THE PHYSICAL MAP OF THE HUMAN RET PROTOONCOGENE

The RET proto-oncogene, a transmembrane tyrosine kinase receptor, is i nvolved in the development of at least five different disease phenotyp es. RET is activated through somatic rearrangements in a number of cas es of papillary thyroid carcinoma while germ-line point mutations are associated with three inherited cancer syndromes MEN 2A, MEN 2B and FM TC. Moreover, point mutations or heterozygous deletions of RET are fou nd in the dominant form of Hirschsprung disease or congenital colonic aganglionosis. We cloned the entire RET genomic sequence in a contig o f cosmids encompassing 150 kb, from the CA repeat sTCL-2 to the region upstream the RET promoter, and established the position of the 20 exo ns of the RET gene with respect to a detailed restriction map based on eight endonucleases. A new highly polymorphic CA repeat sequence was identified within intron 5 of RET (RET-INT5). Finally the orientation of RET on chromosome 10q11.2 made it possible to orientate three other genes rearranged with RET in papillary thyroid carcinomas, namely H4/ D10S170 on 10q21, R1 alpha on 17q23 and RFG2/Ele1 on 10q11.2.