Genetic Basis for Respiratory Control Disorders

The description of the genome in mice and subsequently in humans opened up the field of research into the genetic basis for respiratory control disorders.
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It outlines some of the emerging roles of epigenetic modifications and aims to give a vision of where the field is moving, concluding with current and future prospects for genetically targeted therapies. Mammalian genomes are composed of deoxyribonucleic acid DNA and can be subdivided into a nuclear genome — DNA within the nucleus of each cell — and a separate circular genome housed within each mitochondrion. DNA needs to be replicated each time a cell divides. This strict base pairing ensures accurate copying of the DNA code. This div only appears when the trigger link is hovered over.

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Search within a content type, and even narrow to one or more resources. You can also find results for a single author or contributor. The Genetic Basis of Respiratory Disorders. Accessed September 18, View Table Favorite Table Download. Genes are typically subdivided into exons blocks of protein-coding DNA , introns intervening noncoding DNA , and flanking regulatory regions Exome The entire sequence of all exons within the genome Somatic Relating to any cell of the body other than the germ cells.

Mutations in somatic cells cannot be passed on to the next generation Chromosome A higher order structure into which DNA is packaged. Humans have 23 pairs of chromosomes, 22 autosomes, and a pair of sex chromosome, X and Y, that determine gender Telomere The cap at the ends of each chromosome, composed of hundreds of copies of the repeat sequence TTAGGG Diploid Containing a full complement of 23 chromosome pairs.

All normal somatic cells Username or Email Please enter User Name. Tibetans seem possessed of superior altitude adaptation and have higher hypoxic ventilatory response than Han Chinese and Andean Aymara [5; 56; 57]. Further, individuals of mixed Han-Tibetan ancestry have hypoxic ventilatory response greater than those of pure Han lineage pointing to a dominant effect of Tibetan ancestry [15].

The increased hypoxic ventilatory response of Tibetans reflects in part a resistance to the blunting effect of long-term hypoxic exposure on hypoxic ventilatory response, mentioned earlier, which is a common feature of other populations [37]. These population differences have commonly been considered to suggest genetic effects on ventilatory control, but a recent analysis suggested that they may be unrelated to genetic distance and may instead reflect differential adaptation to hypoxia [50]. Decreased responses are found in species with excellent adaptation to high altitude. Bar-headed geese, which fly at exceptionally high altitude, have lower hypoxic ventilatory responses than the low altitude pekin duck [8].

This was seen in birds raised at low altitude and thus the lower response in the geese could not be ascribed to chronic hypoxic exposure. Variation has also been evident among strains in rats see Chapter 9 and mice see Chapter Interindividual variation in ventilatory response to isocapnic hypoxia among cats. Hypoxic responses are expressed as the shape parameter A, an index of steepness of the hyperbolic response of ventilation to decrease in oxygen tension. Responses were assessed during wakefulness with plethysmographic techniques and were found to be reproducible on repeat testing on several days indicating stable differences among cats.

A study of hypoxic ventilatory response in awake cats showed a large range of responses similar to that seen in humans Fig. Repeat measurements on separate days were similar for individual cats indicating stable interindividual differences. Hereditary aspects of respiratory control in health and disease in humans 13 ents and siblings who were in good health, found a family cluster of low hypoxic, but normal hypercapnic responses Fig. Similar findings were seen in studies of a second case of unexplained hypoventilation in which first degree relatives had low hypoxic ventilatory responses with no depression of the hypercapnic ventilatory response [36].

Data from [21], reproduced with permission from [56]. As mentioned earlier, low values of hypoxic ventilatory response are found in endurance athletes. The findings suggest that decreased hypoxic ventilatory response may be a pre-existent attribute of individuals capable of endurance exercise. Reasons for such linkage are unclear. It might be that this reflects a general cellular ability to maintain normal metabolic function with less metabolic error signal at lower oxygen tensions manifested as lesser ventilatory stimulation and better skeletal muscle function at lower oxygen tensions in blood and skeletal muscle.

Differences in hypoxic ventilatory response have also been found among families of patients with chronic obstructive pulmonary disease COPD. Observations were stimulated by the variation in chronic stable ventilatory status among patients with COPD. It has long been apparent that such patients span a ventilatory spectrum ranging from individuals who chronically maintain nearly normal ventilation pink puffers or fighters to those with chronic hypoventilation blue bloaters or non-fighters [41; 42].

Early studies had shown that PaCO2 in stable COPD patients was not clearly explained by the severity of airway obstruction, but was associated with decreased ventilatory effort response to hypercapnia measured as respiratory work or occlusion pressure [28; 35]. Hypoxic ventilatory responses measured as occlusion pressure were found to be lower in COPD patients with hypoxemia than in those who remained well oxygenated with similar degree of airways obstruction [9].

Depressed values for hypoxic ventilatory response in endurance runners and their healthy, non-athletic parents and siblings. Reproduced with permission from [46]. The possibility that familial factors might contribute to differences in stable ventilation in patients with COPD was explored in studies of families of hypercapnic and normocapnic patients. Healthy offspring of patients with chronic hypoventilation showed lower hypoxic ventilatory response than those of patients with similar airway obstruction who maintained normal ventilation Fig.

