Down-regulation of SHH/BMP4 signalling in human anorectal malformations.

The sonic hedgehog homologue (SHH)/bone morphogenetic protein 4 (BMP4) signalling pathway is involved in the morphogenesis of many organ systems. This study was designed to investigate the expression of SHH/BMP4 pathway components in human anorectal malformations (ARMs) and the relationship between expression of their genes and the occurrence of ARMs. Expression of SHH, GLI family zinc finger 2 (GLI2) and BMP4 mRNA in the posterior wall of the terminal rectum in 40 patients with ARMs (15 high-type and 25 low-type) and 10 normal controls was assessed by reverse transcription-polymerase chain reaction. Levels of SHH, GLI2 and BMP4 proteins were assessed by immunohistochemistry and Western blotting. The expressions of SHH, GLI2 and BMP4 were significantly lower in patients with high-type compared with those with low-type anomalies and controls. Patients with low-type ARMs differed from controls only in the expression of GLI2 mRNA. It is concluded that down-regulation of the SHH/BMP4 signalling pathway may be related to the occurrence of high-type ARMs, but the mechanism responsible for low-type ARMs remains unclear.