Journal Article

A Cryptochrome 2 mutation yields advanced sleep phase in humans

Lipzen, Anna, McMahon, Thomas, Hirano, Arisa, Yamazaki, Maya, Ptáček, Louis J, Pennacchio, Len A, Xu, Ying, Fu, Ying-Hui, Shi, Guangsen, Hallows, William C, Jones, Christopher R

2016

Overview

Familial Advanced Sleep Phase (FASP) is a heritable human sleep phenotype characterized by very early sleep and wake times. We identified a missense mutation in the human Cryptochrome 2 ( CRY2 ) gene that co-segregates with FASP in one family. The mutation leads to replacement of an alanine residue at position 260 with a threonine (A260T). In mice, the CRY2 mutation causes a shortened circadian period and reduced phase-shift to early-night light pulse associated with phase-advanced behavioral rhythms in the light-dark cycle. The A260T mutation is located in the phosphate loop of the flavin adenine dinucleotide (FAD) binding domain of CRY2. The mutation alters the conformation of CRY2, increasing its accessibility and affinity for FBXL3 (an E3 ubiquitin ligase), thus promoting its degradation. These results demonstrate that CRY2 stability controlled by FBXL3 plays a key role in the regulation of human sleep wake behavior. Sleep is an essential process in animals. In humans, the disturbance of normal sleep-wake cycles through shift-work or long-term sleep disorders increases the risk of developing conditions including mental illness, cancer and metabolic syndromes. Understanding how sleep-wake behavior is controlled within cells may help researchers to develop effective therapies to reduce the ill effects of disturbed sleep-wakLouise cycles on health. To understand how our sleep-wake cycles are regulated in cells, researchers have been looking for genetic mutations that affect human sleep schedules. For example, some people have a ‘morning lark’ schedule that makes them prone to go to sleep early and rise early the next day. Others are prone to be ‘night owls’, staying up later at night and waking up later in the morning. By studying the mutations that underlie these behaviors, researchers hope to understand precisely how these genes regulate sleep schedules. Now, Hirano et al. have identified a particular mutation in a gene called Cryptochrome 2 ( CRY2 ) that causes people to have shorter sleep-wake cycles so that they wake up very early in the morning and struggle to stay awake in the evening. For the experiments, mice were genetically engineered to carry the mutant human CRY2 gene, which shortened the sleep-wake cycles of the mice and their responses to light so that they both woke up earlier and went to sleep earlier. Further experiments examined what effect the mutation has on the protein that is produced by CRY2. The mutation changes the shape of the protein, which allows an enzyme called FBXL3 to bind to the mutant protein more easily and rapidly break it down. The length of sleep cycles may be determined by how long it takes FBXL3 to break down the protein produced by CRY2 . The findings of Hirano et al. may help researchers to develop treatments for people with sleep problems.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Adenine / Alanine / Alanine - genetics / Amino Acid Substitution / Amino acids / Animals / BASIC BIOLOGICAL SCIENCES / circadian clock / Circadian rhythm / Circadian rhythms / Conformation / cryptochrome2 / Cryptochromes - genetics / Cryptochromes - metabolism / F-Box Proteins - metabolism / Familial Advanced Sleep Phase / FBXL3 / Flavin-adenine dinucleotide / Gene expression / Gene mutations / Genetic aspects / Genotype & phenotype / Health aspects / Human Biology and Medicine / Humans / Kinases / Life Sciences & Biomedicine - Other Topics / Melatonin / Mice / Missense mutation / Mutant Proteins - genetics / Mutant Proteins - metabolism / Mutation / Mutation, Missense / Neuroscience / Phosphorylation / Protein Conformation / Proteins / Proteolysis / Sleep / Sleep and wakefulness / Sleep Disorders, Circadian Rhythm - genetics / Sleep-wake cycle / Threonine / Threonine - genetics / Ubiquitin / Ubiquitin-protein ligase / Ubiquitination