Enhanced repression by HESX1 as a cause of hypopituitarism and septooptic dysplasia.
HESX1 is a paired-like homeodomain transcription factor that functions as a repressor of PROP1-mediated gene stimulation. Mutations in HESX1 have been implicated in cases of septooptic dysplasia and congenital hypopituitarism. All mutations in HESX1 identified to date have resulted in impaired DNA binding and defective HESX1 action. We have identified a novel HESX1 mutation in genomic nucleotide position 1684 (g.1684delG), which results in a mutant protein with increased DNA binding. In turn, this mutation causes increased repression of PROP1-dependent gene activity. These data suggest that enhancement of transcriptional repression during pituitary organogenesis is a novel mechanism for the development of congenital pituitary disorders.
Cohen
Ronald N
RN
Section of Endocrinology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA. roncohen@medicine.bsd.uchicago.edu
Cohen
Laurie E
LE
Botero
Diego
D
Yu
Christine
C
Sagar
Angela
A
Jurkiewicz
Magdalena
M
Radovick
Sally
S
D051792:Basic Helix-Loop-Helix Proteins; D002460:Cell Line; D015870:Gene Expression / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007018:Hypopituitarism / Q000151:congenital / Q000235:genetics* / Q000503:physiopathology*; D010641:Phenotype; D017354:Point Mutation; D025962:Septo-Optic Dysplasia / Q000151:congenital / Q000235:genetics* / Q000503:physiopathology*; D000072056:Transcription Factor HES-1; D014158:Transcription, Genetic / Q000502:physiology
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D000072056:Transcription Factor HES-1; C489736:HESX1 protein, human; C102134:Prophet of Pit-1 protein; C078493:HES1 protein, human