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The smallest genomic region causing Prader-Willi Syndrome (PWS) deletes the non-coding RNA  SNORD116  cluster; however, the function of  SNORD116  remains a mystery. Previous work in the field revealed the tantalizing possibility that expression of  NHLH2 , a gene previously implicated in both obesity and hypogonadism, was downregulated in PWS patients and differentiated stem cells.  In silico  RNA: RNA modeling identified several potential interaction domains between  SNORD116  and  NHLH2  mRNA. One of these interaction domains was highly conserved in most vertebrate  NHLH2  mRNAs examined. A construct containing the  Nhlh2  mRNA, including its 3’-UTR, linked to a c-myc tag was transfected into a hypothalamic neuron cell line in the presence and absence of exogenously-expressed  Snord116 .  Nhlh2  mRNA expression was upregulated in the presence of  Snord116  dependent on the length and type of 3’UTR used on the construct. Furthermore, use of actinomycin D to stop new transcription in N29/2 cells demonstrated that the upregulation occurred through increased stability of the  Nhlh2  mRNA in the 45 minutes immediately following transcription.  In silico  modeling also revealed that a single nucleotide variant (SNV) in the  NHLH2  mRNA could reduce the predicted interaction strength of the  NHLH2:SNORD116  diad. Indeed, use of an  Nhlh2  mRNA construct containing this SNV significantly reduces the ability of  Snord116  to increase  Nhlh2  mRNA levels. For the first time, these data identify a motif and mechanism for SNORD116-mediated regulation of  NHLH2 , clarifying the mechanism by which deletion of the  SNORD116  snoRNAs locus leads to PWS phenotypes.

Snord116 Post-transcriptionally Increases Nhlh2 mRNA Stability: Implications for Human Prader-Willi Syndrome