title: 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.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Kyorin University School of Medicine, Shinkawa 6-20-2, Mitaka, Tokyo 181-8611, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sakai
authors.forename: Y
authors.initials: Y
authors.lastname: Nirasawa
authors.forename: Y
authors.initials: Y
authors.lastname: Itoh
authors.forename: A
authors.initials: A
authors.lastname: Wakizaka
mesh_terms: D044466:Asian People / Q000235:genetics*; D004252:DNA Mutational Analysis; D029721:Drosophila Proteins; D019334:Endothelin-3 / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D007564:Japan; D008297:Male; D009414:Nerve Growth Factors / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051101:Neurturin; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics*
chemical_list: D029721:Drosophila Proteins; D019334:Endothelin-3; C495039:GDNF protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; C000715470:MAS1 protein, human; C495053:NRTN protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D051101:Neurturin; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila