Some Twist of Molecular Circuitry Fast Forwards Overnight Sleep Hours: A Systematic Review of Natural Short Sleepers' Genes

Abstract

This systematic review focuses on different genetic mutations identified in studies on natural short sleepers, who would not be ill-defined as one type of sleep-related disorder. The reviewed literature is from databases such as PubMed, PMC, Scopus, and ResearchGate. Due to the rare prevalence, the number of studies conducted on natural short sleepers is limited. Hence, searching the search of databases was done without any date restriction and included animal studies, since mouse and fly models share similarities with human sleep behaviors. Of the 12 articles analyzed, four conducted two types of studies, animal and human (cross-sectional or randomized-controlled studies), to testify the effects of human mutant genes in familial natural short sleepers via transgenic mouse or fly models. The remaining eight articles mainly focused on one type of study each: animal study (four articles), cross-sectional study (two articles), review (one article), and case report (one article). Hence, those articles brought different perspectives on the natural short sleep phenomenon by identifying intrinsic factors like DEC2, NPSR1, mGluR1, and β1-AR mutant genes. Natural short sleep traits in either point-mutations or single null mutations in those genes have been examined and confirmed its intrinsic nature in affected individuals without any related health concerns. Finally, this review added a potential limitation in these studies, mainly highlighting intrinsic causes since one case study reported an extrinsically triggered short sleep behavior in an older man without any family history. The overall result of the review study suggests that the molecular mechanisms tuned by identified sleep genes can give some potential points of therapeutic intervention in future studies.

Keywords: adrb1; dec2; familial natural short sleeper; mglur1; natural short sleeper; npsr1; short sleep.

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guideline Flow Diagram 2020

Adapted from: Page MJ et al. [9] DEC2: transcription factor basic helix-loop-helix proteins differentiated embryo chondrocyte 2; NPSR1: neuropeptide S receptor 1; mGluR 5: metabotropic glutamate receptors of subtype 5; ADRB1: β1-adrenergic receptor; PMC: PubMed Central; n: number of studies.

Figure 2. Abundance of PER and CRY Proteins Fluctuates According to Circadian Rhythms

DEC 1:  transcription factor basic helix-loop-helix proteins Differentiated Embryo Chondrocyte 1; DEC2: transcription factor basic helix-loop-helix proteins Differentiated Embryo Chondrocyte 2; BMAL1: transcriptional activator Brain and Muscle Arnt-Like protein-1; CLOCK, transcriptional activator Circadian Locomotor Output Cycles Kaput; NPAS2: transcription factor Neuronal PAS domain protein 2; PER, repressor Period protein; CRY, repressor Cryptochrome protein.

Figure 3. Some Major Regions Where Nps and Npsr1 Are Highly Expressed in Mouse Brain (From the Sagittal View)

Nps: neuropeptide S mouse gene; Npsr1: neuropeptide S receptor 1 mouse gene.

Figure 4. Periodic Changes of Neural Excitability and Synaptic Strength

During the wake period, mGluR1/mGluR5 binds to long-form Homer proteins (tetramer of Homer1a) to anchor IP3R in ER and Shank at the base of PSD, thus increasing calcium release for neuronal excitability and upregulating AMPAR for strengthening synapses, respectively. During sleep, mGluR1/mGluR5 is agonized by Homer1a monomer and dissociated from IP3R and Shank, which, in turn, decreasing neural excitability and synaptic strength [51]. mGluR1/5: Group I metabotrpic glutamate receptors; Homer1a: Homer protein homolog 1 a; AMPAR: AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptor; IP3R: 1,4,5-triphosphate receptor; PSD: postsynaptic density; Shank: Shank protein; ER: endoplasmic reticulum.