Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse).
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.
de Pontual
Loïc
L
Unité de Recherches sur les Handicaps Génétiques de l'Enfant INSERM U-393, and Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France.
Népote
Virginie
V
Attié-Bitach
Tania
T
Al Halabiah
Hassan
H
Trang
Ha
H
Elghouzzi
Vincent
V
Levacher
Béatrice
B
Benihoud
Karim
K
Augé
Joëlle
J
Faure
Christophe
C
Laudier
Béatrice
B
Vekemans
Michel
M
Munnich
Arnold
A
Perricaudet
Michel
M
Guillemot
François
F
Gaultier
Claude
C
Lyonnet
Stanislas
S
Simonneau
Michel
M
Amiel
Jeanne
J
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*
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D014157:Transcription Factors; C065500:ASCL1 protein, human; C499317:Ascl1 protein, mouse