Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome

Hiroko Nobuta, Maria Roberta Cilio, Olivier Danhaive, Hui Hsin Tsai, Srinivasan Tupal, Sandra M. Chang, Alice Murnen, Faith Kreitzer, Verenice Bravo, Catherine Czeisler, Hamza Numan Gokozan, Patrick Gygli, Sean Bush, Debra E. Weese-Mayer, Bruce Conklin, Siu Pok Yee, Eric J. Huang, Paul A. Gray, David Rowitch*, José Javier Otero

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


Human congenital central hypoventilation syndrome (CCHS), resulting from mutations in transcription factor PHOX2B, manifests with impaired responses to hypoxemia and hypercapnia especially during sleep. To identify brainstem structures developmentally affected in CCHS, we analyzed two postmortem neonatal-lethal cases with confirmed polyalanine repeat expansion (PARM) or Non-PARM (PHOX2B∆8) mutation of PHOX2B. Both human cases showed neuronal losses within the locus coeruleus (LC), which is important for central noradrenergic signaling. Using a conditionally active transgenic mouse model of the PHOX2B∆8 mutation, we found that early embryonic expression (<E10.5) caused failure of LC neuronal specification and perinatal respiratory lethality. In contrast, later onset (E11.5) of PHOX2B∆8 expression was not deleterious to LC development and perinatal respiratory lethality was rescued, despite failure of chemosensor retrotrapezoid nucleus formation. Our findings indicate that early-onset mutant PHOX2B expression inhibits LC neuronal development in CCHS. They further suggest that such mutations result in dysregulation of central noradrenergic signaling, and therefore, potential for early pharmacologic intervention in humans with CCHS.

Original languageEnglish (US)
Pages (from-to)171-183
Number of pages13
JournalActa Neuropathologica
Issue number2
StatePublished - Aug 25 2015


  • Congenital central hypoventilation syndrome
  • Locus coeruleus
  • Noradrenergic system
  • PHOX2B

ASJC Scopus subject areas

  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Pathology and Forensic Medicine


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