title: Mutational analysis of multiple endocrine neoplasia type 2A associated with Hirschsprung's disease.
abstract: BACKGROUND
  The clinical association of multiple endocrine neoplasia type 2A (MEN 2A) and Hirschsprung's disease (HD), although rare, has been previously observed. Recently, germline mutations in the RET proto-oncogene, a transmembrane receptor with tyrosine kinase activity, have been detected in patients with familial HD. RET is also the predisposition gene for the inherited cancer syndrome MEN 2A.
  
  
  METHODS
  We describe a DNA sequence variation within the coding region of RET in two large unrelated kindreds with MEN 2A (with 83 and 42 persons affected) in which HD cosegregated with MEN 2A in seven patients. Mutational analysis was performed with a highly sensitive polymerase chain reaction-based denaturing gradient gel electrophoresis technique followed by direct sequencing of mutants.
  
  
  RESULTS
  Genetic analysis by denaturing gradient gel electrophoresis detected mutant bands in RET exon 10 in patients with MEN 2A from both kindreds. Direct DNA sequencing of mutants revealed a thymine-to-adenine base change in codon 618, resulting in a cysteine-to-serine substitution. The identical mutation was present in all seven children with HD. Of these children five underwent thyroidectomy for C-cell abnormalities; one 3-year-old child is awaiting thyroid surgery, and the remaining patient died at age of 12 weeks.
  
  
  CONCLUSIONS
  The RET codon 618 Ser mutation could predispose patients with MEN 2A to HD. RET may assume a critical role in embryologic enteric nerve migration and tumorigenesis of cells from neural crest lineage.
authors.affiliation: Department of Surgery, University of Michigan, School of Medicine, Ann Arbor, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Borst
authors.forename: J M
authors.initials: JM
authors.lastname: VanCamp
authors.forename: M L
authors.initials: ML
authors.lastname: Peacock
authors.forename: R A
authors.initials: RA
authors.lastname: Decker
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D003062:Codon; D004252:DNA Mutational Analysis; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000032:analysis; D029721:Drosophila Proteins; D005091:Exons; D005260:Female; D014644:Genetic Variation; D006627:Hirschsprung Disease / Q000150:complications / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D018813:Multiple Endocrine Neoplasia Type 2a / Q000150:complications / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret; D011519:Proto-Oncogenes; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D017384:Sequence Deletion; D012694:Serine
chemical_list: D003062:Codon; D017931:DNA Primers; D004273:DNA, Neoplasm; D029721:Drosophila Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D012694:Serine; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila