Contributions of PHOX2B in the pathogenesis of Hirschsprung disease.
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.
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.
Raquel María
RM
Fernández
Yves
Y
Mathieu
Berta
B
Luzón-Toro
Rocío
R
Núñez-Torres
Antonio
A
González-Meneses
Guillermo
G
Antiñolo
Jeanne
J
Amiel
Salud
S
Borrego
D016022:Case-Control Studies; D019295:Computational Biology; D004252:DNA Mutational Analysis; D005260:Female; D006627:Hirschsprung Disease / Q000235:genetics* / Q000473:pathology*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D014157:Transcription Factors / Q000235:genetics*
D018398:Homeodomain Proteins; C109220:NBPhox protein; D014157:Transcription Factors