ZFIN ID: ZDB-PUB-060522-1
Phenotype-genotype correlation in Hirschsprung disease is illuminated by comparative analysis of the RET protein sequence
Kashuk, C.S., Stone, E.A., Grice, E.A., Portnoy, M.E., Green, E.D., Sidow, A., Chakravarti, A., and McCallion, A.S.
Date: 2005
Source: Proceedings of the National Academy of Sciences of the United States of America   102(25): 8949-8954 (Journal)
Registered Authors: Stone, Eric
Keywords: deleterious substitutions, evolutionary conservation, physicochemical properties
MeSH Terms:
  • Amino Acid Sequence
  • Evolution, Molecular*
  • Genotype
  • Hirschsprung Disease/genetics*
  • Humans
  • Molecular Sequence Data
  • Oncogene Proteins/chemistry
  • Oncogene Proteins/genetics*
  • Phenotype
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases/chemistry
  • Receptor Protein-Tyrosine Kinases/genetics*
  • Sequence Alignment
  • Sequence Homology, Amino Acid
PubMed: 15956201 Full text @ Proc. Natl. Acad. Sci. USA
The ability to discriminate between deleterious and neutral amino acid substitutions in the genes of patients remains a significant challenge in human genetics. The increasing availability of genomic sequence data from multiple vertebrate species allows inclusion of sequence conservation and physicochemical properties of residues to be used for functional prediction. In this study, the RET receptor tyrosine kinase serves as a model disease gene in which a broad spectrum (> or = 116) of disease-associated mutations has been identified among patients with Hirschsprung disease and multiple endocrine neoplasia type 2. We report the alignment of the human RET protein sequence with the orthologous sequences of 12 non-human vertebrates (eight mammalian, one avian, and three teleost species), their comparative analysis, the evolutionary topology of the RET protein, and predicted tolerance for all published missense mutations. We show that, although evolutionary conservation alone provides significant information to predict the effect of a RET mutation, a model that combines comparative sequence data with analysis of physiochemical properties in a quantitative framework provides far greater accuracy. Although the ability to discern the impact of a mutation is imperfect, our analyses permit substantial discrimination between predicted functional classes of RET mutations and disease severity even for a multigenic disease such as Hirschsprung disease.