Abstract
The human 22q11.2 chromosomal deletion is one of the strongest identified genetic risk factors for schizophrenia. Although the deletion spans a number of known genes, the contribution of each of these to the 22q11.2 deletion syndrome (DS) is not known. To investigate the effect of individual genes within this interval on the pathophysiology associated with the deletion, we analyzed their role in sleep, a behavior affected in virtually all psychiatric disorders, including the 22q11.2 DS. We identified the gene LZTR1 (night owl, nowl) as a regulator of night-time sleep in Drosophila. In humans, LZTR1 has been associated with Ras-dependent neurological diseases also caused by Neurofibromin-1 (Nf1) deficiency. We show that Nf1 loss leads to a night-time sleep phenotype nearly identical to that of nowl loss and that nowl negatively regulates Ras and interacts with Nf1 in sleep regulation. Furthermore, nowl is required for metabolic homeostasis, suggesting that LZTR1 may contribute to the genetic susceptibility to obesity associated with the 22q11.2 DS. Knockdown of nowl or Nf1 in GABA-responsive sleep-promoting neurons elicits the sleep phenotype, and this defect can be rescued by increased GABAA receptor signaling, indicating that Nowl regulates sleep through modulation of GABA signaling. Our results suggest that nowl/LZTR1 may be a conserved regulator of GABA signaling important for normal sleep that contributes to the 22q11.2 DS.
Highlights
Recent genome-wide association studies have identified chromosomal deletions and duplications that confer elevated risk of neuropsychiatric disorders [1, 2]
One of the strongest genetic risk factors for this disorder is a relatively small genetic deletion of 43 genes on the 22nd chromosome, called 22q11.2, which confers about a 25% risk of schizophrenia development
We suggest that LZTR1 is a promising candidate gene that may contribute to the sleep disturbances and behavioral symptoms seen in patients carrying the 22q11.2 deletion
Summary
Recent genome-wide association studies have identified chromosomal deletions and duplications that confer elevated risk of neuropsychiatric disorders [1, 2]. The 22q11.2 deletion, which spans 43 genes and occurs in 1 of every 2–4,000 births worldwide [3], is the most prominent known genetic risk factor for development of schizophrenia and is associated with high risk of neuropsychiatric disease [4, 5]. This deletion leads to a variety of phenotypes, including clinical manifestations such as congenital defects of the palate and heart, learning and cognitive disabilities, and sleep disturbances [6]. Certain disease phenotypes have been linked to single genes, such as TBX1, found to account for cardiac defects observed in 22q11.2 deletion carriers [12], the genes contributing to the 22q11.2-linked behavioral phenotypes such as sleep disturbance are not characterized
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