The clock gene. Every cell in the human body keeps time. This intrinsic rhythm is roughly 24 hours long and driven by the molecular circadian clock: a transcriptional feedback loop that helps regulate sleep, metabolism, and hormone release. But what happens when these timekeepers stop working? In a recent study, we explored the role of BMAL1 (ARNTL), a core circadian regulator, in neurodevelopmental disorders. What we found surprised us: disruption of this central clock gene does not just affect sleep; it shapes the course of development itself.
Figure 1. The core circadian oscillator in human cells is driven by a transcription–translation feedback loop. BMAL1 (ARNTL) dimerizes with CLOCK to form a transcriptional activator complex that binds to E-box elements in the promoters of PER and CRY genes. The translated PER and CRY proteins accumulate in the cytoplasm, heterodimerize, and translocate back into the nucleus, where they inhibit the activity of BMAL1 and CLOCK, repressing their own transcription. This cycle takes approximately 24 hours to complete and represents the molecular pacemaker that governs circadian rhythms such as sleep-wake cycles, hormonal secretion, and metabolic regulation. In our study by Cuddapah and collaborators, we identified ten individuals with de novo or rare heterozygous variants in ARNTL. All individuals presented with neurodevelopmental features, including intellectual disability, hypotonia, and epilepsy. (Figure created with Biorender).
A molecular cornerstone. Anybody who ever had jet lag is familiar with our built-in circadian clock. There is a molecular oscillator in our brain that drives our sleep rhythms and many other associated features. BMAL1 (ARNTL) is part of this pacemaker, it forms the backbone of the molecular circadian oscillator, dimerizing with CLOCK to activate the PER and CRY genes, which in turn repress BMAL1 and CLOCK. This transcription–translation feedback loop takes approximately 24 hours and governs the circadian rhythms of sleep, hormone release, and metabolism. In mice, Arntl knockout leads to arrhythmic behavior, reduced lifespan, and metabolic dysfunction. But—unlike in animal models—human loss-of-function variants in ARNTL had never been reported until now.
Beyond sleep. In the study by Cuddapah and collaborators, we identified ten individuals with rare or de novo heterozygous variants in ARNTL, the gene encoding BMAL1. All individuals presented with neurodevelopmental disorders (NDD), most notably involving developmental delay, hypotonia, and epilepsy. Seizures were a prominent feature, occurring in 9 out of 10 individuals, with a range of seizure types including epileptic spasms, focal seizures, and tonic seizures. In several individuals, seizures were resistant to treatment. Interestingly, most individuals in our cohort did not have overt circadian rhythm sleep disorders, at least not as a primary feature. Instead, clinical features were centered around developmental delay and epilepsy. This raises an intriguing question as to whether the role of BMAL1 in brain development is separable from its circadian function.
Constrained and conserved. One of the striking features of ARNTL is its intolerance to variation. The gene is highly constrained, with a pLI of 0.97 and LOEUF of 0.24—metrics typically seen in well-established developmental disorder genes. Many of the variants in our cohort were missense changes in highly conserved domains, and all de novo variants were absent from gnomAD. Taken together, the genetic evidence supports a role for haploinsufficiency or dominant-negative effects in this disorder. Of note, not all genes in the molecular clock are intolerant to loss-of-function. Only the CRY1 gene has comparable constraint measures, and it will be interesting to see whether CRY1 loss-of-function leads to comparable phenotypic features.
What you need to know. In our recent publication by Cuddapah and collaborators, we identify ARNTL, the gene encoding BMAL1, as a novel cause for neurodevelopmental disorders with epilepsy. BMAL1 is a core component of the circadian clock, and, despite its well-known role in circadian regulation, affected individuals primarily presented with developmental delay, hypotonia, and early-onset epilepsy. The function of BMAL1 involves far more than circadian control and raises new questions about how timekeeping genes shape brain development.
