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⇱ Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome | Nature Genetics

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Abstract

Congenital central hypoventilation syndrome (CCHS or Ondine's curse; OMIM 209880) is a life-threatening disorder involving an impaired ventilatory response to hypercarbia and hypoxemia. This core phenotype is associated with lower-penetrance anomalies of the autonomic nervous system (ANS) including Hirschsprung disease and tumors of neural-crest derivatives such as ganglioneuromas and neuroblastomas. In mice, the development of ANS reflex circuits is dependent on the paired-like homeobox gene Phox2b. Thus, we regarded its human ortholog, PHOX2B, as a candidate gene in CCHS. We found heterozygous de novo mutations in PHOX2B in 18 of 29 individuals with CCHS. Most mutations consisted of 5–9 alanine expansions within a 20-residue polyalanine tract probably resulting from non-homologous recombination. We show that PHOX2B is expressed in both the central and the peripheral ANS during human embryonic development. Our data support an essential role of PHOX2B in the normal patterning of the autonomous ventilation system and, more generally, of the ANS in humans.

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Figure 1: Mutations of PHOX2B in CCHS.
Figure 2: PHOX2B gene expression in developing human brainstem and enteric nervous system.

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Acknowledgements

We thank the individuals with CCHS, their families and the Association Française du Syndrome d'Ondine who participated in this study, J.-F. Brunet and C. Goridis for helpful comments and discussions and G. Mattéi for technical help. This study was supported by grants from the European Community, Association Française contre les Myopathies-INSERM (Maladies Rares) and Hoechst-Marion-Roussel. B.L. is a recipient of a Sanofi-Synthelabo grant.

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Authors and Affiliations

  1. et Département de Génétique, Unité de Recherches sur les Handicaps Génétiques de l'Enfant INSERM U-393, Hôpital Necker-Enfants Malades, 149, rue de Sèvres, Paris, 75743, Cedex 15, France

    Jeanne Amiel, Béatrice Laudier, Tania Attié-Bitach, Loïc de Pontual, Delphine Trochet, Heather Etchevers, Pierre Ray, Michel Vekemans, Arnold Munnich & Stanislas Lyonnet

  2. Service de Physiologie CIC INSERM 9202, et Equipe INSERM E9935, Hôpital Robert Debré, Paris, France

    Ha Trang, Michel Simonneau & Claude Gaultier

  3. Clinica Materno-Infantil, Hospital de Cruces, Barakaldo, 48903, Spain

    Blanca Gener

Authors
  1. Jeanne Amiel
  2. Béatrice Laudier
  3. Tania Attié-Bitach
  4. Ha Trang
  5. Loïc de Pontual
  6. Blanca Gener
  7. Delphine Trochet
  8. Heather Etchevers
  9. Pierre Ray
  10. Michel Simonneau
  11. Michel Vekemans
  12. Arnold Munnich
  13. Claude Gaultier
  14. Stanislas Lyonnet

Corresponding author

Correspondence to Jeanne Amiel.

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Competing interests

The authors declare no competing financial interests.

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Amiel, J., Laudier, B., Attié-Bitach, T. et al. Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet 33, 459–461 (2003). https://doi.org/10.1038/ng1130

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  • DOI: https://doi.org/10.1038/ng1130

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