title: Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse).
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.
authors.affiliation: Unité de Recherches sur les Handicaps Génétiques de l'Enfant INSERM U-393, and Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: de Pontual
authors.forename: Virginie
authors.initials: V
authors.lastname: Népote
authors.forename: Tania
authors.initials: T
authors.lastname: Attié-Bitach
authors.forename: Hassan
authors.initials: H
authors.lastname: Al Halabiah
authors.forename: Ha
authors.initials: H
authors.lastname: Trang
authors.forename: Vincent
authors.initials: V
authors.lastname: Elghouzzi
authors.forename: Béatrice
authors.initials: B
authors.lastname: Levacher
authors.forename: Karim
authors.initials: K
authors.lastname: Benihoud
authors.forename: Joëlle
authors.initials: J
authors.lastname: Augé
authors.forename: Christophe
authors.initials: C
authors.lastname: Faure
authors.forename: Béatrice
authors.initials: B
authors.lastname: Laudier
authors.forename: Michel
authors.initials: M
authors.lastname: Vekemans
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Michel
authors.initials: M
authors.lastname: Perricaudet
authors.forename: François
authors.initials: F
authors.lastname: Guillemot
authors.forename: Claude
authors.initials: C
authors.lastname: Gaultier
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Michel
authors.initials: M
authors.lastname: Simonneau
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D014644:Genetic Variation; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D017386:Sequence Homology, Amino Acid; D020182:Sleep Apnea, Central / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D014157:Transcription Factors; C065500:ASCL1 protein, human; C499317:Ascl1 protein, mouse