Journal article
Eating disorder predisposition is associated with ESRRA and HDAC4 mutations
The Journal of clinical investigation, Vol.123(11), pp.4706-4713
11/01/2013
DOI: 10.1172/JCI71400
PMCID: PMC3809805
PMID: 24216484
Abstract
Anorexia nervosa and bulimia nervosa are common and severe eating disorders (EDs) of unknown etiology. Although genetic factors have been implicated in the psychopathology of EDs, a clear biological pathway has not been delineated. DNA from two large families affected by EDs was collected, and mutations segregating with illness were identified by whole-genome sequencing following linkage mapping or by whole-exome sequencing. In the first family, analysis of twenty members across three generations identified a rare missense mutation in the estrogen-related receptor α (
ESRRA
) gene that segregated with illness. In the second family, analysis of eight members across four generations identified a missense mutation in the histone deacetylase 4 (
HDAC4
) gene that segregated with illness. ESRRA and HDAC4 were determined to interact both in vitro in HeLa cells and in vivo in mouse cortex. Transcriptional analysis revealed that HDAC4 potently represses the expression of known ESRRA-induced target genes. Biochemical analysis of candidate mutations revealed that the identified
ESRRA
mutation decreased its transcriptional activity, while the
HDAC4
mutation increased transcriptional repression of ESRRA. Our findings suggest that mutations that result in decreased ESRRA activity increase the risk of developing EDs.
Details
- Title: Subtitle
- Eating disorder predisposition is associated with ESRRA and HDAC4 mutations
- Creators
- Huxing Cui - Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, Iowa, USAJarrette Moore - Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, Iowa, USASunbola S Ashimi - Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, Iowa, USABrittany L Mason - Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, Iowa, USAJordan N Drawbridge - Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, Iowa, USAShizhong Han - Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, Iowa, USABenjamin Hing - Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, Iowa, USAAbigail Matthews - Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, Iowa, USACarrie J McAdams - Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, Iowa, USABenjamin W Darbro - Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, Iowa, USAAndrew A Pieper - Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, Iowa, USADavid A Waller - Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, Iowa, USAChao Xing - Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, Iowa, USAMichael Lutter - Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.123(11), pp.4706-4713
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/JCI71400
- PMID
- 24216484
- PMCID
- PMC3809805
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Language
- English
- Date published
- 11/01/2013
- Academic Unit
- Molecular Physiology and Biophysics; Psychiatry; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology
- Record Identifier
- 9984040271702771
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