LHX3 transcription factor mutations associated with combined pituitary hormone deficiency impair the activation of pituitary target genes.
The Lhx3 LIM homeodomain transcription factor is critical for pituitary gland formation and specification of the anterior pituitary hormone-secreting cell types. Two mutations in LHX3, a missense mutation changing a tyrosine to a cysteine and an intragenic deletion that results in a truncated protein lacking the DNA-binding homeodomain, have been identified in humans. These mutations were identified in patients with retarded growth and combined pituitary hormone deficiency and also abnormal neck and cervical spine development. For both the LHX3a and LHX3b isoforms, we compared the ability of wild type and mutant LHX3 proteins to trans-activate pituitary genes, bind DNA recognition elements, and interact with partner proteins. The tyrosine missense mutation inhibits the ability of LHX3 to induce transcription from selected target genes but does not prevent DNA binding and interaction with partner proteins such as NLI and Pit-1. Mutant LHX3 proteins lacking a homeodomain do not bind DNA and do not induce transcription from pituitary genes. These studies demonstrate that mutations in the LHX3 isoforms impair their gene regulatory functions and support the hypothesis that defects in the LHX3 gene cause complex pituitary disease in humans.
Department of Biology, Indiana University-Purdue University Indianapolis, 723 West Michigan Street, 46202-5132, Indianapolis, IN, USA.
K W
KW
Sloop
G E
GE
Parker
K R
KR
Hanna
H A
HA
Wright
S J
SJ
Rhodes
D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D060850:LIM-Homeodomain Proteins; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010902:Pituitary Gland / Q000378:metabolism*; D010907:Pituitary Hormones / Q000172:deficiency*; D010957:Plasmids / Q000235:genetics; D011388:Prolactin / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; C094898:Lhx3 protein; D010907:Pituitary Hormones; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D011388:Prolactin; D004247:DNA; D008156:Luciferases