Further, the extent of hypoventilation measured as PaCO2 during acute exacerbations of airways obstruction in COPD patients was inversely related to the strength of the hypoxic response of their offspring Fig. In these studies the linkage of ventilatory responses of offspring to the ventilatory status of the patients was mainly, or exclusively, to the hypoxic response with little or no relationship evident for the response to hypercapnia. Overall, these findings pointed to familial determinants of the hypoxic ventilatory response and of ventilation in the face of chronic airway obstruction.

Familial clustering of decreased hypoxic ventilatory responses has also been found in relation to patients with sleep apnea see Chapter 8 , but not with patients with the obesity hypoventilation syndrome [22]. When combined, hypoxic responses in first degree relatives of endurance athletes and patients with hypoventilation show a distribution is strongly shifted to lower end of the broad spectrum seen in the general population Fig. These familial effects on the hypoxic response seemed to be quite strong given that they were evident with small groups of subjects.

Familial influence on ventilation in COPD. Ventilation in the COPD patients is correlated with the hypoxic response of their healthy offspring. Hypoxic responses are plotted as the shape parameter A, an index of steepness of the hyperbolic response normalized for body surface area BSA. Drawn from [24] and reproduced with permission from [56]. Familial influence on ventilation in patients with COPD. Alveolar ventilation measured as PaCO2 in patients during acute exacerbation of COPD is correlated with hypoxic ventilatory response of their offspring.

Ventilatory responses were measured as the slope of the linear response of increasing ventilation VE to decreasing arterial oxygen saturation SaO2 normalised for vital capacity VC. Drawn from data of [16] and reproduced from [56]. To explore this issue studies were undertaken to compare responses among monozygotic and dizygotic twins. The approach was to compare similarity of responses between the two members of a twin pair within-pair variance for the two classes of twins.

The extent to which there is greater similarity of responses within pairs of monozygotic identical twins, measured as within-pair variance, compared to that of dizygotic fraternal twins is taken as an indicator of genetic contribution. Studies by the Denver, Hokkaido and Edinburgh groups found greater concordance within adult monozygotic than in dyzgotic twins suggesting a genetic contribution to the hypoxic response [14; 24; 29] Fig. Similar concordance was found in infant monozygotic twins [51]. Findings for the hypercapnic response among twins varied. No genetic effect was evident in work by the Denver investigators [14] and by Arkinstall [3], while two studies by the Hokaido group indicated a genetic contribution [24; 25].

In studies of families and of twins, coherence of hypoxic ventilatory responses were evident with very small group sizes subjects suggesting a strong heritable effect.

Studies in humans and animals indicate a dominant influence on responses to hypoxia rather than to hypercapnia suggesting an effect on peripheral chemosensitivity. The lack of clear effect on the hypercapnic response limits the likelihood that respiratory mechanics account for the findings. The role of an effect on peripheral chemosensitivity is further supported by a study in adult female twins, which showed a genetic influence on a rapid test, consisting of the administration of two breaths of oxygen during steady state hypoxia, pointing to an effect on fast-responding peripheral chemosensitivity [2].

Similar findings were evident in infant twins, in whom a single breath oxygen test showed greater concordance among monozygotic twins [51]. These effects could reflect influences either the peripheral chemoreceptor carotid body per se or on the central translation of chemoreceptor input into ven- 2. Hereditary aspects of respiratory control in health and disease in humans 17 tilatory output. This was explored in cats, which as mentioned show a broad range of interindividual differences in hypoxic response.

Simultaneous measurement of carotid sinus nerve and ventilatory responses to hypoxia showed that the responses were correlated, suggesting that differences in carotid body hypoxic sensitivity were contributors to variation of the hypoxic ventilatory response Fig. Hypoxic ventilatory responses HVR , plotted as the shape parameter A, measured within pairs of monozygotic left panel and dizygotic right panel twins. The data are plotted in relation to the line of identity solid line. The findings show greater similarity of hypoxic ventilatory response within pairs of monozygotic than is dizygotic twins suggesting a genetic influence on the response.

Further, the ratio of ventilatory to carotid sinus nerve response was unchanged over the broad range of hypoxic ventilatory responses indicating that differences in central nervous system translation of peripheral chemoreceptor activity to ventilation were unlikely factors. Thus it appears that among cats the variation in hypoxic ventilatory response is most likely a reflection of variable peripheral chemosensitivity. To explore the potential heritability of this effect, we began a breeding colony to study the offspring of high and low responder cats.

Unfortunately the effort was aborted by high costs, but studies were completed in 12 offspring of low responders. It was found that both the ventilatory and carotid sinus nerve responses of the offspring tended to cluster at the low end of the range of hypoxic responses with values similar to those of their parents J. Weil, unpublished data , Fig. Ventilatory and carotid sinus nerve responses to hypoxia in cats filled circles.

The wide distribution of ventilatory response shows correlation with carotid sinus nerve responses suggesting a role of varied hypoxic sensitivity of the carotid body in the variation in ventilatory response. From [52] and unpublished data. These effects on the response of the carotid body could reflect variation in intrinsic chemosensitivity or the influence of neural or humoral modulation. This was addressed in a comparison of strains of rats which found that carotid sinus nerve responses to hypoxia were greater in the spontaneously hypertensive SHR than in the Fischer F strain Fig.

