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- Title
A Family with Congenital Hypothyroidism Caused by a Combination of Loss-of-Function Mutations in the Thyrotropin Receptor and Adenylate Cyclase-Stimulating G Alpha-Protein Subunit Genes.
- Authors
Joaquin Lado-Abeal; Isabel Castro-Piedras; Fernando Palos-Paz; Jose Ignacio Labarta-Aizpún; Ramon Albero-Gamboa
- Abstract
Background:Resistance to thyrotropin (TSH) causes congenital hypothyroidism (CH). TSH receptor (TSHR) and adenylate cyclase-stimulating G alpha protein subunit (GNAS) loss-of-function mutations cause TSH resistance. We describe a family with TSH resistance and CH bearing a combination of inactivating mutations in TSHRand GNASgenes. We describe studies to determine the molecular mechanisms involved in TSH resistance in this family.Methods:DNA sequencing to identify TSHRand GNASgene mutations was performed. In vitroeffects of the mutations on cAMPproduction and TSH binding were investigated in COS7cells. cAMPproduction was evaluated by transfecting a cAMPresponse element (CRE)-luciferase reporter with pSVL-TSHR and pSVK3-GNAS vectors. For binding studies, cells transfected with pSVL-TSHR vectors were incubated with iodine-125 bovine TSH (125IbTSH).Results:Family members with and without CH were heterozygous for the TSHRmutant p.E34K or the GNASmutant c.750_751insA (=GNASMut). The propositus had CH and he was heterozygous for TSHRp.E34K; his mother, also heterozygous for TSHRp.E34K, did not have CH. The euthyroid propositus'' wife was heterozygous for GNASMut. The propositus'' two daughters had CH, one was heterozygous for GNASMutand the other a compound heterezygous for TSHRp.E34K and GNASMut. Albright''s hereditary osteodystrophy phenotype was present in those with GNASMutmutation but only the daughters had pseudohypoparathyroidism type 1a. Cells transfected with TSHRE34Khad lower TSH affinity and less CRE-luciferase response than cells transfected with TSHR wild-type(WT). Cells transfected with GNASMutdid not stimulate CRE-luciferase activity, but when cells were transfected with GNASMutplus GNASWT, a similar response to GNASWTalone was observed. The combination of TSHRWTand GNASWTshowed higher CRE-luciferase response than TSHRWTand TSHRE34K with either GNASWTor GNASWTplus GNASMut.Conclusions:CH was caused by loss-of-function mutations in TSHRand/or GNAS. The absence of CH in the propositus'' mother argues against a role for TSHRp.E34K being the only cause of CH. The minimal thyroidal phenotypic differences between the sisters with pseudohypoparathyroidism type 1a and TSH resistance, both heterozygous for GNASc.750_751insA but only one bearing the TSHRp.E34K mutant, suggest that the main cause for CH was preferential expression of the mutated maternal GNASallele in the thyroid gland.
- Subjects
CONGENITAL hypothyroidism; GENETIC mutation; THYROTROPIN; ADENYLATE cyclase; G proteins; PSEUDOHYPOPARATHYROIDISM; LUCIFERASES; PROTEIN binding
- Publication
Thyroid, 2011, Vol 21, Issue 2, p103
- ISSN
1050-7256
- Publication type
Article
- DOI
10.1089/thy.2010.0187