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

Hôpital Universitaire Robert Debré, Lutetia Parisorum, Île-de-France, France
Human Molecular Genetics (Impact Factor: 6.68). 01/2004; 12(23):3173-80. DOI: 10.1093/hmg/ddg339
Source: PubMed

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.

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    • "To this end we investigated mutations affecting afferent neurons in the distal sensory ganglia of the ninth and tenth cranial nerves (petrosal and nodose ganglia respectively) and particularly the subpopulation of chemoafferent cells expressing Tyrosine Hydroxylase (TH) in the petrosal ganglia. It appears that developmental genes such as Phox2 paralogs may be responsible for reflex arches set up and for unconscious breathing control (Amiel et al. 2003; de Pontual et al. 2003). Phox2 is a family of homeodomain transcription factors that includes two paralogs, Phox2a and Phox2b, which are considered to be master regulators of neuronal phenotype and survival in specific subsets of central and peripheral neurons (Pattyn et al, 1997). "
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    ABSTRACT: Summary Central, congenital, idiopathic hypoventilation syndrome known asOndines Curse¨, is a non frequent disease characterized by an abnormal ventilation control in the absence of pulmonary, neuromuscular, neurological or cardiac disease. Multiple genes are associated with this disease as well as to other related phenotypes such as Hirschsprung disease. A case showing its treatment difficulties is presented. Genetic aspects, etiology and differential diagnosis are exposed.
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