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Prevalence of mutations in TSHR, GNAS, PRKAR1A and RAS genes in a large series of toxic thyroid adenomas from Galicia, an iodine deficient area in NW Spain

J Lado-Abeal, UETeM. Medicine, University of Santiago de Compostela, Santiago de Compostela, 15705, Spain
F Palos-Paz, UETeM. Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain
O Perez-Guerra, UETeM. Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain
J Cameselle-Teijeiro, Pathology, University of Santiago de Compostela, Santiago de Compostela, Spain
J Rueda-Chimeno, Surgery, Complexo Hospitalario de Pontevedra, Pontevedra, Spain
F Barreiro-Morandeira, Surgery, University of Santiago de Compostela, Santiago de Compostela, Spain

Correspondence: Joaquin Lado-Abeal, Email: melado61{at}usc.es

Abstract

Objective: Toxic thyroid adenoma (TA) is a common cause of hyperthyroidism. Mutations in the TSHR gene and, less frequently in GNAS, are well established causes of TA in Europe. However, genetic causes of TA remain unknown in a small percentage of cases. We report the first study to investigate mutations in TSHR, GNAS, PRKAR1A and RAS genes, in a large series of TA from Galicia, an iodine deficient region in NW Spain.

Design and methods: 85 TA samples were obtained surgically from 77 hyperthyroid patients, operated on for treatment of non-autoimmune toxic nodular goitre. After DNA extraction all coding exons of TSHR, GNAS and PRKAR1A genes, and exons 2 and 3 of HRAS, KRAs and NRAS were amplified by PCR and sequenced. Previously unreported mutants were cloned in expression vectors and their basal constitutive activities were determined by quantification of cAMP response element (CRE)-luciferase activity in CO7 cells transfected with wild-type and mutant plasmids.

Results: TSHR gene mutations were found in 52 (61.2%) samples, GNAS gene mutations in 4 (4.71%) samples; no PRKAR1A or RAS mutations were found. Only three new mutations were found, two affecting the TSH receptor, A623F and I635V, and one affecting the G protein alpha subunit, L203P. Mutant proteins showed higher CRE-luciferase activity than their wild-type counterparts.

Conclusions: TA in a hyperthyroid population living in Galicia, a Spanish iodine deficient region, harbours elevated frequencies of TSHR and GNAS mutations activating the cAMP pathway. However, the genetic cause of TA was undetermined in 34% of the samples.