Genetic Mutation Underlying Sleep Patterns 

Sleep is often an overlooked component of our health and wellbeing. While adults require 8 – 8.5 hours of sleep to function optimally, nearly 40% of United States adults fail to achieve this amount with an average of less than 7 hours of sleep per weeknight.1 This sleep deprivation has been shown to significantly correlate with increased risks of stroke, diabetes, and coronary heart disease.2 Many individuals may claim to function optimally with less sleep, but the overwhelming number of clinical studies tend to disagree. Suboptimal sleep in students leads to poorer neurocognitive function and learning outcomes along with greater memory impairment.1,3 While these negative outcomes are true for the majority, there are of course exceptions. A small percentage of people are able to function on an average of 4-6 hours of sleep without any observed detrimental effects- a trait known as familial natural short sleep (FNSS) .1 The mechanisms underlying this trait have been largely unknown until recently.    

A discovery made by Lijuan et al. regarding a gain of function mutation to neuropeptide S receptor (NPS) has helped us to elucidate the discrepancies in sleep required among humans. Whole exome sequencing was performed on two members of a family with reported sleep durations of 4.3 and 5.5 hours per night. A common point mutation of Y206H on the G-protein coupled receptor neuropeptide S receptor 1 (NPSR1) was found. CRISPR Cas9 was used to induce this mutation in mice for in vivo testing. NREM as well as REM sleep was reduced in mutant mice compared to those with the WT genotype. Additionally, cognitive function was tested using a fear conditioning test based on memory. Despite the lack of sleep, mutant mice performed equally well as their wild type counterparts. When faced with equal amounts of sleep, mutants fared better than their wild type counterparts. These data corroborate the hypothesis of the NPSR1 mutation leading to less sleep without impaired neurologic function.1

Currently, only partial explanations exist for the phenomena resulting from the NPSR1 mutation. It has already been established that NPSR1 is coupled to G proteins. To test the effect of the Y206H point mutation on this pathway, brain lysates were used to quantify phosho-cAMP response element-binding protein (CREB). More CREB was seen in the mutant mice at time points 2 and 11. With injection of NPS, a greater dose dependent increase was seen in the mutants than the WT’s. Additionally, visualization of neurons using calcium imaging showed mutant mice cells have a stronger and longer lasting activation response to NPS. Both experiments corroborate the hypothesis that the mutant cells are more active in vivo. The fact that the point mutation occurs on the extracellular domain implies that it may be involved in greater ligand affinity, although more research is necessary to pinpoint the exact mechanism.1   

In our current society and extreme work culture, there seems to be a stigma of getting an appropriate amount of sleep. Prior to the discovery of this NPSR1 mutation, being able to function on less sleep has been seen as a strength of self-will. Not much thought has been placed into the possibility of genetic dispositions leading to different sleep patterns. Past studies have detailed the detrimental effects to neurological function and morbidity that come with less than ideal sleep. The study by Lijuan et al. shows that this ideal amount of sleep varies among individuals. There are individuals who are able to function optimally with less sleep, but not because of shear determination. Considering the rarity of NPSR1 mutations, it can be assumed that a majority of people getting less than ideal sleep do not have a NSPR1 mutations but are, in fact, sleep deprived and require more sleep. Hopefully this study sheds light on the genetic basis of sleep and allows us to alleviate some of the negative stereotypes that surround over or under sleeping.

References:

1. L. Xing, G. Shi, Y. Mostovoy, N. W. Gentry, Z. Fan, T. B. Mcmahon, P.-Y. Kwok, C. R. Jones, L. J. Ptáček, Y.-H. Fu, Mutant neuropeptide S receptor reduces sleep duration with preserved memory consolidation. Sci. Transl. Med. 11, eaax2014 (2019).
2. Liu Y; Wheaton AG; Chapman DP; Croft JB. Sleep duration and chronic diseases among US adults age 45 years and older: evidence from the 2010 Behavioral Risk Factor Surveillance System. SLEEP 2013;36(10):1421-1427.
3. G. Curcio, M. Ferrara, L. De Gennaro, Sleep loss, learning capacity and academic performance. Sleep Med. Rev. 10, 323–337 (2006).

Author:

I am an MS1 at Sackler School of Medicine from Westchester, New York interested in translational research as well personalized medicine based on genetic testing. I have enjoyed my first few months here with my amazing classmates and look forward to the next four years.  

-Rohan Sharma