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© 1994 Oxford University Press

OTHER

Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene

Lois M. Mulligan1,2,*, Charts Eng1,3, Tanla Attlé4, Stanislas Lyonnet4, Debbie J. Marsh5, Valentine J. Hyland5, Bruce G. Robinson5, Andrea Frilling6, Christine Verellen-Dumoulln7, Anne Safar8, Deon J. Venter9, Arnold Munnich4 and Bruce A.J. Ponder1

1Cancer Research Campaign Human Cancer Genetics Research Group, Department of Pathotogy, University of Cambridge Tennis Court Road, Cambridge CB2 1QP, UK 2Departments of Paediatrics and Pathology, Queen's University Kingston, Ontario K7L 3N6, Canada 3Divisions of Medical Oncology and Cancer Epidemiology and Control, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School Boston, MA 02115-6084, USA 4Service de Genetique Medicale, Clinique Chirurgicale Infantile et Unite de Recherches sur les Handicaps Genetques de I1 Enfant, INSERM U-393, Hdprtal Necker-Enfants Malades 149 Rue de Sevres, 75743 Paris cedex 15, France 5Department of Molecular Genetics, Kollmg Institute of MedicaJ Research, RoyaJ North Shore HosprtaJ St Leonards, NSW 2065, Australia 6Universits-Krankenhaus, Chirurgtsche Klmik, University Hamburg Martinstrasse 52, 2000 Hamburg 20, Germany 7Centre de Genetique Medicale, Universrte Catholique de Louvain 1200 Bruxeltes, Belgium 8Service de Chirurgie Pediatrique, Hfiprtal Saint-Vincent de Paul, Parts France 9Royal Children's Hospital, Parkville Melbourne, Victoria 3052, Australia

*To whom correspondence should be addressed at: Department of Paediatrics, Queen's University, 20 Barrie Street, Kingston, Ontario K7L 3N6, Canada

Received July 25, 1994; Accepted October 5, 1994

Mutations of the RET proto-oncogene are the underlying cause of some cases of Hlrschsprung disease (HSCR) and the Inherited cancer syndromes multiple endocrine neoplasia types 2A (MEN 2A) and 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). In HSCR these mutations are dispersed throughout the gene, while in MEN 2A and FMTC, they are tightly clustered In five cystelne codons of the RET extracellular domain. HSCR and MEN 2 are usually distinct but occasional families have been reported wtth both diseases. In each of five families with HSCR with or without MEN 2A or FMTC, we have identified a nucleotide substitution In one of the five cystelne codons previously associated with MEN 2A or FMTC. In one family, which had HSCR as its only phenotype, we detected a Cys-Trp mutation at codon 609 which had not been previously observed. In three families, both HSCR and MEN 2A were associated with a single Cys—Arg mutation at either codon 618 or 620 of RET. In the fifth family, FMTC and HSCR were present but we could not determine whether HSCR arose from mutation of the RET locus. We suggest that specific mutations In cysteine codons 618 and 620 result In MEN 2A or FMTC, but can also predispose to HSCR with low penetrance.


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