Mutations in the LHX3 gene cause dysregulation of pituitary and neural target genes that reflect patient phenotypes

Jesse J. Savage, Chad S. Hunter, Surilda L. Clark-Sturm, Tanya M. Jacob, Roland W. Pfaeffle, Simon J. Rhodes

Research output: Contribution to journalArticle

19 Scopus citations


The LHX3 LIM-homeodomain transcription factor is required for correct development of the mammalian pituitary gland and spinal motoneurons. Mutations in the LHX3 gene underlie complex diseases featuring combined anterior pituitary hormone deficiency and, in specific cases, loss of neck rotation considered to result from nervous system abnormalities. The molecular basis for LHX3 protein actions in both normal and aberrant pituitary and nervous system development is poorly understood. In this study, the gene regulatory abilities of mutant LHX3 proteins associated with distinct types of diseases (LHX3a A210V, LHX3a E173Ter, and LHX3a W224Ter) were investigated. The capacity of these proteins to activate pituitary hormone and transcription factor gene promoters, nervous system target genes, and to localize to the nucleus of pituitary cells was measured. Consistent with the symptoms of patients with these mutations, the abnormal proteins displayed diminished capacities to activate the promoters of genes expressed in the pituitary gland. On nervous system promoters, several mutant proteins retained some activity. The ability of the mutant proteins to concentrate in the nucleus of pituitary cells was correlated with the retention of defined nuclear localization signals in the protein sequence, except for the E173Ter protein which unexpectedly localizes to the nucleus, likely due to the insertion of cryptic nuclear localization signals by a frame shift caused by the mutation. This study extends the molecular characterization of the severe neuroendocrine diseases associated with LHX3 gene mutations.

Original languageEnglish (US)
Pages (from-to)44-51
Number of pages8
Issue number1-2
StatePublished - Oct 1 2007


  • Development
  • Growth
  • Homeodomain
  • Hormone
  • LIM

ASJC Scopus subject areas

  • Genetics

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