The SNORD116-NHLH2 pathway: insights into the molecular genetic basis of Prader-Willi Syndrome

Prader-Willi Syndrome (PWS) is a genetic condition resulting from paternal inheritance of a deletion within an imprinted region of chromosome 15q. The smallest known deleted region encompasses a small nucleolar non-coding RNA locus called SNORD116 (SNORD116), but very little is known about how deletion of SNORD116 leads to PWS. As shown using pluripotent stem cells from PWS patients and control individuals, expression of the NHLH2 and PCSK1 genes are significantly reduced in PWS patients. NHLH2 is a transcription factor that transcriptionally-regulates the PCSK1 gene, while PSCK1 acts as a protease that cleaves and activates neuropeptides. In mouse models, deletion of NHLH2 and PSCK1 leads to obesity and other conditions that overlap with phenotypes of PWS. Human PSCK1 deletion or variants that inactivate PSCK1 protein lead to in human obesity. The identification of NHLH2 and PSCK1 as potential SNORD116@ regulatory targets allows us to begin to address a major unanswered question for PWS patients and their families: How does deletion of this region of chromosome 15q lead to PWS? What is known is that SNORD116 is a C/D box small RNA that potentially acts as an RNA guide for proteins that methylate RNA. Methylation difference could change the stability of the RNA, or could lead to differential RNA splicing of target mRNAs. We proposed that if SNORD116 RNAs serve as guides for methyltransferases, loss of SNORD116 from the deleted region in patients could explain differences in NHLH2 and PSCK1 expression, and possibly the phenotype of PWS patients. Dr. Good’s laboratory has worked on the NHLH2 gene for 20 years, and has many tools that will allow her laboratory to study how both NHLH2 and PCSK1 mRNAs are differentially expressed in PWS, as compared to control neurons. Her lab will use pluripotent stem cells from PWS patients and controls, as well as the PWS mouse mode, and mouse hypothalamic neurons in cell- and mouse-based studies to identify the molecular genetic mechanism underlying the SNORD116--NHLH2 and PSCK1 interacting pathway. Understanding the basic molecular genetic biology of the SNORD116 locus and its targets will lay the foundation for identifying future clinical targets or therapeutic interventions for PWS patients and their families.

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