Eating disorder predisposition is associated  with ESRRA and HDAC4 mutations.
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.
Huxing
H
Cui
Jarrette
J
Moore
Sunbola S
SS
Ashimi
Brittany L
BL
Mason
Jordan N
JN
Drawbridge
Shizhong
S
Han
Benjamin
B
Hing
Abigail
A
Matthews
Carrie J
CJ
McAdams
Benjamin W
BW
Darbro
Andrew A
AA
Pieper
David A
DA
Waller
Chao
C
Xing
Michael
M
Lutter
D000595:Amino Acid Sequence; D000818:Animals; D000856:Anorexia Nervosa / Q000235:genetics / Q000378:metabolism; D052018:Bulimia Nervosa / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D001068:Feeding and Eating Disorders / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D010375:Pedigree; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic; D000097983:ERRalpha Estrogen-Related Receptor
D006655:Histone Deacetylases; D050505:Mutant Proteins; D011960:Receptors, Estrogen; D011994:Recombinant Proteins; D012097:Repressor Proteins; D000097983:ERRalpha Estrogen-Related Receptor; C400300:HDAC4 protein, human; C498618:Hdac5 protein, mouse