Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.99.7 (sialyltransferase)
 1,534 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The integrity of the Tg structure as a protein is essential for adequate synthesis of thyroid hormone. Also a large supply of iodine and of thyroid hormone is stored into the Tg molecule and available for secretion on demand. Mutations in Tg gene or hyposialylated Tg due to a defective sialyltransferase activity would cause a structurally defective protein and severely impair the functional ability of Tg. In this review we attempt to cover the abnormalities in the synthesis of Tg described in both animals and man. Hereditary congenital goiter with or without hypothyroidism is the phenotypic major clinical finding in these species. Affected animals include sheep, bovine cattle, bongo antelope, goats, and mice. As in man the inheritance mode is autosomal recessive. In most animal studies structurally abnormal Tg is present. The molecular basis for the defective Tg synthesis was attributable to nonsense mutation in exon 9 (Afrikander cattle) and in exon 8 (Dutch goats). In man the Tg defective synthesis has been reported in 89 subjects and frequently more than one sibling is affected in a given generation. Characteristically these patients exhibit hereditary congenital goiter with relatively low Tg levels that do not increase after stimulation with bovine TSH. High PBI concentrations with low serum T4 values indicate the serum presence of iodinated proteins (mainly iodoalbumin). Also iodinated peptides are frequently excreted into the urine. Tissue studies confirm that there is an absent Tg peak at gel filtration, and virtually no immunoassayable Tg is present in the tissue extracts. The molecular basis of these defects have been recently reported in a patient and includes low tissue Tg mRNA probably due to premature degradation of a defective Tg mRNA. The responsible mutation is a cytosine to thymine transition creating a stop codon at position 1510. The point mutation is removed by the preferential accumulation of a 171 nt deleted Tg mRNA. In another subject molecular studies revealed that exon 4 was missing from the major Tg transcript due to a cytosine to guanine transversion at position minus 3 in the acceptor splice site of intron 3. It is anticipated that other mutations responsible for these defects will be identifiable in the near future.
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PMID:Defective thyroglobulin synthesis and secretion causing goiter and hypothyroidism. 832 50

Variation in asparagine-linked carbohydrate chains have a major impact on TSH biological properties. In particular, highly sialylated TSH is characterized by impaired intrinsic bioactivity and prolonged half-life. The aim of the present study was to investigate the changes in the degree of sialylation of circulating TSH isoforms that may occur in several physiological and clinical situations. Bioactivity and terminal sugar residues of immunopurified TSH were studied in 26 normal adults (day- and nighttime serum pools), 2 cord serum pools from normal fetuses during the third trimester, 1 fetus with primary hypothyroidism (PH; 27th week), 1 fetus with resistance to thyroid hormone (RTH; 28th and 33rd weeks), 24 patients with PH (before and during L-T4 treatment), and 5 patients with RTH before and during triiodothyrocetic acid (TRIAC) treatment. Nighttime TSH isoforms have an increased degree of sialylation compared to daytime TSH (35.8 +/- 9.7% vs. 23.8 +/- 5.8%; P < 0.03), thus accounting for the lower bioactivity [biological/immunological TSH ratio (TSH B/I), 1.3 +/- 0.4 vs. 2.0 +/- 0.2; P < 0.0007]. In adult PH, TSH isoforms are highly sialylated (45.4 +/- 7.6%; P < 0.007), showing an impaired bioactivity (0.7 +/- 0.3; P < 0.001). L-T4 therapy was accompanied by a trend toward normalization of TSH biological properties; TSH B/I was higher (1.0 +/- 0.3; P < 0.01), and the degree of sialylation was lower (36.8 +/- 7.0%; P < 0.02). A significant inverse correlation between TSH B/I values and the degree of sialylation was observed (P < 0.001). In normal fetuses, extremely bioactive asialo-TSH isoforms are circulating during the 3rd trimester. The impaired thyroid hormone action, such as that occurring in hypothyroid or RTH fetuses, induces an early expression of alpha-2,6-sialyltransferase activity within thyrotropes and results in the secretion of high amounts of sialylated TSH isoforms (34.6% and 26.3%). A hybrid TSH with peculiar terminal sugar residues and enhanced bioactivity is circulating in patients with RTH (TSH B/I, > or = 2.2). Treatment with low doses of TRIAC can initially reduce thyroid hormone secretion in RTH, mainly through the secretion of TSH isoforms with changed terminal sugar residues and reduced bioactivity (TSH B/I, 0.9-1.7). In conclusion, changes in the terminal sialic acid residues modulate the biological properties of circulating TSH, play a relevant physiopathological role in various situations, and contribute to adjust thyroid-stimulating activity to temporary needs.
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PMID:Changes in the degree of sialylation of carbohydrate chains modify the biological properties of circulating thyrotropin isoforms in various physiological and pathological states. 966 32