Eating disorder predisposition is associated with ESRRA and HDAC4 mutations

Huxing Cui, Jarrette Moore, Sunbola S. Ashimi, Brittany L. Mason, Jordan N. Drawbridge, Shizhong Han, Benjamin Hing, Abigail Matthews, Carrie J. McAdams, Benjamin W. Darbro, Andrew A. Pieper, David A. Waller, Chao Xing, Michael Lutter

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)4706-4713
Number of pages8
JournalJournal of Clinical Investigation
Volume123
Issue number11
DOIs
StatePublished - Nov 1 2013

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Histone Deacetylases
Estrogen Receptors
Mutation
Missense Mutation
Genes
Exome
Bulimia Nervosa
Chromosome Mapping
Anorexia Nervosa
Psychopathology
HeLa Cells
Feeding and Eating Disorders
Genome
DNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cui, H., Moore, J., Ashimi, S. S., Mason, B. L., Drawbridge, J. N., Han, S., ... Lutter, M. (2013). Eating disorder predisposition is associated with ESRRA and HDAC4 mutations. Journal of Clinical Investigation, 123(11), 4706-4713. https://doi.org/10.1172/JCI71400

Eating disorder predisposition is associated with ESRRA and HDAC4 mutations. / Cui, Huxing; Moore, Jarrette; Ashimi, Sunbola S.; Mason, Brittany L.; Drawbridge, Jordan N.; Han, Shizhong; Hing, Benjamin; Matthews, Abigail; McAdams, Carrie J.; Darbro, Benjamin W.; Pieper, Andrew A.; Waller, David A.; Xing, Chao; Lutter, Michael.

In: Journal of Clinical Investigation, Vol. 123, No. 11, 01.11.2013, p. 4706-4713.

Research output: Contribution to journalArticle

Cui, H, Moore, J, Ashimi, SS, Mason, BL, Drawbridge, JN, Han, S, Hing, B, Matthews, A, McAdams, CJ, Darbro, BW, Pieper, AA, Waller, DA, Xing, C & Lutter, M 2013, 'Eating disorder predisposition is associated with ESRRA and HDAC4 mutations', Journal of Clinical Investigation, vol. 123, no. 11, pp. 4706-4713. https://doi.org/10.1172/JCI71400
Cui, Huxing ; Moore, Jarrette ; Ashimi, Sunbola S. ; Mason, Brittany L. ; Drawbridge, Jordan N. ; Han, Shizhong ; Hing, Benjamin ; Matthews, Abigail ; McAdams, Carrie J. ; Darbro, Benjamin W. ; Pieper, Andrew A. ; Waller, David A. ; Xing, Chao ; Lutter, Michael. / Eating disorder predisposition is associated with ESRRA and HDAC4 mutations. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 11. pp. 4706-4713.
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