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 gla nd 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 protei n lacking the DNA-binding homeodomain, have been identified in humans. Thes e mutations were identified in patients with retarded growth and combined p ituitary hormone deficiency and also abnormal neck and cervical spine devel opment. For both the LHX3a and LHX3b isoforms, we compared the ability of w ild type and mutant LHX3 proteins to trans-activate pituitary genes, bind D NA recognition elements, and interact with partner proteins. The tyrosine m issense 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 hom eodomain do not bind DNA and do not induce transcription from pituitary gen es. These studies demonstrate that mutations in the LHX3 isoforms impair th eir gene regulatory functions and support the hypothesis that defects in th e LHX3 gene cause complex pituitary disease in humans. (C) 2001 Elsevier Sc ience B.V. All rights reserved.