FURTHER ANALYSIS OF SPORADIC HIRSCHSPRUNG DISEASE
WITH RECEPTOR TYROSINE KINAE AND ENDOTHELIN-SIGNALING PATHWAYS
Sakai T1,
Nirasawa Y2, Hashimoto Y3 & Wakizaka A1.
Kyorin Univ.Sch.Med., 1Dept.Biochem. &
Molec.Biol., 2Dept.Pediatr.Surg., 3Kyorin Univ.Sch.Health
Sci., Dept.Nrusing, Tokyo, Japan
Objective: Further mutation analysis of the
receptor tyrosine kinase (RET) and the endothelin-signaling pathways in
sporadic patients with Hirschsprung disease (HSCR), including four patients associated with congenital central
hypoventilation syndrome (CCHS), was reported.
Methods:
Thirty-five sporadic HSCR patients were examined for their DNA sequence
with five genes involved in the RET proto-oncogene, glial cell line-derived
neurotrophic factor (GDNF), neurturin (NTN), endothelin-B receptor (EDNRB)
and endothelin-3 (EDN-3) by the direct sequencing.
Results:
Analysis of DNA revealed five disease causative mutations in the RET
proto-oncogene, in exon 9 (D584G), exon 10 (C620S), the splice donor site
of intron 10 (+2 T to A), exon 11 (A654T), and 12 (T706A). Two disease
causative mutations were detected in the EDNRB gene, in non-coding region
of exon 1 (-26 G to A) and in exon 4 (A310T). One heterozygous T to C
mutation was found in the GDNF gene in 25 bases upstream of the coding
region in exon 1. No nucleotidic changes were detected in either the EDN-3
or NTN genes. Disease causative mutation rates in the RET proto-oncogene
and the EDNRB gene were estimated at 14.3% (5/35) and 8.6% (3/35),
respectively. One out of four patients with CCHS had a disease causative
mutation in the RET proto-oncogene.
Conclusion: Mutations in the GDNF or NTN
gene are neither necessary nor sufficient to manifest the disease. In
addition to mutations in the RET and EDNRB genes, other genetic factors
and/or environmental factors might appear to be involved in the development
of HSCR.