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.
Soo-Jeong Kim, M.D.
Seattle Children’s Research Institute