Prader-Willi syndrome is a rare neurodevelopmental disorder that presents sleep abnormalities, among other symptoms. It is caused by errors in genomic imprinting that result from loss of expression of paternally inherited genes on the human 15q11-q13 locus. The PWS imprinted cluster is epigenetically regulated for monoallelic expression. Monoallelically-expressed alleles, such as in haploidy, promote the selection and fixation of adaptive mutations into the population, therefore providing selective advantages when environmental constraints occur. In searching for imprinted genes that have undergone changes during the evolution of modern humans, we found that NPAP1, a gene of the PWS locus, contains variants specific to modern human sequence in comparison to the ancestral orthologous sequences in the Neanderthal genomes. The two major protein variants found in the human population are characterized by a completely derived SNPs combination (~60% of the human population), and an ancestral/derived mixed combination (~40% of humans). Our efforts are focused on characterizing the primate specific NPAP1 gene and using CRISPR-based epigenetic writers as novel therapeutic tools. We generated a novel humanized mouse model in which NPAP1 coding sequence is cloned in the mouse orthologous region. In this proposal, we will study sleep and circadian rhythms in this new PWS mouse line. Moreover, we will use our novel class of target specific epigenetic writers to modulate gene expression within the PWS locus. This technology can be instrumental to recover the miss-imprinted genes and to rescue the loss of orexinergic neurons in PWS. Therefore, to ameliorate the sleep problems in PWS.
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Prader-Willi Syndrome: the role of primate-specific NPAP1 in sleep and circadian rhythms