Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autosomal dominant nonautoimmune hyperthyroidism (ADNAH) is caused by gain of function mutations in the TSH receptor (TSHr) gene and characterized by toxic thyroid hyperplasia with a variable age of onset in the absence of thyroid antibodies and clinical symptoms of autoimmune thyroid disease in at least two generations. We report here a Turkish family with a novel TSHr gene mutation with distinct features all consistent with ADNAH. Thyroid function tests of the proband were as follows: free T3: 13.1 pg/ml (N: 1.8-4.6); free T4: 5.1 ng/dl (N: 0.9-1.7); TSH: 0.01 microIU/ml (N: 0.2-4.2); and TSH receptor antibody: 2 IU/ml (N: 0-10). A heterozygous missense mutation in exon 10 of the TSHr gene (c.1454C>T) resulting in the substitution of valine for alanine at codon 485 (p.Ala485Val) was found in the father and his son and daughter. This mutation had arisen de novo in the father. Functional studies of the novel TSHr germline mutation demonstrated a higher constitutive activation of adenyl cyclase than wild type without any effect on phospholipase C activity. In conclusion, our data indicate that gain of function germline mutations in the TSHr gene should be investigated in families with members suffering from thyrotoxicosis and progressive growth of goiter, but without clinical and biochemical evidence of autoimmune thyroid disease. In addition, patients harboring the same mutation of the TSHr gene may show wide phenotypic variability with respect to the age at onset, and severity of hyperthyroidism and thyroid growth.
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PMID:A family with a novel TSH receptor activating germline mutation (p.Ala485Val). 1817 46

Thyroid stimulating hormone receptor (TSHR) is a guanine nucleotide-binding protein-coupled seven-transmembrane-domain receptor that controls the differentiation, growth, and function of the thyroid gland through stimulation of adenylyl cyclase and phospholipase C pathways. Thyroid stimulating hormone (TSH) is the main TSHR ligand, and unliganded receptor remains silent due to the interaction of its large extracellular domain with the extracellular loops of the serpentine. The TSHR gene is highly mutagenic and constitutively active mutations have been extensively described. Naturally occurring TSHR-activating mutations can affect any part of the receptor, but most activating mutations affect the serpentine region, and the majority of these are located in the third intracellular loop or transmembrane domain six. We describe several simple and relatively cheap methods used in our laboratory to study constitutive TSHR mutations that include (1) screening of TSHR gene mutations in paraffin-embedded thyroid tissue samples, (2) measurement of TSHR constitutive activity in vitro, (3) measurement of TSHR expression at cell surface by flow cytometry analysis, (4) TSH binding to TSHR, and (5) TSHR phosphorylation analysis.
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PMID:Identification and evaluation of constitutively active thyroid stimulating hormone receptor mutations. 2103 42


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