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.
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Notes
Our findings were confirmed by recent publications from Sasaki A et al. Hum Genet 2003; 119:22–25, and Weese-Mayer et al. Am J Hum Genet 2003; 123:267–278.
Abbreviations
- CCHS:
-
congenital central hypoventilation syndrome
- SIDS:
-
sudden infant death syndrome
- ALTE:
-
apparently life-threatening event
- HSCR:
-
Hirschsprung's disease
- RET :
-
rearranged after transfection gene
- GDNF :
-
glial-derived neurotrophic factor gene
- GDNFR :
-
glial-derived neurotrophic factor receptor gene
- MASH1 :
-
mammalian achaete-scute homologous 1 gene
- HASH1 :
-
human achaete-scute homologous 1 gene
- EDN1 :
-
endothelin 1 gene
- EDN3 :
-
endothelin 3 gene
- ECE1 :
-
endothelin-converting enzyme gene
- BDNF :
-
brain-derived neurotrophic factor gene
- PHOX2A :
-
paired-like homeobox 2a gene
- PHOX2B :
-
paired-like homeobox 2b gene
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Acknowledgements
The authors thank Virginie Nepote, Béatrice Levacher, and Fabien Guimiot (INSERM E9935) for genetic analyses in newborn mice and for Figure 1, and Loîc de Pontual, Béatrice Laudier, and Delphine Trochet (INSERM U393) for genetics studies. We also thank the CCHS children, their parents, and the Association Française du Syndrome d'Ondine for their cooperation and active participation.
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Personal studies were funded by the Institut National de la Santé et de la Recherche Médicale (C.G., J.A., S.D., H.T., S.L., J.G., M.S.), the Fondation pour la Recherche Médicale, the Paris VII University (J.A., S.L.), and the Legs Poix (C.G., J.G., M.S.).
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Gaultier, C., Amiel, J., Dauger, S. et al. Genetics and Early Disturbances of Breathing Control: The Genetics of Childhood Disease and Development: A Series of Review Articles. Pediatr Res 55, 729–733 (2004). https://doi.org/10.1203/01.PDR.0000115677.78759.C5
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DOI: https://doi.org/10.1203/01.PDR.0000115677.78759.C5
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