Cys 618 Arg mutation in the RET proto-oncogene associated with familial medullary thyroid carcinoma and maternally transmitted Hirschsprung's disease suggesting a role for imprinting

Hum Mutat. 1997;10(2):155-9. doi: 10.1002/(SICI)1098-1004(1997)10:2<155::AID-HUMU7>3.0.CO;2-J.


The multiple endocrine neoplasia type 2 (MEN2) syndromes and Hirschsprung's disease (HSCR) are inherited neurocristopathies characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, parathyroid disease, and gastrointestinal neuromatosis. Mutations in the RET proto-oncogene are the underlying cause of the MEN2 syndromes and some cases of HSCR. In this report, we show that Cys 618 Arg mutation cosegregates with familial MTC and HSCR in two Moroccan Jewish families in which no involvement of pheochromocytoma or parathyroidism was observed. A single haplotype shared by chromosomes bearing the Cys 618 Arg mutation in both families strongly suggests a founder effect for this mutation. We have observed in our and in several other previously reported families, an excess of maternal over paternal mutated RET alleles in offsprings affected by HSCR. We suggest that parental imprinting may play a role in the ethiology of HSCR caused by mutations in the RET protooncogene.

MeSH terms

  • Arginine / genetics
  • Carcinoma, Medullary / genetics*
  • Deoxyribonucleases, Type II Site-Specific / genetics
  • Drosophila Proteins*
  • Female
  • Genomic Imprinting
  • Haplotypes
  • Hirschsprung Disease / genetics*
  • Humans
  • Infant
  • Jews
  • Male
  • Morocco / ethnology
  • Multiple Endocrine Neoplasia / genetics
  • Mutation*
  • Pedigree
  • Polymorphism, Single-Stranded Conformational
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Sex Ratio
  • Thyroid Neoplasms / genetics*


  • Drosophila Proteins
  • Proto-Oncogene Proteins
  • Arginine
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, Drosophila
  • Deoxyribonucleases, Type II Site-Specific
  • GCGC-specific type II deoxyribonucleases