNA) [MIM:609152]: A condition characterized by abnormally high levels of serum thyroid hormones, thyroid hyperplasia, goiter and lack of anti-thyroid antibodies. Typical features of Graves disease such as exophthalmia, myxedema, antibodies anti-TSH receptor and lymphocytic infiltration of the thyroid gland are absent. Note=The disease is caused by mutations affecting the gene represented in this entry.
Cellular location:
Cell membrane; Multi-pass membrane protein.
Tissue specificity:
Expressed in the thyroid.
Genetic variants
The Asp727Glu polymorphism is associated with Graves disease in a Russian population. The Glu727 allele and the heterozygous Asp727Glu genotype are related to higher risk of the disease. The Asp727Glu polymorphism significantly ameliorates G(s)alpha protein activation in the presence of the gain-of- function mutation Ala593Asn although it is functionally inert in the context of the wild-type TSHR.
34 - 34
E -> K (in dbSNP:rs45499704). VAR_055925
45499704
36 - 36
D -> H (in a patient with Graves disease; dbSNP:rs61747482). VAR_003564
61747482
41 - 41
C -> S (in CHNG1). VAR_011519
52 - 52
P -> T (does not contribute to the genetic susceptibility to Graves disease; dbSNP:rs2234919). VAR_003565
2234919
109 - 109
R -> Q (in CHNG1). VAR_011520
162 - 162
P -> A (in CHNG1; dbSNP:rs121908863). VAR_011521
121908863
167 - 167
I -> N (in CHNG1). VAR_011522
183 - 183
K -> R (in HTFG; enhances receptor response to chorionic gonadotropin). VAR_003566
197 - 197
F -> I (in papillary cancer). VAR_003567
219 - 219
D -> E (in papillary cancer). VAR_003568
252 - 252
L -> P (in CHNG1; displays a low expression at the cell surface and a reduced response to bovine TSH in terms of cAMP production). VAR_021495
281 - 281
S -> I (in hyperthyroidism; congenital; due to a toxic adenoma). VAR_003569
281 - 281
S -> N (in HTNA; gain of function; found in toxic thyroid nodules and hyperfunctioning thyroid adenomas). VAR_003570
281 - 281
S -> T (in hyperthyroidism; associated with hyperfunctioning thyroid adenomas). VAR_011523
310 - 310
R -> C (in CHNG1). VAR_011524
390 - 390
C -> W (in CHNG1; persistent hypothyroidism and defective thyroid development; habolishes high affinity hormone binding). VAR_011525
410 - 410
D -> N (in CHNG1; lack of adenylate cyclase activation). VAR_011526
425 - 425
S -> I (in TTNs; 8 to 9 times higher levels of basal cAMP than wild-type TSHR and similar response to maximal TSH stimulation). VAR_021496
431 - 431
G -> S (in HTNA; gain of function; constitutive activation of the G(s)/ adenylyl cyclase system). VAR_011527
450 - 450
R -> H (in CHNG1). VAR_011528
453 - 453
M -> T (in HTNA; sporadic; found in toxic thyroid nodules and hyperfunctioning thyroid adenomas). VAR_011529
463 - 463
M -> V (in HTNA; gain of function). VAR_011530
467 - 467
L -> P (in CHNG1). VAR_017295
477 - 477
T -> I (in CHNG1; severe hypothyroidism). VAR_017296
486 - 486
I -> F (in HTNA; found in thyroid toxic nodules and hyperfunctioning thyroid adenomas; also in hyperfunctioning follicular carcinoma). VAR_011531
486 - 486
I -> M (in HTNA; found in hyperfunctioning thyroid adenomas). VAR_011532
498 - 498
G -> S (in CHNG1). VAR_011533
505 - 505
S -> N (in HTNA; found in toxic thyroid nodules). VAR_003571
505 - 505
S -> R (in HTNA; gain of function). VAR_011534
509 - 509
V -> A (in HTNA; gain of function). VAR_011535
512 - 512
L -> Q (in TTNs; 5 times higher levels of basal cAMP than wild-type TSHR and slightly less response to maximal TSH stimulation). VAR_021497
512 - 512
L -> R (in hyperthyroidism and TTNs; associated with autonomously functioning thyroid nodules; 3.3-fold increase in basal cAMP level). VAR_011536
525 - 525
