title: Genetics and early disturbances of breathing control.
abstract: Early disturbances in breathing control, including apneas of prematurity and apparently life-threatening events, account for some cases of sudden infant death syndrome and for a rare disorder called congenital central hypoventilation syndrome (CCHS). Data suggesting a genetic basis for CCHS have been obtained. Recently, we found heterozygous de novo mutations of the PHOX2B gene in 18 of 29 individuals with CCHS. Most mutations consisted of five to nine alanine expansions within a 20-residue polyalanine tract, probably resulting from nonhomologous recombination. Other mutations, generally inherited from one of the parents, in the coding regions of genes involved in the endothelin and RET signaling pathways and in the brain-derived-neurotrophic factor (BDNF) gene have been found in a few CCHS patients. Interestingly, all these genes are involved in the development of neural crest cells. Targeted disruption of these genes in mice has provided information on the pathophysiological mechanisms underlying CCHS. Despite the identification of these genes involved in breathing control, none of the genetically engineered mice developed to date replicate the full human CCHS respiratory phenotype. Recent insights into the genetic basis for CCHS may shed light on the genetics of other early disturbances in breathing control, such as apnea of prematurity and sudden infant death syndrome.
authors.affiliation: INSERM E9935, Réanimation Médicale Pédiatrique, Hôpital Robert Debré, 75019 Paris, France. claude.gaultier@rdb.ap-hop-paris.fr
authors.forename: Claude
authors.initials: C
authors.lastname: Gaultier
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.forename: Stéphane
authors.initials: S
authors.lastname: Dauger
authors.forename: Ha
authors.initials: H
authors.lastname: Trang
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Jorge
authors.initials: J
authors.lastname: Gallego
authors.forename: Michel
authors.initials: M
authors.lastname: Simonneau
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype; D012119:Respiration / Q000235:genetics*; D012120:Respiration Disorders / Q000151:congenital / Q000235:genetics*; D012891:Sleep Apnea Syndromes / Q000235:genetics; D020182:Sleep Apnea, Central / Q000235:genetics*; D013398:Sudden Infant Death / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; C109220:NBPhox protein; D014157:Transcription Factors