Hypoxic responses measured in isolated carotid bodies by fluorometric measures of carotid body cytosolic free calcium in response to hypoxic superfusion showed greater response in the SHR strain Fig. The findings suggest the existence of inter-strain differences in intrinsic hypoxic chemosensitivity. Thus, collectively the findings are consistent with a possible role of genetically directed effects on intrinsic chemosensitivity in variation of hypoxic ventilatory response.

However, the extent to which these findings in animals apply to human variation in hypoxic ventilatory response remains uncertain. There is little information concerning the question of which specific genes might be involved in variation of hypoxic ventilatory response. Studies in rats suggest possible roles for genes on chromosomes 9 and 18 in differences among Dahl Salt Sensitive and Brown Norway strains [17] and in mice a role for genes on chromosome 9 possibly reflecting effects on dopamine D2 receptor or acetylcholine nicotinic receptor expression have been suggested [49].

Hereditary aspects of respiratory control in health and disease in humans 19 A B Fig. Familial influences are evident in the similarity of ventilatory responses among first degree relatives and a genetic effect is indicated by concordance within identical twins. These factors have their predominant effects on the ventilatory response to hypoxia rather than to the response to hypercapnia. This suggests that heritable influences may act on peripheral chemosensitivity. Studies of interindividual variation in hypoxic ventilatory responses in animals show correlation with carotid body responses, which appear to reflect intrinsic differences in hypoxic sensitivity.

Finally, variation in the hypoxic ventilatory response seems related to ventilatory adaptation and function in exposure to high altitude, in endurance athletics and in chronic obstructive pulmonary disease. J Physiol Pharmacol 57 Suppl 4: J Assoc Physicians India Am Rev Respir Dis High Alt Med Biol 5: J Clin Invest Hereditary aspects of respiratory control in health and disease in humans Respir Physiol Neurobiol Eur Respir J 8: Ann Intern Med Eur J Respir Dis Ann Hum Biol 3: Med Sci Sports Exerc Clin Sci Mol Med N Engl J Med The role of familial factors.

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Control of ventilation in chronic obstructive pulmonary disease. Arch Environ Hlth 7: Brit Med J 2: Am J Physiol L Weil JV Variation in human ventilatory control-genetic influence on the hypoxic ventilatory response. Wilderness Environ Med This extremely combinatorial system entails that the expression pattern of any individual transcription factor in the forming brain has little predictive value for the final wiring and function of its constituent neurons. One transcription factor, however, enigmatically stands out: We will describe the system-wide implication of Phox2b in the ontogeny of the visceral nervous system and discuss its embryological, physiopathological and evolutionary ramifications.

Brunet, unpublished data are congruent. Structures expressing Phox2 genes List of structures expressing Phox2 genes. Structures depending only on Phox2b are in plain text. Structures depending only on Phox2a are in italics; Structures depending on both genes are in bold. Structures for which no data is available yet are in small font. The spinal interneurons expressing Phox2a but not Phox2b have been omitted for clarity. In every neural structure examined to date, expression starts very early: This seemingly random set of neurons, on closer inspection, turns out to match with uncanny accuracy the anatomical concept proposed by Blessing [9]: On the afferent path of visceral reflexes, Phox2b is expressed in primary visceral sensory neurons, forming the three distal ganglia of cranial nerves VII, IX and X, the geniculate, petrosal and nodose ganglia, as well as in the carotid body, a chemosensory organ presynaptic to the petrosal ganglion.

It is also expressed in their central targets, the second-order visceral sensory neurons of the hindbrain forming the nucleus of the solitary tract nTS and their associated chemosensory center, the area postrema AP. Sympathetic premotor neurons, or at least the majority of them the C1 adrenergic center [70] express Phox2b. Phox2b is also expressed in the branchiomotor BM neurons located in cranial motor nuclei V trigeminal , 3. Phox2b and the homeostatic brain 27 VII facial , IX nucleus ambiguus nA pars compacta and XI spinal accessory nucleus , which innervate the muscles that motorize the face and neck.

However, a global zoological perspective reveals the bias in this exclusion: Moreover, their targets branchial archderived muscles are ontogenetically quite distinct from the somite-derived muscles innervated by somatic motoneurons [52]. Two examples of visceral reflex circuits made entirely of Phox2b-positive neurons. Left Pathway that slows down the heart in response to hyperoxia. Right Digestive reflexes utilizing either intrinsic enteric neurons or passing through the CNS via the vagus nerve. Note that some sensori-motor vago-vagal synapses bypass the nucleus of the solitary tract. Examples of such pathways are represented in Fig.

This represents, by far, the most extensive correlation between the expression of a transcription factor and a neuronal circuit, or set thereof. Two other examples, however limited to two or three relays on an afferent pathway, deserve mention: From a developmental viewpoint, it is striking that Phox2b-positive neurons share little besides their visceral function. They share neither position nor lineage: Phox2b-expressing neurons arise from the neural crest, epibranchial placodes or the neural tube and, in the latter, both from the ventral e.

