1. ¹Department of Pediatric Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China
2. ²Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan, Republic of China
3. ³Department of Life Sciences, Chung Shan Medical University, 110 Sec. 1, Chein-Kuo North Road, Taichung, Taiwan, Republic of China
4. ⁴Division of Pediatric Surgery, God's Heart Hospital, Chiayi, Taiwan, Republic of China
5. ⁵Tian-Sheng Memorial Hospital, Tong Kang, Pin-Tong, Taiwan, Republic of China
6. ⁶Department of Biology, Tunghai University, Taichung, Taiwan, Republic of China

Correspondence: Chuan Li, Department of Life Sciences, Chung Shan Medical University, 110 Sec. 1, Chein-Kuo North Road, Taichung, Taiwan, Republic of China. Fax: +886-4-2475-7412. E-mail: cli@csmu.edu.tw

Received 9 December 2004; Accepted 20 January 2005; Published online 15 April 2005.

Abstract

Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a relatively common disorder characterized by the absence of ganglion cells in the nerve plexuses of the lower digestive tract, resulting in intestinal obstruction in neonates. Mutations in genes of the RET receptor tyrosine kinase and endothelin receptor B (EDNRB) signaling pathways have been shown to be associated in HSCR patients. In this study, we collected genomic DNA samples from 55 HSCR patients in central Taiwan and analyzed the coding regions of the RET and EDNRB genes by PCR amplification and DNA sequencing. In the 55 patients, an A to G transition was detected in two (identical twin brothers). The mutation was at the end of RET exon 19 at codon 1062 (Y1062C), a reported critical site for the signaling pathways. Single nucleotide polymorphisms (SNP) in exons 2, 7, 11, 13, and 15 of RET and exon 4 of EDNRB in the HSCR patients or controls were detected. The differences between patients and controls in allele distribution of the five RET polymorphic sites were statistically significant. The most frequent genotype encompassing exons 2 and 13 SNPs (the polymorphic sites with the highest percentage of heterozygotes) was AA/GG in patients, which was different from the AG/GT in the normal controls. Transmission disequilibrium was observed in exons 2, 7, and 13, indicating nonrandom association of the susceptibility alleles with the disease in the patients. This study represents the first comprehensive genetic analysis of HSCR disease in Taiwan.