Contributions of PHOX2B in the Pathogenesis of Hirschsprung Disease

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Abstract

Hirschsprung disease (HSCR) is a congenital malformation of the hindgut resulting from a disruption of neural crest cell migration during embryonic development. It has a complex genetic aetiology with several genes involved in its pathogenesis. PHOX2B plays a key function in the development of neural crest derivatives, and heterozygous mutations cause a complex dysautonomia associating HSCR, Congenital Central Hypoventilation Syndrome (CCHS) and neuroblastoma (NB) in various combinations. In order to determine the role of PHOX2B in isolated HSCR, we performed a mutational screening in a cohort of 207 Spanish HSCR patients. Our most relevant finding has been the identification of a de novo and novel deletion (c.393_410del18) in a patient with HSCR. Results of in silico and functional assays support its pathogenic effect related to HSCR. Therefore our results support that PHOX2B loss-of-function is a rare cause of HSCR phenotype.

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The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives.

X Morin, Jean-François Brunet, Christo Goridis … (1999)

The sympathetic, parasympathetic and enteric ganglia are the main components of the peripheral autonomic nervous system, and are all derived from the neural crest. The factors needed for these structures to develop include the transcription factor Mash1, the glial-derived neurotrophic factor GNDF and its receptor subunits, and the neuregulin signalling system, each of which is essential for the differentiation and survival of subsets of autonomic neurons. Here we show that all autonomic ganglia fail to form properly and degenerate in mice lacking the homeodomain transcription factor Phox2b, as do the three cranial sensory ganglia that are part of the autonomic reflex circuits. In the anlagen of the enteric nervous system and the sympathetic ganglia, Phox2b is needed for the expression of the GDNF-receptor subunit Ret and for maintaining Mash1 expression. Mutant ganglionic anlagen also fail to switch on the genes that encode two enzymes needed for the biosynthesis of the neurotransmitter noradrenaline, dopamine-beta-hydroxylase and tyrosine hydroxylase, demonstrating that Phox2b regulates the noradrenergic phenotype in vertebrates.

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

Jeanne Amiel, Béatrice Laudier, Tania Attie-Bitach … (2003)

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.

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An official ATS clinical policy statement: Congenital central hypoventilation syndrome: genetic basis, diagnosis, and management.

, Thomas G. Keens, Debra Weese-Mayer … (2010)

Congenital central hypoventilation syndrome (CCHS) is characterized by alveolar hypoventilation and autonomic dysregulation. (1) To demonstrate the importance of PHOX2B testing in diagnosing and treating patients with CCHS, (2) to summarize recent advances in understanding how mutations in the PHOX2B gene lead to the CCHS phenotype, and (3) to provide an update on recommendations for diagnosis and treatment of patients with CCHS. Committee members were invited on the basis of their expertise in CCHS and asked to review the current state of the science by independently completing literature searches. Consensus on recommendations was reached by agreement among members of the Committee. A review of pertinent literature allowed for the development of a document that summarizes recent advances in understanding CCHS and expert interpretation of the evidence for management of affected patients. A PHOX2B mutation is required to confirm the diagnosis of CCHS. Knowledge of the specific PHOX2B mutation aids in anticipating the CCHS phenotype severity. Parents of patients with CCHS should be tested for PHOX2B mutations. Maintaining a high index of suspicion in cases of unexplained alveolar hypoventilation will likely identify a higher incidence of milder cases of CCHS. Recommended management options aimed toward maximizing safety and optimizing neurocognitive outcome include: (1) biannual then annual in-hospital comprehensive evaluation with (i) physiologic studies during awake and asleep states to assess ventilatory needs during varying levels of activity and concentration, in all stages of sleep, with spontaneous breathing, and with artificial ventilation, and to assess ventilatory responsiveness to physiologic challenges while awake and asleep, (ii) 72-hour Holter monitoring, (iii) echocardiogram, (iv) evaluation of ANS dysregulation across all organ systems affected by the ANS, and (v) formal neurocognitive assessment; (2) barium enema or manometry and/or full thickness rectal biopsy for patients with a history of constipation; and (3) imaging for neural crest tumors in individuals at greatest risk based on PHOX2B mutation.

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Author and article information

Contributors

Reiner Albert Veitia: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 14 January 2013

Volume: 8

Issue: 1

Electronic Location Identifier: e54043

Affiliations

[1 ]Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/Centro Superior de Investigaciones Científicas/University of Seville, Seville, Spain

[2 ]Centre for Biomedical Network Research on Rare Diseases, Seville, Spain

[3 ]INSERM U-781, AP-HP Hôpital Necker-Enfants Malades, Paris, France

[4 ]Department of Paediatrics. University Hospital Virgen del Rocío, Seville, Spain

Institut Jacques Monod, France

Author notes

* E-mail: salud.borrego.sspa@ 123456juntadeandalucia.es

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: SB JA GA AG-M. Performed the experiments: RMF YM BL-T RN-T. Analyzed the data: RMF YM BL-T RN-T. Wrote the paper: RM-F YM GA JA SB.

Article

Publisher ID: PONE-D-12-29123

DOI: 10.1371/journal.pone.0054043

PMC ID: 3544660

PubMed ID: 23342068

SO-VID: 462680f6-156d-4313-a142-572e969a8912

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 25 September 2012

Date accepted : 5 December 2012

Page count

Pages: 6

Funding

This work was supported by the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness, Spain (PI1001290) and Regional Ministry of Innovation, Science and Enterprise of the Autonomous Government of Andalucia (CTS-7447), the Fondation pour la Recherche Médicale and the Agence Nationale de la Recherche. The CIBERER is an initiative of the ISCIII, Spanish Ministry of Economy and Competitiveness. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Contributions of PHOX2B in the Pathogenesis of Hirschsprung Disease

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Alternative approaches to Alzheimer's Disease

Most cited references 21

The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives.

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

An official ATS clinical policy statement: Congenital central hypoventilation syndrome: genetic basis, diagnosis, and management.

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