Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162871 (abdominal aortic aneurysm)
 8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Constitutively activating mutations have recently been identified in the thyrotropin receptor (TSHR) of hyperfunctioning thyroid adenomas and familial hyperthyroidism. In the present study, we evaluated the frequency of constitutively activating TSHR mutations in a large series of autonomously functioning thyroid nodules (AFTNs) in Japan. Forty-five AFTNs (38 solitary hyperfunctioning thyroid adenomas and 7 toxic multinodular goiters) were analyzed. Genomic DNA was extracted from paraffin-embedded tissue sections, from which DNA fragments encoding the mutational hot spots of the receptor (the third cytoplasmic loop and the sixth transmembrane segment) were amplified by polymerase chain reaction. In the single-stranded conformation polymorphism (SSCP) analysis, only one hyperfunctioning adenoma (no. 21) displayed a migration abnormality. In sequence analysis, an unusual mutation of alternate three-base deletions at nucleotides 1953-1957 (AAA GAT ACC to AAG TCC), resulting in one amino acid deletion (Asp at 619) and one conservative amino acid substitution (Thr to Ser at 620), was identified in tumor DNA but not in leukocyte DNA of no. 21. Further, the normal sequence in these regions was confirmed in 10 randomly selected samples with normal migrating patterns in SSCP analysis. The functional property of the mutant with delta 619 and T620S (designated TSHR delta 619) was then evaluated with in vitro mutagenesis and transfection studies. Unexpectedly, however, there were no significant differences in TSH binding affinity, and basal and TSH-stimulated levels of cAMP and inositol 1,4,5-triphosphate between the TSHR delta 619 and the wt-TSHR. In conclusion, the incidence of the constitutively activating TSHR mutations in AFTNs appears to be low in Japan. The oncogenic potential of a novel somatic mutant TSHR delta 619 identified in a hyperfunctioning adenoma in this study is at present uncertain because of its intact function.
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PMID:Rarity of oncogenic mutations in the thyrotropin receptor of autonomously functioning thyroid nodules in Japan. 767 2

The thyrotropin receptor (TSHR) exists in two forms (single polypeptide and two subunits), whereas the lutropin/chorionic gonadotropin receptor (LH/CGR) is a single chain. Recent data suggest that the TSHR cleaves at two sites. We mutagenized selected chimeric TSH-LH/CGR to localize the cleavage sites in the TSHR. All 23 receptors mutated in the estimated vicinity of the upstream site cleaved into two subunits as determined by 125I-TSH cross-linking to intact cells. In contrast, in a series of mutations homologous to the noncleaving LH/CGR, the downstream TSHR cleavage site localized to three amino acids (GQE367-369). Remarkably, group substitution of these residues, but not substitution of individual residues, abolished cleavage. Moreover, the mutation that prevented cleavage (GQE367-369NET) transposed a motif (NET291-293) that is glycosylated in the LH/CGR. TSHR cleavage or noncleavage after substitution of GQE367-369 with other triplets (AAA, NQE, and NQT) was consistent with a role for N-linked glycosylation at this site. In summary, our data (i) support the concept that the TSHR cleaves at two sites, (ii) relate TSHR residues GQE367-369 to cleavage at the second, downstream site, and (iii) suggest that cleavage or noncleavage at site two is related to N-linked glycosylation. These findings provide new insight into the evolutionary divergence of two closely related receptors.
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PMID:An N-linked glycosylation motif from the noncleaving luteinizing hormone receptor substituted for the homologous region (Gly367 to Glu369) of the thyrotropin receptor prevents cleavage at its second, downstream site. 935 84

To gain insight into the thyrotropin hormone (TSH) receptor (TSHR) cleavage, we sought to convert the noncleaving luteinizing hormone (LH) receptor (LHR) into a cleaved, two-subunit molecule. For this purpose, we generated a series of LHR mutants and chimeric LH-TSH receptors. Cleavage of mature, ligand binding receptors on the cell surface was determined by covalent 125I-labeled hCG crosslinking to intact, stably transfected mammalian cells. We first targeted a cluster of three N-linked glycans in the LHR (N295, N303, N317) in a region corresponding to the primary TSHR cleavage site, which has only one N-linked glycan. Elimination by mutagenesis of the most strategic N-linked glycan (LHR-N317Q) generated only a trace amount of LHR cleavage. Removal of the other N-linked glycans had no additive effect. A much greater degree of cleavage ( approximately 50%) was evident in a chimeric LH-TSHR in which the juxtamembrane segment of the LHR (domain E; amino acids 317-367) was replaced with the corresponding domain of the TSHR (residues 363-418). Similarly cleaving LHR were created using a much smaller component within this region, namely LHR-NET317-319 replaced with TSHR-GQE367-369, or by substitution of the same three amino-acid residues with AAA (LHR-NET317-319AAA). In summary, our data alter current concepts regarding TSHR cleavage by suggesting limited (not absent) amino-acid specificity in a region important for TSHR cleavage (GQE367-369). The data also support the concept of a separate and distinct downstream cleavage site 2 in the TSHR.
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PMID:Insight into thyrotropin receptor cleavage by engineering the single polypeptide chain luteinizing hormone receptor into a cleaving, two subunit receptor. 1129 43