LHX3 transcription factor mutations associated with combined pituitary hormone deficiency impair the activation of pituitary target genes

Kyle W. Sloop, Gretchen E. Parker, Kimberly R. Hanna, Heather A. Wright, Simon Rhodes

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)61-69
Number of pages9
JournalGene
Volume265
Issue number1-2
DOIs
StatePublished - Mar 7 2001

Fingerprint

Transcription Factors
Mutation
Missense Mutation
Mutant Proteins
Genes
Tyrosine
DNA
Protein Isoforms
Pituitary Diseases
Anterior Pituitary Hormones
DNA-Binding Proteins
Pituitary Gland
Regulator Genes
Cysteine
Proteins
Spine
Neck
Combined Pituitary Hormone Deficiency
Growth

Keywords

  • Alpha glycoprotein subunit
  • Growth
  • Homeodomain
  • LIM
  • Prolactin

ASJC Scopus subject areas

  • Genetics

Cite this

LHX3 transcription factor mutations associated with combined pituitary hormone deficiency impair the activation of pituitary target genes. / Sloop, Kyle W.; Parker, Gretchen E.; Hanna, Kimberly R.; Wright, Heather A.; Rhodes, Simon.

In: Gene, Vol. 265, No. 1-2, 07.03.2001, p. 61-69.

Research output: Contribution to journalArticle

Sloop, Kyle W. ; Parker, Gretchen E. ; Hanna, Kimberly R. ; Wright, Heather A. ; Rhodes, Simon. / LHX3 transcription factor mutations associated with combined pituitary hormone deficiency impair the activation of pituitary target genes. In: Gene. 2001 ; Vol. 265, No. 1-2. pp. 61-69.
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