VM neurons and dorsal aspects e. The only anatomical demarcation is that, within the CNS, Phox2b-positive cells are confined to the hindbrain and mid-hindbrain boundary. Phox2b-expressing neurons do not share conspicuous phenotypic traits either: VM neurons , noradrenergic e.

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For the sake of exhaustiveness, one should finally list the few mismatches between the expression pattern of Phox2b and the visceral nervous system. The most conspicuous one, already mentioned, consists in preganglionic sympathetic neurons of the spinal cord, which do not express Phox2b and, based on their transcriptional code and differentiation pathway, look very much like spinal somatic motoneurons [76].

Finally, the ventro-lateral medulla VLM contains a large class of Phox2b-positive interneurons whose status remains to be assessed. The homeodomains of Phox2a and Phox2b are identical in human, rat and mouse and diverge at one residue in chicken, xenopus, and zebrafish. Their Nterminal sequences have extensive similarity, while their C-terminus is very divergent. As its name betrays, Phox2a was characterized before Phox2b, and it was in fact the expression pattern of the former, very similar to the latter, that drew attention to the correlation of Phox2 genes with the visceral reflex circuits [77].

However, a closer look at the dynamic of expression of both genes soon revealed a sharp divide between the temporal sequences of Phox2a and Phox2b expression [58]. At every site where the matter was examined, one of the two genes is expressed first and the other one slightly later and under the control of the first , 3.

Genetic Basis for Respiratory Control Disorders

Phox2b and the homeostatic brain 29 leading to pervasive co-expression, at least transiently. This is evidence that the promoters of Phox2a and Phox2b have radically diverged after the duplication of the ancestral Phox2 gene, in line with the lack of extensive sequence homologies in the promoter regions. The dividing line between the respective patterns of expression has a striking topographic neatness: Rostral to this line, Phox2a precedes Phox2b in every Phox2-positive neuronal group examined, while caudal to it, Phox2b precedes Phox2a.

Finally, Phox2a is expressed alone in a few interneurons in the spinal cord [77]. Topographical relationship of Phox2-dependent structures. A representative sample of Phox2-dependent ganglia and nuclei are schematized on a parasagittal section of a P0 mouse pup. The structures contained in the large triangle depend on both Phox2a and Phox2b, those below, only on Phox2b. The most rostral ones, enclosed in the small triangle, depend on Phox2a only.


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In the PNS, sympathetic, parasympathetic, enteric neurons [59] as well as adrenal medullary and carotid body cells [40; 59] are absent and the geniculate, petrosal and nodose ganglia are massively atrophic [18; 59]. The fate of the unidentified interneurons in the VLM has not been examined. Differentiation of Phox2b-dependent neurons is stalled very early in all cases examined, followed by cell death or fate switches. For example, enteric neuronal precursors invade the esophagus, but fail to express Ret, never migrate past the rostral stomach, and then degenerate [59].

Sympathetic precursors aggregate close to the dorsal aorta but never differentiate and soon disappear by apoptosis [59] and see below. Thus, in most cases, the loss of Phox2b expression disrupts every aspect of subsequent neuronal differentiation. Phox2a knock-outs Phox2a knock-outs die soon after birth, with an empty stomach and a collapsed esophagus evocative of an impaired swallowing reflex [48]. Histological examination at birth reveals that all Phox2-positive neural structures located in the head e. It is notable that in all these structures Phox2a lies upstream of Phox2b, raising the possibility that Phox2a merely serves as a surrogate promoter for Phox2b, which would control differentiation.

This hypothesis is supported by reciprocal knock-ins [16] and see below. In remarkable contrast with the mouse 3. Phox2b and the homeostatic brain 31 mutation, the condition is viable, perhaps reflecting a lesser role for human PHOX2A than murine Phox2a in cranial ganglion formation. Concerning the neural control of breathing, assessment of the role of Phox2b has been hampered by the intrinsic complexity of this function in terrestrial vertebrates, a somewhat patchier knowledge of the anatomy and the embryonic death of Phox2b null mutants, which precludes a physiological analysis.

At the advent of terrestrial life, the muscle control of breathing has been for the most part discharged on skeletal muscles, innervated by spinal somatic motoneurons which do not express Phox2b. As argued by Blessing [10], this is paralleled by the evolution of breathing, from a purely homeostatic function to a partially voluntary and relational one including vocalization, sniffing, etc. However, as discussed earlier, the ancestral, i. On the afferent side of respiratory reflexes, Phox2b is required in such paramount providers of sensory feedback as the nodose ganglion which contains the cell bodies of pulmonary stretch receptors , the carotid body which contains oxygen and carbon dioxide sensors , the petrosal ganglion which innervates the carotid body and the nTS which integrates chemosensory and barosensory information.

Phox2b is also required for the generation of all noradrenergic centers, among which A5 and the LC function as modulators of the respiratory rhythm reviewed in [31]. Incidentally, the disappearance of the LC, but not of A5 which have opposite effects on respiratory rhythm [31] has been incriminated in the slowed-down breathing of perinatal Phox2a null fetuses [85]. Recently, human genetics has unveiled a new dimension of the involvement of Phox2b in the neurophysiology of breathing: CCHS comprises a whole list of partially penetrant symptoms that read staightforwardly like a list of Phox2b expression sites: However, the defining, fully penetrant symptom of CCHS consists in respiratory arrests typically occurring during sleep, which have been attributed to a reduced, in the worst cases abolished sensitivity to CO2.

