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Published on: November 19, 2015
Genetics and early disturbances of breathing control
Claude Gaultier1, Jeanne Amiel, Stéphane Dauger
1INSERM E9935, Réanimation Médicale Pédiatrique, Hôpital Robert Debré, 75019 Paris, France. claude.gaultier@rdb.ap-hop-paris.fr
Insights
Genetic mutations in the PHOX2B gene are linked to congenital central hypoventilation syndrome (CCHS) in infants. Further research into these genetic factors may illuminate other infant breathing control disorders.
Area of Science:
- Genetics
- Developmental Biology
- Respiratory Medicine
Background:
- Early infant breathing control disturbances, including apneas and life-threatening events, are linked to SIDS and CCHS.
- Congenital central hypoventilation syndrome (CCHS) has a suspected genetic basis.
- Neural crest cell development pathways are implicated in CCHS.
Purpose of the Study:
- To investigate the genetic underpinnings of congenital central hypoventilation syndrome (CCHS).
- To identify specific genes and mutation types associated with CCHS.
- To explore the role of identified genes in infant respiratory control.
Main Methods:
- Genetic analysis of individuals diagnosed with CCHS.
- Identification of mutations in the PHOX2B gene, including polyalanine expansions.
- Examination of mutations in genes within the endothelin and RET signaling pathways, and the BDNF gene.
- Comparative analysis using genetically engineered mouse models.
Main Results:
- Heterozygous de novo mutations in the PHOX2B gene were identified in a majority of CCHS patients studied.
- The most common PHOX2B mutations involved expansions in a polyalanine tract.
- Mutations in other genes crucial for neural crest development were found in a subset of CCHS patients.
- Mouse models, while informative, did not fully replicate the human CCHS respiratory phenotype.
Conclusions:
- PHOX2B gene mutations are a significant genetic cause of CCHS.
- Genetic factors influencing neural crest development play a critical role in infant respiratory control.
- Further research into CCHS genetics may provide insights into apnea of prematurity and SIDS.
- Current animal models do not fully recapitulate the human CCHS phenotype, highlighting the complexity of the disorder.
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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