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A new PHOX2B polymorphism is associated with Hirschsprung’s disease

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Unravelling the complexities of Hirschsprung’s disease (HSCR) is a step closer, with the first association study of PHOX2B as a candidate gene in Chinese people. The disease is polygenic so gene interactions may occur—but first, the susceptibility genes must be identified.

An A→G1364 substitution in intron 2—one of three new PHOX2B polymorphisms found—differed significantly in genotype frequency between patient and control groups and controls and almost all of another patient group with the disease but no RET mutation. Significant linkage disequilibrium occurred between this and a DEL2609 deletion of five alanine residues at codons 254–258, but whether directly or by gene interaction is unclear, say the authors. There were no sex differences in genotype frequencies of each of the three polymorphisms, and each polymorphism in all groups was in Hardy-Weinberg equilibrium.

DNA amplification and sequencing of the whole PHOX2B gene and its flanking regions were performed in 91 patients with HSCR in Hong Kong, 71 ethnically matched Chinese controls, and 75 patients with HSCR but no RET mutation.

Ganglion cells are absent in the nerve plexus of the lower gut in HSCR. RET expression and HSCR genes coding for proteins in two signalling pathways—RET and endothelin receptor B pathways—account for only some cases. Neurone development also depends on a transcription factor encoded by the.PHOX2B gene. Mice with the homozygous mutation have no enteric ganglia and do not express RET, suggesting that PHOX2B regulation of RET determines nerve development—the hypothesis tested in the current study.

Gut 2003;52:563–567.

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