F -> L (in CHNG1; impairs adenylate cyclase activation). VAR_011537
528 - 528
R -> H. VAR_003572
553 - 553
A -> T (in CHNG1; severe hypothyroidism). VAR_011538
568 - 568
I -> T (in HTNA; found in thyroid toxic nodules and hyperfunctioning thyroid adenomas). VAR_011539
593 - 593
A -> N (in toxic thyroid adenoma; requires 2 nucleotide substitutions; somatic mutation; N-593 and N-593/E-727 constitutively activate the cAMP cascade; double mutant's specific constitutive activity is 2.3-fold lower than the N-593 mutant). VAR_021498
597 - 597
V -> F (in HTNA; 11-fold increase in specific constitutive activity associated with reduction in receptor protein expression). VAR_021499
597 - 597
V -> L (in hyperthyroidism; congenital with severe thyrotoxicosis). VAR_011540
600 - 600
C -> R (in CHNG1). VAR_017297
606 - 606
I -> M. VAR_011541
619 - 619
D -> G (in hyperthyroidism and TTNs; associated with hyperfunctioning thyroid adenomas). VAR_003573
623 - 623
A -> I (in hyperthyroidism; associated with hyperfunctioning thyroid adenomas; gain of function; requires 2 nucleotide substitutions). VAR_003574
623 - 623
A -> V (in hyperthyroidism and TTNs; associated with hyperfunctioning thyroid adenomas; gain of function). VAR_011542
629 - 629
L -> F (in HTNA; also in hyperfunctioning thyroid adenomas and non-adenomatous nodules). VAR_003575
630 - 630
I -> L (in hyperthyroidism; associated with hyperfunctioning thyroid adenomas). VAR_011543
631 - 631
F -> C (in hyperthyroidism; associated with hyperfunctioning thyroid adenomas). VAR_011544
631 - 631
F -> L (in HTNA; gain of function; found in toxic thyroid nodules and hyperfunctioning thyroid adenomas). VAR_011545
632 - 632
T -> A (in HTNA; gain of function; found in toxic thyroid nodules and hyperfunctioning non-adenomatous nodules). VAR_011546
632 - 632
T -> I (in HTNA; gain of function; found in thyroid toxic nodules and hyperfunctioning thyroid adenomas). VAR_011547
633 - 633
D -> A (in hyperthyroidism; associated with hyperfunctioning thyroid adenomas). VAR_011548
633 - 633
D -> E (in HTNA; found in thyroid toxic nodules and hyperfunctioning thyroid adenomas). VAR_011549
633 - 633
D -> H (in hyperthyroidism and TTNs; associated with hyperfunctioning thyroid adenomas; also in hyperfunctioning insular carcinoma; with severe thyrotoxicosis; gain of function; dbSNP:rs28937584). VAR_011550
28937584
633 - 633
D -> Y (in hyperthyroidism and TTNs; associated with hyperfunctioning thyroid adenomas). VAR_011551
639 - 639
P -> A (in TTNs). VAR_021500
639 - 639
P -> S (in HTNA; gain of function). VAR_011552
647 - 647
A -> V (in HTNA; found in non-adenomatous hyperfunctioning nodules). VAR_011553
650 - 650
N -> Y (in HTNA; gain of function). VAR_011554
656 - 656
V -> F (in TTNs). VAR_021501
658 - 661
Missing (in hyperthyroidism; associated with hyperfunctioning thyroid adenomas). VAR_011555
670 - 670
N -> S (in HTNA; gain of function). VAR_011556
672 - 672
C -> Y (in HTNA; gain of function). VAR_011557
677 - 677
L -> V (in thyroid carcinoma; with thyrotoxicosis; gain of function). VAR_011558
703 - 703
A -> G. VAR_011559
715 - 715
N -> D (in papillary cancer). VAR_003576
720 - 720
Q -> E. VAR_011560
723 - 723
K -> M (in papillary cancer). VAR_003577
727 - 727
D -> E (may be a predisposing factor in toxic multinodular goiter pathogenesis; activation of the cAMP cascade does not differ from the wild-type; dbSNP:rs1991517). VAR_003578
1991517
Database cross-references
UniProt:
P16473
Ensembl:
ENST00000342443
Ensembl:
ENST00000554435
MIM:
275200
MIM:
603372
MIM:
603373
MIM:
609152
neXtProt:
NX_P16473
Antibodypedia:
P16473
(may not find the protein thus also not any antibody)
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