Comparison of Genomic and Epigenomic Expression in Monozygotic Twins Discordant for Rett SyndromeReportar como inadecuado

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Monozygotic identical twins have been widely used in genetic studies to determine the relative contributions of heredity and the environment in human diseases. Discordance in disease manifestation between affected monozygotic twins has been attributed to either environmental factors or different patterns of X chromosome inactivation XCI. However, recent studies have identified genetic and epigenetic differences between monozygotic twins, thereby challenging the accepted experimental model for distinguishing the effects of nature and nurture. Here, we report the genomic and epigenomic sequences in skin fibroblasts of a discordant monozygotic twin pair with Rett syndrome, an X-linked neurodevelopmental disorder characterized by autistic features, epileptic seizures, gait ataxia and stereotypical hand movements. The twins shared the same de novo mutation in exon 4 of the MECP2 gene G269AfsX288, which was paternal in origin and occurred during spermatogenesis. The XCI patterns in the twins did not differ in lymphocytes, skin fibroblasts, and hair cells which originate from ectoderm as does neuronal tissue. No reproducible differences were detected between the twins in single nucleotide polymorphisms SNPs, insertion-deletion polymorphisms indels, or copy number variations. Differences in DNA methylation between the twins were detected in fibroblasts in the upstream regions of genes involved in brain function and skeletal tissues such as Mohawk Homeobox MKX, Brain-type Creatine Kinase CKB, and FYN Tyrosine Kinase Protooncogene FYN. The level of methylation in these upstream regions was inversely correlated with the level of gene expression. Thus, differences in DNA methylation patterns likely underlie the discordance in Rett phenotypes between the twins.

Autor: Miyake Kunio, Chunshu Yang, Yohei Minakuchi, Kenta Ohori, Masaki Soutome, Takae Hirasawa, Yasuhiro Kazuki, Noboru Adachi, Seiko S



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