CLOSE LINKAGE WITH THE RET PROTOONCOGENE AND BOUNDARIES OF DELETION MUTATIONS IN AUTOSOMAL-DOMINANT HIRSCHSPRUNG DISEASE

Tight linkage with the RET proto-oncogene (Zmax = 3.41 at THETA = 0.00 ), analysis of recombinants and detection of a familial microdeletion in a large pedigree restrict the mapping of the Hirschsprung (HSCR) ge ne previously localized on proximal 10q. The molecular characterizatio n of the familial microdeletion and of 3 additional cytogenetically vi sible de novo deletions, isolated in somatic cell hybrids, identify a smallest region of overlap of 250 Kb. This contains the RET proto-onco gene where missense mutations causing multiple endocrine neoplasia typ e 2A (MEN 2A) phenotype were recently found. The pentagastrin test (wh ich detects preclinical forms of MEN 2A or B) is negative in adult HSC R patients with deletions of the RET gene. This represents a good cand idate for the search of mutations causing HSCR.