Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.

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.
Nature Genetics (Impact Factor: 35.21). 05/2003; 33(4):459-61. DOI: 10.1038/ng1130
Source: PubMed

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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Certain motor activities - like walking or breathing - present the interesting property of proceeding either automatically or under voluntary control. In the case of breathing, brainstem structures located in the medulla are in charge of the automatic mode, whereas cortico-subcortical brain networks - including various frontal lobe areas - subtend the voluntary mode. We speculated that the involvement of cortical activity during voluntary breathing could impact both on the "resting state" pattern of cortical-subcortical connectivity, and on the recruitment of executive functions mediated by the frontal lobe. In order to test this prediction we explored a patient suffering from central congenital hypoventilation syndrome (CCHS), a very rare developmental condition secondary to brainstem dysfunction. Typically, CCHS patients demonstrate efficient cortically-controlled breathing while awake, but require mechanically-assisted ventilation during sleep to overcome the inability of brainstem structures to mediate automatic breathing. We used simultaneous EEG-fMRI recordings to compare patterns of brain activity between these two types of ventilation during wakefulness. As compared with spontaneous breathing (SB), mechanical ventilation (MV) restored the default mode network (DMN) associated with self-consciousness, mind-wandering, creativity and introspection in healthy subjects. SB on the other hand resulted in a specific increase of functional connectivity between brainstem and frontal lobe. Behaviorally, the patient was more efficient in cognitive tasks requiring executive control during MV than during SB, in agreement with her subjective reports in everyday life. Taken together our results provide insight into the cognitive and neural costs of spontaneous breathing in one CCHS patient, and suggest that MV during waking periods may free up frontal lobe resources, and make them available for cognitive recruitment. More generally, this study reveals how the active maintenance of cortical control over a continuous motor activity impacts on brain functioning and cognition.
    PLoS ONE 01/2014; 9(9):e107850. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Central Congenital Hypoventilation Syndrome is a neuro-respiratory disease characterized by the dysfunction of the CO2/H(+) chemosensitive neurons of the retrotrapezoid nucleus/parafacial respiratory group. A recovery of CO2/H(+) chemosensitivity has been observed in some Central Congenital Hypoventilation Syndrome patients coincidental with contraceptive treatment by a potent progestin, desogestrel (Straus et al., 2010). The mechanisms of this progestin effect remain unknown, although structures of medulla oblongata, midbrain or diencephalon are known to be targets for progesterone. In the present study, on ex vivo preparations of central nervous system of newborn rats, we show that acute exposure to etonogestrel (active metabolite of desogestrel) enhanced the increased respiratory frequency induced by metabolic acidosis via a mechanism involving supramedullary structures located in pontine, mesencephalic or diencephalic regions.
    Neuroscience Letters 03/2014; · 2.03 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The cells that constitute the sympathetic nervous system originate from the neural crest. This review addresses the current understanding of sympathetic ganglion development viewed from molecular and morphological perspectives. Development of the sympathetic nervous system is categorized into three main steps, as follows: (1) differentiation and migration of cells in the neural crest lineage for formation of the primary sympathetic chain, (2) differentiation of sympathetic progenitors, and (3) growth and survival of sympathetic ganglia. The signaling molecules and transcription factors involved in each of these developmental stages are elaborated mostly on the basis of the results of targeted mutation of respective genes. Analyses in mutant mice revealed differences between the superior cervical ganglion (SCG) and the other posterior sympathetic ganglia. This review provides a summary of the similarities and differences in the development of the SCG and other posterior sympathetic ganglia. Relevant to the development of sympathetic ganglia is the demonstration that neuroendocrine cells, such as adrenal chromaffin cells and carotid body glomus cells, share a common origin with the sympathetic ganglia. Neural crest cells at the trunk level give rise to common sympathoadrenal progenitors of sympathetic neurons and chromaffin cells, while progenitors segregated from the SCG give rise to glomus cells. After separation from the sympathetic primordium, the progenitors of both chromaffin cells and glomus cells colonize the anlage of the adrenal gland and carotid body, respectively. This review highlights the biological properties of chromaffin cells and glomus cells, because, although both cell types are derivatives of sympathetic primordium, they are distinct in many respects.
    Cell and Tissue Research 04/2014; · 3.68 Impact Factor


Available from
May 31, 2014