Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

Analysis of genes within the schizophrenia-linked 22q11.2 deletion identifies interaction of night owl/LZTR1 and NF1 in GABAergic sleep control

Research output: Contribution to journalJournal articleResearchpeer-review

  1. Genome-wide association study identifies 16 genomic regions associated with circulating cytokines at birth

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Pharmacogenetic genotype and phenotype frequencies in a large Danish population-based case-cohort sample

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Gestational age-dependent development of the neonatal metabolome

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Co-occurring hydrocephalus in autism spectrum disorder: a Danish population-based cohort study

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. Author Correction: Population genomics of the Viking world

    Research output: Contribution to journalComment/debateResearchpeer-review

  • Gianna W Maurer
  • Alina Malita
  • Stanislav Nagy
  • Takashi Koyama
  • Thomas M Werge
  • Kenneth A Halberg
  • Michael J Texada
  • Kim Rewitz
View graph of relations

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.

Original languageEnglish
Article numbere1008727
JournalPlos Genetics
Volume16
Issue number4
Pages (from-to)e1008727
ISSN1553-7404
DOIs
Publication statusPublished - 27 Apr 2020

    Research areas

  • 22q11 Deletion Syndrome/genetics, Adaptor Proteins, Signal Transducing/genetics, Animals, Drosophila, Drosophila Proteins/genetics, GABAergic Neurons/metabolism, Humans, Neurofibromin 1/genetics, Receptors, GABA-A/metabolism, Schizophrenia/genetics, Sleep/genetics, Transcription Factors/genetics

ID: 61432682