PUBLICATION
A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk
- Authors
- Emison, E.S., McCallion, A.S., Kashuk, C.S., Bush, R.T., Grice, E., Lin, S., Portnoy, M.E., Cutler, D.J., Green, E.D., and Chakravarti, A.
- ID
- ZDB-PUB-050428-1
- Date
- 2005
- Source
- Nature 434: 857-863 (Journal)
- Registered Authors
- McCallion, Andy
- Keywords
- none
- MeSH Terms
-
- Hirschsprung Disease/genetics*
- Animals
- Enhancer Elements, Genetic/genetics*
- Humans
- Receptor Protein-Tyrosine Kinases/genetics*
- Female
- Mutation/genetics*
- Genomics
- Sex Characteristics*
- Genetic Predisposition to Disease/genetics*
- Gene Frequency
- Mice
- Male
- Polymorphism, Single Nucleotide/genetics
- Molecular Sequence Data
- Proto-Oncogene Proteins/genetics*
- Haplotypes
- Proto-Oncogene Proteins c-ret
- Linkage Disequilibrium/genetics
- PubMed
- 15829955 Full text @ Nature
Citation
Emison, E.S., McCallion, A.S., Kashuk, C.S., Bush, R.T., Grice, E., Lin, S., Portnoy, M.E., Cutler, D.J., Green, E.D., and Chakravarti, A. (2005) A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk. Nature. 434:857-863.
Abstract
The identification of common variants that contribute to the genesis of human inherited disorders remains a significant challenge. Hirschsprung disease (HSCR) is a multifactorial, non-mendelian disorder in which rare high-penetrance coding sequence mutations in the receptor tyrosine kinase RET contribute to risk in combination with mutations at other genes. We have used family-based association studies to identify a disease interval, and integrated this with comparative and functional genomic analysis to prioritize conserved and functional elements within which mutations can be sought. We now show that a common non-coding RET variant within a conserved enhancer-like sequence in intron 1 is significantly associated with HSCR susceptibility and makes a 20-fold greater contribution to risk than rare alleles do. This mutation reduces in vitro enhancer activity markedly, has low penetrance, has different genetic effects in males and females, and explains several features of the complex inheritance pattern of HSCR. Thus, common low-penetrance variants, identified by association studies, can underlie both common and rare diseases.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping