European Journal of Endocrinology www.eje-online.org © 2017 European Society of Endocrinology Printed in Great Britain Published by Bioscientifica Ltd. DOI: 10.1530/EJE-16-1021 Evidence for the founder effect of RET533 as the common Greek and Brazilian ancestor spreading multiple endocrine neoplasia 2A Lucas L Cunha 1 , Susan C Lindsey 1 , Maria Inez C França 1 , Leda Sarika 3 , Alexandra Papathoma 3 , Ilda S Kunii 1 , Janete M Cerutti 2 , Magnus R Dias-da-Silva 1 , Maria Alevizaki 3 and Rui M B Maciel 1 1 Departments of Medicine and 2 Morphology and Genetics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil, and 3 Endocrine Unit, Department of Medical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece Abstract Objectives: About one-quarter of patients with medullary thyroid cancer (MTC) have inherited disease due to mutations in the RET gene. A rare mutation in exon 8 (G533C) of RET, previously described in a large Brazilian family with MEN2A, also appeared to be clustering in Greece, whereas it was rarely reported in other ethnic groups. The aim of this study was to identify a possible common ancestry between these carriers. Patients and methods: Twelve RET G533C mutation carriers, four randomly selected from the Brazilian cohort and eight from apparently unrelated Greek families, were studied for a possible common ancestral origin. RET fanking microsatellite markers at chromosome 10q (D10S197, D10S196, D10S1652 and D10S537) were used. Results: Genomic DNA analysis using these markers showed that many of these apparently unrelated individuals shared a common haplotype indicating a common ancestral origin. Conclusion: Our data suggest that Brazilian and Greek patients with MTC carrying the G533C mutation in exon 8 of RET gene originate from a common ancestor. Due to historical reasons, we speculate that the more plausible explanation for the origin of this mutation is in Greece. Introduction More than 25% of medullary carcinoma patients (MTC) have familial disease, which is due to germ line mutations of the RET gene. The clinical presentation varies according to the type of RET mutation. After the routine application of genetic analysis in all MTC cases (1), it became apparent that some apparently sporadic cases were in fact familial as they carried a RET mutation. Furthermore, a wider distribution of mutations across the RET gene was identifed, which were different from those originally described. In this context, we recently described a large family with medullary thyroid carcinoma (MTC) carrying a missense mutation in exon 8 of RET, which corresponds to a glycine-to-cysteine substitution at codon 533 (2); this was later confrmed to be MEN2A. This family comprises 728 members of Caucasian origin with ancestors from Catalunia, Spain, who immigrated to Brazil at the end of the 19th century. Most of the family members live in Southeastern Brazil and have been followed at an outpatient Endocrine Unit either in Vitoria or São Paulo by the same team of physicians for over ffteen years. During this long-term follow-up, molecular and clinical characteristics of these patients have been described in detail (3, 4). However, the ancestry related to the origin of G533C RET mutation remains to be elucidated. Correspondence should be addressed to R M B Maciel Email rui.maciel@unifesp.br European Journal of Endocrinology (2017) 176, 515–519 www.eje-online.org © 2017 European Society of Endocrinology 176:5 515–519 L L Cunha and others Founder effect of RET533 in MEN2A patients Clinical Study Downloaded from Bioscientifica.com at 05/26/2020 09:09:34PM via free access