This implies that the CO2 response passes through an obligatory Phox2b-positive dependent neuronal relay. Two of the better documented candidates are raphe serotonergic nuclei [66] and the Retro-Trapezoid Nucleus RTN , a group of glutamatergic neurons found at the medullary surface, just beneath the facial nucleus [50]. The latter turn out to express Phox2b [73]. Moreover, Phox2b-expressing CO2-sensitive neurons of the RTN receive direct projections from nTS neurons which relay O2 responsiveness by virtue of an input from the carotid body, via the petrosal ganglion [73].

Thus, subject to the confirmation of the RTN as key to central CO2 sensitivity, a major pathway for monitoring blood gazes would consist of an entirely Phox2b-positive four-relay circuit. This putative role could underlie the observation that in the most severe cases of CCHS, affected infants will not spontaneously breathe at birth [28]. The mutations that cause CCHS, mostly expansions of a 20 residue-long alanine stretch in the C-terminal part of the protein but also frame shift and missense mutations [86] are probably not null mutations and thus do not cause disease by a simple haploinsufficiency on the grounds that, in mouse, Phox2b heterozygotes display a much subtler phenotype [17; 18; 22], that patients with heterozygous deletions of the PHOX2B region do not have CCHS reviewed in [86] and that different PHOX2B mutations are associated with different combinations and frequencies of symptoms [25; 86].

Rather, the mutant protein may cause CCHS by a dominant-negative mechanism or by toxic gain-of-function [5; 79]. Moreover, mice in which the polyalanine expansion has been introduced into the Phox2b locus die at birth due to respiratory failure V. In man, an argument for a dominant-negative mechanism or cellular toxicity is that a fraction of CCHS patients have strabismus [26], implying a dysfunction of the Phox2a-dependent IIIrd and IVth motor nuclei, where Phox2b is expressed but not required. CCHS patients have a greatly increased risk of developing sympathoadrenal tumors, which may also occur in the absence of CCHS in patients with frameshift mutations [49; 62; 80; 81; 84], and PHOX2B is the first identified gene in which germline mutations predispose to neuroblastoma [49; 80].

Abrogation of its proneural activity, demonstrated in motoneuron precursors [60], may underlie the occurrence of these tumors. Phox2b and the homeostatic brain 33 3. It seems likely that downstream of their common transcriptional determinant — Phox2b — and upstream of their common physiological role-controlling the viscera- visceral neurons follow some common differentiation pathway. One hypothesis is that this pathway could determine connectivity: Tantalizingly, a role in axonal guidance was found for the C.

Its role in noradrenergic differentiation is still a much studied molecular aspect of Phox2 function. Sympathetic neurons are the Phox2b-dependent cell-type, whose transcriptional control is best understood. The combined data are a challenge to schematic representations [27; 47]. Phox2b is absolutely required for SA differentiation: Similarly, at the organ level, the loss of Phox2b leads to agenesis of the sympathetic chains [59] whereas the loss of Mash1 or Gata3 only leads to atrophy [29; 32; 56; 82].

Transcriptional network controling sympathoadrenal differentiation, including Th, Dbh, and generic neuronal differentiation traits. Partial dependence is represented by a thick arrow pointing at a frame enclosing the set of downstream markers, complete dependence by a thin arrow pointing at an individual downstream gene. A curvy arrow represents a putative feedback regulation revealed by gain-of-function experiments. A broken line represents a demonstrated role in maintenance rather than activation. Tfap2 is omitted for simplicity, since its epistatic relationships have not been explored in any detail, apart from its independence from Phox2 genes [34].

An alternative interpretation is that the loss of function of Phox2b leads to cell death so abruptly that other factors do not have the time to partially compensate. The cross-regulations among the members of this transcriptional network might insure the maintenance of upstream genes, thus the robustness and stability of the pathway. A maintenance role is indeed likely for dHand [45] and demonstrated for Gata3 [46].

Finally, the case of Phox2a begs for clarification: However, SA differentiation proceeds normally in the absence of Phox2a [48], implying that Phox2b can fully compensate for any role of Phox2a in SA differentiation. To unmask this putative role which cannot be assessed in the Phox2b knock-out, since Phox2a is no longer expressed a Phox2a-only situation was cre- 3. Phox2b and the homeostatic brain 35 ated by placing the Phox2a coding sequence under the control of the Phox2b locus [16]. This Phox2bKIPhox2a allele failed to rescue the Phox2b knock out phenotype in the sympathetic chain, demonstrating that, despite its identical DNA binding domain, Phox2a is lacking properties found in Phox2b that are required to trigger Dbh expression and SA differentiation in vivo.

All in all, if one cannot exclude that Phox2a has yet undetected roles in the late maturation or postnatal maintenance of the SA phenotype, it can be ruled out as a determinant of this lineage. The SA differentiation observed after forced expression of Phox2a [44; 72] most likely results from the up-regulation of Phox2b, by virtue of the feedback mechanisms outlined above.

