Mammal-restricted elements predispose human RET to folding impairment by HSCR mutations

Nat Struct Mol Biol. 2010 Jun;17(6):726-31. doi: 10.1038/nsmb.1808. Epub 2010 May 16.


The maturation of human RET is adversely affected by a range of missense mutations found in patients with Hirschsprung's disease (HSCR), a complex multigenic disease. Here we show that two N-terminal cadherin-like domains, CLD1 and CLD2 (CLD(1-2)), from human RET adopt a clam-shell arrangement distinct from that of classical cadherins. CLD1 structural elements and disulfide composition are unique to mammals, indicating an unexpected structural diversity within higher and lower vertebrate RET CLD regions. We identify two unpaired cysteines that predispose human RET to maturation impediments in the endoplasmic reticulum and establish a quantitative cell-based RET maturation assay that offers a biochemical correlate of HSCR disease severity. Our findings provide a key conceptual framework and means of testing and predicting genotype-phenotype correlations in HSCR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cysteine / chemistry
  • Endoplasmic Reticulum / metabolism
  • Genetic Association Studies
  • Hirschsprung Disease / genetics*
  • Hirschsprung Disease / metabolism*
  • Humans
  • Mammals
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation, Missense*
  • Phylogeny
  • Protein Folding
  • Protein Interaction Domains and Motifs
  • Protein Multimerization
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins c-ret / chemistry*
  • Proto-Oncogene Proteins c-ret / genetics*
  • Proto-Oncogene Proteins c-ret / metabolism
  • Sequence Homology, Amino Acid
  • Static Electricity


  • Proto-Oncogene Proteins c-ret
  • RET protein, human
  • Cysteine