title: Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.
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.
authors.affiliation: Unité de Recherches sur les Handicaps Génétiques de l'Enfant INSERM U-393, et Département de Génétique, Hôpital Necker-Enfants Malades, 149, rue de Sèvres, 75743 Paris Cedex 15, France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.forename: Béatrice
authors.initials: B
authors.lastname: Laudier
authors.forename: Tania
authors.initials: T
authors.lastname: Attié-Bitach
authors.forename: Ha
authors.initials: H
authors.lastname: Trang
authors.forename: Loïc
authors.initials: L
authors.lastname: de Pontual
authors.forename: Blanca
authors.initials: B
authors.lastname: Gener
authors.forename: Delphine
authors.initials: D
authors.lastname: Trochet
authors.forename: Heather
authors.initials: H
authors.lastname: Etchevers
authors.forename: Pierre
authors.initials: P
authors.lastname: Ray
authors.forename: Michel
authors.initials: M
authors.lastname: Simonneau
authors.forename: Michel
authors.initials: M
authors.lastname: Vekemans
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Claude
authors.initials: C
authors.lastname: Gaultier
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
mesh_terms: D000409:Alanine / Q000235:genetics; D001933:Brain Stem / Q000378:metabolism; D016368:Frameshift Mutation; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009420:Nervous System / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010455:Peptides; D010641:Phenotype; D011995:Recombination, Genetic; D020182:Sleep Apnea, Central / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C109220:NBPhox protein; D010455:Peptides; D014157:Transcription Factors; C019529:polyalanine; D000409:Alanine