It is thus unfortunate that most of the molecular work on the role of Phox2 promoters and proteins during SA differentiation, summarized below, has so far focused almost exclusively on Phox2a. At the molecular level, sympathetic differentiation has been shown to require signaling by BMPs reviewed in [27] , and, at least in vitro, elevated cAMP levels reviewed in [38].

As made clear earlier, if these pathways turn out to be relevant in vivo, it is likely that they impinge also on Phox2b, which was not considered in these studies. There again, any physiological relevance implies that Phox2a is replaced by Phox2b, at least at the onset of Dbh transcription. Not only peripheral noradrenergic and adrenergic cell types depend on Phox2b, but also central ones.

The LC is born and located in rhombomere one r1 [4], all other centers are caudal to it, in the myelencephalon r Does the dependence of the LC on Phox2a in addition to Phox2b indicate a direct role of the former in noradrenergic differentiation? It remains possible that Phox2a plays a role in the maintenance of noradrenergic differentiation of LC cells, in which Phox2b expression, at least in mouse, is transient [55].

VM neurons presynaptic to parasympathetic and enteric ganglia located in the dorsal motor nucleus of the vagus nerve dmnX , the nA and the salivatory nuclei and BM neurons innervating branchial arch-derived muscles located in the Vth, VIIth, nA and XIth nuclei. Their birth occurs from E9 to E Subsequently, the same neuroepithelial domain gives rise to serotonergic neurons, except in the region where facial BM neurons are born [61]. During motoneuron generation, Phox2b is expressed in the dividing progenitors of pMNv where it acts as a proneural gene, promoting cell cycle exit and neuronal differentiation [19; 20; 60].

Thus, in pMNv, in addition to its proneural role, Phox2b serves as a phenotypic switch: Finally, a fourth category of Phox2-expressing motoneurons arises at the mesencephalic-metencephalic junction: However, their transcription factor code sets them sharply apart from bona fide somatic motoneurons: At the molecular level, the role of Phox2b in motoneuronal generation has been little studied.


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Phox2b and the homeostatic brain 37 genes [20], and is most likely not mediated by classical proneural genes of the bHLH class [60]. In conclusion to this section, it should be emphasized that the expression of both Phox2b and Phox2a not only starts very early, but lasts for very long, throughout adult life in some neuronal classes. It is therefore possible that these transcription factors have late developmental roles in addition to those uncovered so far in simple knock-outs, or even post-developmental roles in the adult, that can be revealed only by inducible knock-outs.

Homology of the adult ascidian brain with the vertebrate visceral nervous system. A, Expression of a CiPhox YFP transgene in the neck of the swimming larva, which is homologous to the vertebrate hindbrain [21]. Copyright , National Academy of Sciences, U. Moreover, like the latter, they derive from a hindbrain-like region of the embryonic and larval CNS Fig. Thus, cranial motoneurons of the branchial class, used for feeding and breathing purposes, are candidates at representing the ancestral form of the visceral nervous system.

Conclusion Phox2b is a transcription factor specifically required for the ontogeny of the visceral nervous system, more precisely for proper development of the control of the three cardinal homeostatic functions: In turn, the involvement of PHOX2B in CCHS promises to yield insights in yet poorly understood aspects of the neuronal control of rhythmic breathing, that are defective in this disease. Further elucidation might come from conditional mutations of Phox2b in specific medullary interneurons. Adachi M, Lewis EJ The paired-like homeodomain protein, Arix, mediates protein kinase A-stimulated dopamine beta-hydroxylase gene transcription through its phosphorylation status.

J Biol Chem DNA Cell Biol Phox2b and the homeostatic brain 3. Hum Mol Genet The lower brainstem and bodily homeostasis, 1 Edition Blessing WW, ed , pp The lower brainstem and bodily homeostasis, pp Mol Cell Neurosci J Pediatr Ophthalmol Strabismus Nat Rev Neurosci 3: Phox2b and the homeostatic brain Brain Res Mol Brain Res Mol Cell Biol Annu Rev Physiol Nat Rev Neurosci 5: Gene Expr Patterns 4: Am J Ophthalmol A broad range of autonomic nervous system ANS dysfunction is associated. Treatment is currently supportive by a lifelong dependence on ventilatory support.

In , Haddad et al. In , Amiel et al. Studies in transgenic mice see Chapters 3 and 14 have guided the search of genetic mutations in humans and functional and anatomical studies in patients with CCHS allow insight into its physiopathology see Chapter 5. The discovery of the CCHScausing mutation further contributes to the recognition of new phenotypes and raises a great hope for a specific treatment in the future. However, the overall spectrum of CCHS phenotype involves a more global ANS dysfunction, with a large inter-individual variability among patients [35].

Neonates with CCHS exhibit recurrent apneas, periods of cyanosis during sleep, and despite severe hypoxia and bradycardia, fail to increase their breathing. Polysomnography showed severe central alveolar hypoventilation during sleep due to shallow breathing and low respiratory rate which caused reduced minute ventilation. Alveolar hypoventilation was more severe during quiet sleep than during active sleep.

