Probing genetics and biology of human sleep homeostasis

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Project Summary Familial Natural Short Sleep (FNSS) is a rare Mendelian form of sleep where affected individuals have a lifelong requirement for sleep that is significantly less than the average person. These people often sleep 4-6 hours per night yet report feeling well-rested. In 2009, we reported the first human FNSS trait, identification of the causative gene/mutation. and characterization of a similarly short sleep phenotype in modeled mice (and a corresponding rest-activity phenotype in Drosophila). We have since identified over 90 FNSS probands and have been expanding these families with phenotyping and DNA banking of additional affected and unaffected family members. Subsequent whole exome sequencing (WES) identified 2 candidate genes/mutations (1 in each of 2 families). In both cases, we've generated mouse models of the human mutations. Both of these mice also show short sleep phenotype as seen in human subjects. Another gene (GRM1) was found to harbor distinct mutations in 2 different families. A mouse model of one GRM1 allele also shows short sleep by EEG. These 4 genes (DEC2, ADRB1, NPSR1, and GRM1) still only explain a minority of the ~30 families that underwent initial WES. In this proposal, we plan to continue collecting FNSS subjects from existing `unexplained' families and to continue collecting new probands and their families. Our growing database is an incredible resource for identifying additional FNSS genes/mutations via whole exome sequencing and whole genome sequencing. Studies of this growing list of FNSS genes will help us and others to better understand pathways and brain circuits that contribute to sleep regulation and efficiency. Ultimately, understanding of such biological pathways may lead to novel targets for developing better drugs to improve sleep quality and efficiency.