FURTHER ANALYSIS OF SPORADIC HIRSCHSPRUNG DISEASE WITH RECEPTOR
TYROSINE KINASE AND ENDOTHELIN-SIGNALING PATHWAYS
Sakai T 1, Nirasawa Y 2, Hashimoto Y 3 & Wakizak A 1
1 Dept.of Biochem. & Molec. Biol., 2 Dept. of Pediatric, Surg.,
Kyorin Univ. Sch. of Med., 3 Dept. of Nursing, Kyorin Univ. Sch. of Health
Sci., 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), endothlin-B receptor (EDNRB) and endothelin-3 (END-3) by
the direct sequencing.
Results: Analysis of DNA revealed five disease causative
mutations in the RET proto-oncogene, in exon 9 (D 584 G), exon 10 (C 620
S), the splice donor sited of intron 10 (+2 T to A), exon 11 (A 654 T), and
exon 12 (T 706 A). Two disease causative mutations were detected in the
endothelin receptor (EDNRB) gene, in non-coding region of exon 1 (-26 G to
A) and in exon 4 (A 310 T). One heterozygous T to C mutations was found in
the GDNF gene in 25 bases upstram 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% (3/3.5), 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.