Ventilatory responses to hypercapnia, to hypoxia were absent or markedly reduced in all states of alertness. Abnormal central control of breathing persists during the whole life. With advancing postnatal age, central hypoventilation becomes more marked during non-rapid eye movement sleep. During wakefulness, most patients can breathe spontaneously with acceptable alveolar ventilation and gas exchange. However, those severely affected may hypoventilate both while asleep and while awake.

Mecanisms underlying respiratory drive in CCHS Normal central control of breathing relies on the integrity of peripheral chemoreceptors, of central chemoreceptors, of integration processes mediating signals from chemoreceptors to the brainstem, and of the brainstem respiratory generator itself.

A number of functional ventilatory studies, recently coupled to new imaging techniques, have aimed to investigate the range of deficient and intact components of control of breathing in CCHS. Ventilatory responses to sustained hypercapnia, to sustained hypoxia, are absent or markedly reduced whatever the state of alertness in patients with CCHS Fig. Alveolar hypoventilation is most severe during non rapid eye movement sleep, a sleep state during which control of breathing depends quasi-exclusively upon central CO2 level.

Most of the patients are able to breathe adequately during wakefulness [31; 35], despite loss of perception of breathlessness [28]. Infant with CCHS at 8 days of age. As the infant spontaneously breathes room air, tidal volume, respiratory rate and minute ventilation dramatically decrease in active sleep, compared to wakefulness, and in quiet sleep compared to active sleep.

Hypercapnic and hypoxic ventilatory responses are abnormally low in all states of alertness. Patients with CCHS can breathe adequately if stimulated by mechanisms other than chemoreception, i. Suprapontine stimulation increases significantly respiratory drive during wakefulness in CCHS. Its impact may depend on the level of mental activity. Moderate mental activity has been shown to increase ventilation in a small group of patients with CCHS, whereas challenge with intense mental activity may result in decrease of breathing in some of them [28].

Passive motion of the lower limbs preferentially involves a mechanoreceptor feedback without activation of feed-forward centers. Thus, the dysfunctional brain structures that mediate the abnormal ventilatory response to hypercapnia or hypoxia do not appear to disrupt the on-response of reflex ventilatory changes elicited by passive motion.

Peripheral chemoreceptor drive has been shown to be active in a small group of patients with CCHS, presumably in those who can have adequate spontaneous ventilation during daytime [13]. However, structural abnormalities reduced size and number of glomus cells have been clearly identified in the carotid bodies of two children with CCHS [7]. In CCHS, the defect is located at the level of central chemoreception.

Interestingly, despite the absence of ventilatory responses to hypercapnia, patients with CCHS arise from sleep during a hypercapnic challenge [22].

Two hypotheses may be suggested: Use of functional magnetic resonance imaging demonstrated that responses to hypercapnia, to hypoxia or to loaded breathing involved widespread brain areas not classically thought to mediate respiratory drive [17; 20; 21; 39]. Cerebellar and basal ganglia contributions in responding to hypercapnia are shown to be altered in patients with CCHS, whereas thalamic and midbrain regions fail to mediate the perception of breathlessness [17]. Moreover, imaging techniques using diffusion tensor imaging show increased mean diffusivity in regions in the brainstem, but in also the cerebellum, forebrain and temporal and frontal cortices [19].

Thus, these data suggest that there are both functional and structural impairments of these cerebral areas in CCHS see Chapter 5. In summary, the intrinsic deficit of central control of breathing is present in patients with CCHS whatever the state of alertness. However, it may be overcome under conditions in which other operative mechanisms are active, such as wakefulness and motion, at least in part of the CCHS population. One limitation of the studies cited above is the small number of patients included due to the rarity of the disease.

Because of the phenotypic variability in CCHS, this may explain in part some of the conflicting data and therefore, it is likely that compensatory respiratory drive mechanisms may vary across patients. Heart rate variability is decreased [40]. Moreover, the circadian pattern of blood pressure is abnormal with loss of the physiological decrease in the values during transition from wakefulness to sleep [30]. The spontaneous baroreflex sensitivity is shown to be altered, with a predominant vagal dysfunction and a relatively preserved sympathetic function [25; 32].

The hypothesis is that impaired control of the baroreflex likely derives in affected brain regions from the ventral frontal, insular and cingulate cortices [20]. Other ANS dysfunction Various manifestations of ANS dysfunction have been reported, such as ocular dysmotility [35], esophageal dysmotility [11], abnormal thermoregulation. Central hypoventilation may occur during early childhood or adulthood namely late onset central hypoventilation syndromes [10; 23; 33]. CCHS can be associated with brainstem anomalies identified using magnetic resonance image, as shown in two patients, one with a Chiari I malformation and the other with hypoplasia of the pons [4].

In the pursuit of the genes responsible for CCHS, several independent teams have used the candidate gene approach. Later, screening was expanded to genes thought to be involved in neural crest cell migration and in ANS development. Data are number of patients and percentage. PHOX2B gene is a paired-like homeobox, located on chromosome 4p12 and encoding a highly conserved transcription factor that usually contains two polyalanine repeat sequences of 9 and 20 residues see Chapters 3 and 6. Penetrance of the mutation is incomplete, as phenotype show elevated inter-variability among patients, and parents of patients with CCHS who carry the PHOX2B mutation have been shown to be unaffected [23].

