Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder.
Level 4 - case-series / case-control
Familial genetic linkage and reverse phenotyping case-series combined with mechanistic bench assays
PubMed 28388406 · doi:10.1016/j.cell.2017.03.027
What was done
Identified a dominant coding variant in the core circadian clock gene CRY1 in individuals with familial delayed sleep phase disorder (DSPD). The authors characterized the molecular properties of the mutant protein (binding affinity for Clock and Bmal1, downstream target transcription, and period length of circadian molecular rhythms) and performed reverse phenotyping in unrelated carrier families while assessing the variant's population allele frequency.
What was found
The identified CRY1 variant acts as a gain-of-function transcriptional inhibitor with increased affinity for the activator proteins CLOCK and BMAL1, suppressing key target genes and lengthening the molecular circadian period. The allele showed a population frequency of up to 0.6%, and reverse phenotyping in unrelated families confirmed late and/or fragmented sleep patterns in carriers. Exact counts of families, individuals, and quantitative sleep timing measurements are not reported in the abstract.
Why it matters
This paper identifies a specific molecular mechanism linking a common human circadian disorder to an altered core clock gene, demonstrating that single-gene variants that lengthen the circadian period can drive familial DSPD.
Limits
The abstract reports no exact sample sizes (n is unstated), quantitative sleep metrics, effect sizes, or demographic details. The penetrance and variable expressivity across broader populations cannot be determined from the provided text.
Cited by
- supports Genetic polymorphisms cause certain individuals to be natural night owls with delayed sleep phases.