PLoS ONE (Jan 2013)

Contributions of PHOX2B in the pathogenesis of Hirschsprung disease.

  • Raquel María Fernández,
  • Yves Mathieu,
  • Berta Luzón-Toro,
  • Rocío Núñez-Torres,
  • Antonio González-Meneses,
  • Guillermo Antiñolo,
  • Jeanne Amiel,
  • Salud Borrego

DOI
https://doi.org/10.1371/journal.pone.0054043
Journal volume & issue
Vol. 8, no. 1
p. e54043

Abstract

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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.