Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse) - Archive ouverte HAL Access content directly
Journal Articles Human Molecular Genetics Year : 2003

Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse)

Virginie Népote
  • Function : Author
Hassan Al Halabiah
  • Function : Author
Vincent Elghouzzi
Karim Benihoud
Joëlle Augé
  • Function : Author
Christophe Faure
  • Function : Author
Claude Gaultier
  • Function : Author
Jeanne Amiel
  • Function : Author
  • PersonId : 853872

Abstract

Congenital central hypoventilation syndrome (CCHS, Ondine's curse) is a rare disorder of the chemical control of breathing. It is frequently associated with a broad spectrum of dysautonomic symptoms, suggesting the involvement of genes widely expressed in the autonomic nervous system. In particular, the HASH-1-PHOX2A-PHOX2B developmental cascade was proposed as a candidate pathway because it controls the development of neurons with a definitive or transient noradrenergic phenotype, upstream from the RET receptor tyrosine kinase and tyrosine hydroxylase. We recently showed that PHOX2B is the major CCHS locus, whose mutation accounts for 60% of cases. We also studied the proneural HASH-1 gene and identified a heterozygous nucleotide substitution in three CCHS patients. To analyze the functional consequences of HASH-1 mutations, we developed an in vitro model of noradrenergic differentiation in neuronal progenitors derived from the mouse vagal neural crest, reproducing in vitro the HASH-PHOX-RET pathway. All HASH-1 mutant alleles impaired noradrenergic neuronal development, when overexpressed from adenoviral constructs. Thus, HASH-1 mutations may contribute to the CCHS phenotype in rare cases, consistent with the view that the abnormal chemical control of breathing observed in CCHS patients is due to the impairment of noradrenergic neurons during early steps of brainstem development.

Dates and versions

hal-02342800 , version 1 (01-11-2019)

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Loïc de Pontual, Virginie Népote, Tania Attié-Bitach, Hassan Al Halabiah, Ha Trang, et al.. Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse). Human Molecular Genetics, 2003, 12 (23), pp.3173-3180. ⟨10.1093/hmg/ddg339⟩. ⟨hal-02342800⟩
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