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Eating disorder predisposition is associated with ESRRA and HDAC4 mutations
Huxing Cui, … , Chao Xing, Michael Lutter
Huxing Cui, … , Chao Xing, Michael Lutter
Published October 8, 2013
Citation Information: J Clin Invest. 2013;123(11):4706-4713. https://doi.org/10.1172/JCI71400.
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Research Article Genetics

Eating disorder predisposition is associated with ESRRA and HDAC4 mutations

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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.

Authors

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

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Figure 1

Identification of R188Q mutation in ESRRA in the AN-1 family.

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Identification of R188Q mutation in ESRRA in the AN-1 family.
(A) Pedigr...
(A) Pedigree of the AN-1 family with the arrow highlighting the proband (first identified family member) and the stars marking the two individuals selected for whole-genome sequencing. (B) Linkage analysis for chromosome 11. (C) Amino acid alignment of arginine 188 of ESRRA (underlined) in different species and in the human estrogen receptor family. Lod, logarithm (base 10) of odds; ESR1, estrogen receptor α; ESRRB, estrogen-related receptor β; ESRRG, estrogen-related receptor γ.
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