Eating disorders such as anorexia nervosa and bulimia nervosa are primarily cultural but the search is also on for a biological disposition that would confirm it outside primarily middle-class white girls in developed nations. Eating disorders are found in families but no genetic basis for predisposition has been identified.
In a recent paper, researchers identified genetic mutations in two such families affected by eating disorders. Mutations were linked to the same transcriptional pathway using 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 while 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. The mutant forms of both ERRSA and HDAC4 resulted in reduced expression of known ERRSA-dependent genes.
They conclude that individuals with mutations that reduce ESRRA activity have an increased risk of developing eating disorders.
Citation: 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, 'Eating disorder predisposition is associated with ESRRA and HDAC4 mutations', The Journal of Clinical Investigation 2013; doi:10.1172/JCI71400