Genome-wide survey of DNA methylation in PWS

Prader-Willi syndrome (PWS) is a rare genomic imprinting disorder caused by an abnormality in the PWS critical region (PWSCR), a particular region of 15th chromosome (15q11-q13). Genomic imprinting refers to a phenomenon in which genes from specific parent can be expressed. PWSCR contains several imprinted genes that are only expressed from either maternally or paternally inherited chromosome. PWS results from absence of paternally imprinted genes via three main genetic mechanisms: (a) deletion; (b) maternal uniparental disomy; and (c) imprinting defect. Genomic imprinting is most commonly mediated by a mechanism called DNA methylation, a process to add a methyl group to a cytosine, one of the building blocks of DNA. Methylated genes remain inactive, while unmethylated genes are expressed.

Clinically, PWS is frequently associated with developmental delay, intellectual disability, learning disability, neurobehavioral disturbances, such as autism spectrum disorder, mood disorder and psychosis. Remarkably these phenotypes vary across individuals with PWS. While underlying genetic mechanisms for PWS are clearly understood, we still do not know how the abnormality of PWSCR brings about systemic and variable phenotype expression.

In the present research study, we hypothesized that the abnormality in PWSCR may produce cascading effects on DNA methylation in other regions of genome. Because DNA methylation can turn on or off expression of genes, we aim to find regions related to the changes in DNA methylation. We will examine the DNA methylation profile in 16 individuals with PWS along with their siblings without PWS (total 32 individuals). We anticipate the results from this study will help find the downstream changes mediated by the abnormality of PWSCR and ultimately lead to the novel targets for treatment.

This project is in honor of Jean Deleage.

Research Outcomes:

DNA methylation plays a critical role in the expression of imprinted genes. Methylated genes remain inactive, while unmethylated genes are expressed: e.g., paternally imprinted genes would be 100% methylated in PWS, 0% methylated in Angelman syndrome (AS), and 50% methylated in control. However, our preliminary data suggest that DNA methylation may not be an "all" or "none" phenomenon. Differences in DNA methylation may result in different level of gene expression, which, in turn, induce variable phenotypic expressivity. Furthermore, the level of DNA methylation at one locus (15q11-q13) may affect the DNA methylation at other loci based on CpG methylation clustering and the pattern of DMRs in other chromosomes. To date, we have examined 16 PWS sibling pairs (same gender and age closely matched). The preliminary data shown above may support for a hypothesis that an epigenetic alteration at PWSCR may affect DNA methylation in other regions of genome (downstream targets), which that may correlate with multisystem involvement and/or variable phenotypic expressivity. Because this data is obtained from a very small sample, a replication study may be needed to confirm this finding.

Funded Year:


Awarded to:

Soo-Jeong Kim, M.D.




Seattle Children’s Research Institute

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