D Gentilini1,2, M Muzza3, T de Filippis3, M C Vigone4, G Weber4, L Calzari1, A Cassio5, M Di Frenna4, M Bartolucci6, E S Grassi7, E Carbone3, A Olivieri8, L Persani9,10. 1. Bioinformatics and Statistical Genomics Unit, Istituto Auxologico Italiano IRCCS, Cusano Milanino, 20095, Milan, Italy. 2. Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy. 3. Laboratory of Endocrine and Metabolic Research, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Piazzale Brescia 20, 20149, Milan, Italy. 4. Department of Pediatrics, Endocrine Unit, IRCCS San Raffaele Hospital, Milan, Italy. 5. Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy. 6. Department of Maternal and Child Sciences and Urology, University "La Sapienza", Rome, Italy. 7. Department of Medical Biotechnology and Experimental Medicine, University of Milan, 20122, Milan, Italy. 8. Department of Cardiovascular and Endocrine-Metabolic Diseases and Aging, Italian National Institute of Health, 00161, Rome, Italy. 9. Laboratory of Endocrine and Metabolic Research, Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Piazzale Brescia 20, 20149, Milan, Italy. luca.persani@unimi.it. 10. Department of Medical Biotechnology and Experimental Medicine, University of Milan, 20122, Milan, Italy. luca.persani@unimi.it.
Abstract
PURPOSE: The elevated frequency of discordance for congenital hypothyroidism (CH) phenotype between monozygotic twins suggests the involvement of non-mendelian mechanisms. The aim of the study was to investigate the role of epigenetics in CH pathogenesis. METHODS: A genome-wide DNA methylation analysis was performed on the peripheral blood of 23 twin pairs (10 monozygotic and 13 dizygotic), 4 concordant and 19 discordant pairs for CH at birth. RESULTS: Differential methylation analysis did not show significant differences in methylation levels between CH cases and controls, but a different methylation status of several genes may explain the CH discordance of a monozygotic twin couple carrying a monoallelic nonsense mutation of DUOX2. In addition, the median number of hypo-methylated Stochastic Epigenetic Mutations (SEMs) resulted significantly increased in cases compared to controls. The prioritization analysis for CH performed on the genes epimutated exclusively in the cases identified SLC26A4, FOXI1, NKX2-5 and TSHB as the genes with the highest score. The analysis of significantly SEMs-enriched regions led to the identification of two genes (FAM50B and MEG8) that resulted epigenetically dysregulated in cases. CONCLUSION: Epigenetic modifications may potentially account for CH pathogenesis and explain discordance among monozygotic twins.
PURPOSE: The elevated frequency of discordance for congenital hypothyroidism (CH) phenotype between monozygotic twins suggests the involvement of non-mendelian mechanisms. The aim of the study was to investigate the role of epigenetics in CH pathogenesis. METHODS: A genome-wide DNA methylation analysis was performed on the peripheral blood of 23 twin pairs (10 monozygotic and 13 dizygotic), 4 concordant and 19 discordant pairs for CH at birth. RESULTS: Differential methylation analysis did not show significant differences in methylation levels between CH cases and controls, but a different methylation status of several genes may explain the CH discordance of a monozygotic twin couple carrying a monoallelic nonsense mutation of DUOX2. In addition, the median number of hypo-methylated Stochastic Epigenetic Mutations (SEMs) resulted significantly increased in cases compared to controls. The prioritization analysis for CH performed on the genes epimutated exclusively in the cases identified SLC26A4, FOXI1, NKX2-5 and TSHB as the genes with the highest score. The analysis of significantly SEMs-enriched regions led to the identification of two genes (FAM50B and MEG8) that resulted epigenetically dysregulated in cases. CONCLUSION: Epigenetic modifications may potentially account for CH pathogenesis and explain discordance among monozygotic twins.
Authors: Rasha Abu-Khudir; Jean Paquette; Anne Lefort; Frederick Libert; Jean-Pierre Chanoine; Gilbert Vassart; Johnny Deladoëy Journal: PLoS One Date: 2010-10-15 Impact factor: 3.240
Authors: Sasha E Parets; Karen N Conneely; Varun Kilaru; Stephen J Fortunato; Tariq Ali Syed; George Saade; Alicia K Smith; Ramkumar Menon Journal: PLoS One Date: 2013-06-27 Impact factor: 3.240