The discovery of the CCHS-causing gene shows a high clinical relevance for genetic counselling and prenatal diagnosis. The longest alanine expansions are associated with the most severe respiratory deficiencies in patients with CCHS [23; 34; 36]. However, it can also be found in patients with neonatal onset of central hypoventilation.

Thus, a similar genetic mutation can be associated with variable onset of central hypoventilation, suggesting a role for epigenetic influences. A high predisposition to neural crest tumors has been long recognized in patients with CCHS [23; 27]. The presence of non-alanine expansion mutations i.

Hence, molecular testing may help to identify a subset of patients with CCHS at high risk for developing malignant tumors. Synergistic effects of others modifier genes as the mechanisms underlying the variable phenotype of CCHS are likely. The phenotype reveals to be unremarkable for these patients with two genetic mutations, but their limited number should prevent from definite conclusions. There is a need for further genetic studies looking for mutations or polymorphisms of others genes associated with PHOX2B mutations.

However, functional brain deficits have been shown to extend far beyond the areas of PHOX2B expression during development. One hypothesis would be that impaired PHOX2B gene function targeting the autonomic ganglia exerts a direct effect on control of the cerebral vasculature, thereby altering the development of structures in brain areas that control respiratory, cardiovascular and other vital functions see Chapter 5. Thus, to be efficient in patients with CCHS, the specific treatment should target altogether brain areas which express PHOX2B and those thought to be secondarily affected.

PHOX-2B mutations and phenotype. J Med Genet Report of an infant born with this syndrome and review of the literature. Clin Sci Lond Am J Med Genet The purported genetic process underlying the disorder, mutation of the PHOX2B gene [4; 6; 44; 52; 53], is associated with injury to specific regions of the medulla and peripheral autonomic ganglia [12]. However, a complete description of the symptomology of CCHS points to a broad range of neural influences being deficient, implying that more than just brain stem functions are affected.

CCHS children show a range of physiologic and especially autonomic aberrations in addition to the loss of ventilatory drive during sleep and reduced CO2 or O2 ventilatory sensitivity see Chapter 4. Although symptoms vary among patients, deficiencies in autonomic nervous system control are especially prominent, with both sympathetic and parasympathetic components of that control affected.

The sympathetic aspects include profuse sweating [50], disturbed cardiovascular control, as manifested by syncope and inappropriate heart rate changes to blood pressure challenges [27], and an absence of blood pressure lowering at night [49]. Parasympathetic deficiencies include unequal pupillary constriction, defects in glandular secretion [50], and impaired vagal influences on heart rate variability [56].

Other altered physiologic and emotional measures are pronounced, including poor thermoregulation [50], a loss of affect including emotions associated with the urge to breathe accompanying high CO2 or hypoxia [42; 45], difficulties in initiating urination, and alterations in fluid regulation M. Many of the physiological and emotional functions that are deficient are regulated in rostral brain areas, and especially in limbic structures. Fluid regulation depends on structures in the anterior hypothalamus near the lamina terminalis, and thermoregulation is principally mediated by anterior hypothalamic structures.

Voluntary initiation of urination depends on the anterior cingulate cortex [7; 8], and anecdotal evidence indicates that a number of CCHS children show a deficit in such control. Since the perception of suffocation is a powerful drive for inspiratory effort, and low O2 or high CO2 leads to that perception, loss of this urge to breathe in CCHS represents yet another significant removal of influence on respiratory effort. Negative perceptions, such as dyspnea from loaded breathing or from hypoxia or hypercapnia, are not regulated by medullary structures, except perhaps for final common path output of autonomic action to strong emotions.

Instead, these perceptions are mediated by limbic areas, including the amygdala, insular cortex, and cingulate cortex [2; 5; 15; 40]. In addition to perception of affect associated with sensory processing of ventilatory stimuli, expression of emotion on motor systems is an issue in CCHS. Such expression can operate independently of traditional motor pathways [], as evidenced by an inability to trigger appropriate facial muscle action to emotional stimuli with retention of voluntary action [51] , a common occurrence in CCHS. Since affect exerts marked effects on breathing musculature, defects in forebrain emotional structures can have a profound effect on ventilation.

An obvious question stemming from the affective and autonomic findings is how such influences associated with rostral brain functions are related to the expression of the PHOX2B gene. PHOX2B principally affects autonomic ganglia and autonomic nervous system structures in medullary sites, rather than forebrain structures [12].

A recent study [47] also suggests that PHOX2B is expressed in chemosensory integration neurons of the retrotrapezoid nucleus. Mutant Phox2b preparations also show impaired ventilation during sleep [14] and to hyperoxic exposure [43]. The mutant preparations demonstrate that Phox2b exerts a significant role on ventilation, although the investigators caution that several characteristics of breathing differ from the human CCHS condition see Chapter A principal issue is that some of the breathing characteristics are especially deficient in rapid eye movement REM sleep rather than quiet sleep, as is the case in CCHS.

Thus, a relationship between Phox2b and breathing is established, but these mutant demonstrations do not explain the forebrain-mediated physiological symptoms, the emotional characteristics of the condition, or the state-related variations in breathing regulation in CCHS.