caa a22 4500 475785142 CHVBK 20180406123655.0 cr unu---uuuuu 170329e20000201xx s 000 0 eng 10.1007/s004310050043 doi (NATIONALLICENCE)springer-10.1007/s004310050043 Japanese patients with sporadic Hirschsprung: mutation analysis of the receptor tyrosine kinase proto-oncogene, endothelin-B receptor, endothelin-3, glial cell line-derived neurotrophic factor and neurturin genes: a comparison with similar studies [Elektronische Daten] [T. Sakai, Y. Nirasawa, Y. Itoh, A. Wakizaka] We report on mutation analysis of five genes involved in the receptor tyrosine kinase (RET) or the endothelin-signalling pathways in 28 sporadic Japanese patients with Hirschsprung disease. Analysis of DNA obtained from peripheral blood cells revealed six mutations in the RET proto-oncogene, four of which were disease-causing mutations in exon 9 (D584G), the splice donor site of intron 10 (+2T to A), exon 11 (A654T), and exon 12 (T706A). A heterozygous A to G transition was found in 47 bases upstream from the 5′ end of exon 2 in two HD patients but was also seen in one control subject (2/28; 1/24). A silent 2307T to G transversion was observed in exon 13. Two disease-causing mutations were detected in the endothelin receptor (EDNRB) gene, in the non-coding region of exon 1 (−26 G to A) and in exon 4 (A301T); the latter mutation was a novel one. One silent mutation was observed in exon 4 (codon 277). One heterozygous T to C mutation was found in the glial cell line-derived neurotrophic factor gene in 25 bases upstream of the coding region in exon 1. No nucleotide changes were detected in either the endothelin-3 or neurturin genes. Disease-causing mutation rates in the RET proto-oncogene and the EDNRB gene were estimated at 14.3% (4/28) and 10.7% (3/28), respectively. In addition to mutations in the RET and EDNRB genes, embryonic environmental factors and/or other genetic factors appear to be involved in the development of Hirschsprung disease. Further systematic studies of genetic variation in a large series of patients and controls are necessary for elucidating the pathogenesis of this disorder. Conclusion This study provides further gene alterations as disease-causing mutations in Japanese cases of sporadic Hirschsprung disease. However, the low mutation rate of the susceptibility genes may indicate that Hirschsprung disease arises from a combination of genetic and environmental factors. Springer-Verlag Berlin Heidelberg, 2000 Key words Hirschsprung disease nationallicence Receptor tyrosine kinase proto-oncogene nationallicence Endothelin-B receptor nationallicence Endothelin-3 nationallicence Glial cell line-derived neurotrophic factor nationallicence Sakai T. Department of Biochemistry and Molecular Biology, Kyorin University School of Medicine, Shinkawa 6-20-2, Mitaka, Tokyo 181-8611, Japan Tel.: +81-422-475511; Fax: +81-422-407281, JP aut Nirasawa Y. Department of Paediatric Surgery, Kyorin University School of Medicine, Tokyo, Japan, JP aut Itoh Y. Department of Paediatric Surgery, Kyorin University School of Medicine, Tokyo, Japan, JP aut Wakizaka A. Department of Biochemistry and Molecular Biology, Kyorin University School of Medicine, Shinkawa 6-20-2, Mitaka, Tokyo 181-8611, Japan Tel.: +81-422-475511; Fax: +81-422-407281, JP aut https://doi.org/10.1007/s004310050043 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s004310050043 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Sakai T. Department of Biochemistry and Molecular Biology, Kyorin University School of Medicine, Shinkawa 6-20-2, Mitaka, Tokyo 181-8611, Japan Tel.: +81-422-475511; Fax: +81-422-407281, JP aut NATIONALLICENCE 700 1- Nirasawa Y. Department of Paediatric Surgery, Kyorin University School of Medicine, Tokyo, Japan, JP aut NATIONALLICENCE 700 1- Itoh Y. Department of Paediatric Surgery, Kyorin University School of Medicine, Tokyo, Japan, JP aut NATIONALLICENCE 700 1- Wakizaka A. Department of Biochemistry and Molecular Biology, Kyorin University School of Medicine, Shinkawa 6-20-2, Mitaka, Tokyo 181-8611, Japan Tel.: +81-422-475511; Fax: +81-422-407281, JP aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer