Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome

Acta Neuropathol. 2015 Aug;130(2):171-83. doi: 10.1007/s00401-015-1441-0. Epub 2015 May 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Animals
  • Disease Models, Animal
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Hypoventilation / congenital*
  • Hypoventilation / genetics
  • Hypoventilation / pathology
  • Hypoventilation / physiopathology
  • Infant, Newborn
  • Infant, Premature
  • Locus Coeruleus / growth & development*
  • Locus Coeruleus / pathology*
  • Locus Coeruleus / physiopathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Neurogenesis / physiology
  • Neurons / pathology
  • Neurons / physiology
  • Respiration
  • Sleep Apnea, Central / genetics
  • Sleep Apnea, Central / pathology*
  • Sleep Apnea, Central / physiopathology*
  • Tissue Culture Techniques
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • Homeodomain Proteins
  • NBPhox protein
  • Transcription Factors

Supplementary concepts

  • Congenital central hypoventilation syndrome