Access
To read this story in full you will need to login or make a payment (see right).
Article
Nature 434, 857-863 (14 April 2005) | doi:10.1038/nature03467; Received 14 December 2004; Accepted 15 February 2005
Open Innovation Challenges
-
Single-cell Analysis Platform
This Challenge is looking for novel approaches to analyzing changes at a single-cell level. This is...
-
Methods of Modeling Adaptation in Populations
The analysis of adaptation with a population is a frequently encountered computational modeling scen...
nature jobs
Postdoctoral Position Studying Immunology
- The University of Chicago
- Chicago, IL
Tenure-Track Faculty Positions
- The University of Texas Southwestern Medical Center
- Dallas, TX 75390-9148 United States
A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk
Eileen Sproat Emison1,4, Andrew S. McCallion1,4, Carl S. Kashuk1, Richard T. Bush1, Elizabeth Grice1, Shin Lin1, Matthew E. Portnoy2, David J. Cutler1, Eric D. Green2,3 & Aravinda Chakravarti1
- McKusick – Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
- Genome Technology Branch and
- NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
- These authors contributed equally to this work
Correspondence to: Aravinda Chakravarti1
Correspondence and requests for materials should be addressed to A.C. (Email: aravinda@jhmi.edu).
GenBank accession numbers for genomic sequences reported in this paper are as follows: AC125509 and AC125512 (baboon), AC124166 (cat), AC138567 (chicken), RP43-171H18 (chimpanzee), AC124163 and AC124164 (cow), AC123973 (dog), AC124911 and AC125500 (fugu), AC122156 and AC124165 (pig), AC114881 (rat), AC135546 (tetra) and AC124155 (zebrafish).
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.
To read this story in full you will need to login or make a payment (see right).
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
NEWS AND VIEWS
Dissecting Hirschsprung diseaseNature Genetics News and Views (01 May 2002)
Wither polygenic inheritance: Mapping Hirschsprung diseaseNature Genetics News and Views (01 Aug 1993)
See all 3 matches for News And ViewsRESEARCH
Mapping of a Hirschsprung's disease locus in 3p21European Journal of Human Genetics Article Response
Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung diseaseNature Genetics Article (01 Oct 2002)
See all 29 matches for Research
