Date of Award
Master of Science (MS)
Dr. Khalid Amiri
Fragile X Mental Retardation 1 (FMR1) gene produces an FMR protein (FMRP) which is known to regulate the translation process in various organs. It has a significant role in neurons function, maturation, and synaptic plasticity. FMR1 gene encompasses 5 - 30 CGG repeats and the greater number of repeats has the potential to expand during gametogenesis. The expansion depending on the number of CGG repeat undergoes hyper-methylation and is considered as a dynamic mutation in which the expansion increases through generation. Methylation of expanded CGG repeats results in inhibiting the transcription and silencing the gene. There are two types of affected individuals of Fragile X Syndrome, one has the methylated full mutation (no protein produced) and the other is mosaic (low amount of protein produced), which are a result of having different sizes expansion or both methylated and unmethylated alleles. It is not clear yet what causes the differential methylation in different individuals. Therefore, we hypothesize that background gene, such as methyltransferase genes varies between individuals causing the observed epigenetic differences. The phenotypic severity depends on the number of repeats and the degree of methylation, which corresponds to the concentration of FMRP. The study is focusing on DNA and Histone methyltransferase genes, which have an important role in genome imprinting, gene regulation, X chromosome inactivation, and embryonic development. In this study, we identified nine genetic variations in lysine methyltransferase genes only. No variation was identified in DNA and other histone methyltransferase genes. Whole exome analysis resulted in a total of 37 variations which were presented in more than 35 % of mosaic and full mutation samples, 17 were novel variants and ˃28 variants were presented in more than 50 % of mosaic and full mutation samples, and not found in the control. In this preliminary study of fragile X syndrome, we found more variations in introns and intergenic regions that might be associated with methylation level and physical and mental phenotypes. This preliminary data requires further genetic and functional studies, which can ultimately use genetic counseling, precision medicines, and early interventions.
Humaid Sembaij, Sara, "THE ASSOCIATION OF DNA AND HISTONE METHYLTRANSFERASE GENES WITH DIFFERENT METHYLATION LEVELS IN FRAGILE X SYNDROME INDIVIDUALS" (2019). Theses. 853.