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Gene Review

LHX3  -  LIM homeobox 3

Homo sapiens

Synonyms: CPHD3, LIM homeobox protein 3, LIM/homeobox protein Lhx3, LIM3, M2-LHX3
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Disease relevance of LHX3

  • Thus, we hypothesized that mutations in one or both of the two human LHX3 isoforms are responsible for posterior pituitary ectopia associated with anterior pituitary hypopituitarism [1].
  • 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 [2].
  • Mutations in the human LHX3 gene are associated with severe hormone deficiency diseases [3].

Psychiatry related information on LHX3

  • Pathophysiology of syndromic combined pituitary hormone deficiency due to a LHX3 defect in light of LHX3 and LHX4 expression during early human development [4].

High impact information on LHX3

  • These LHX3 mutations consist of a missense mutation (Y116C) in the LIM2 domain at a phylogenetically conserved residue and an intragenic deletion predicting a severely truncated protein lacking the entire homeodomain [5].
  • A recent report has described a point mutation in the human LHX3 gene that is associated with a combined pituitary hormone disorder [6].
  • The mutation is predicted to lead to the replacement of a tyrosine residue with a cysteine in the second LIM domain of LHX3 [6].
  • Transfection assays using an expression vector for either full-length Lhx3 or a GAL4-Lhx3 LIM domain fusion provided evidence that the Lhx3 Y114C mutant has a decreased ability to stimulate transcription [6].
  • The findings provide insights into the mechanisms mediating transcriptional activation by Lhx3 and suggest that the observed phenotype of the human mutation probably involves reduced transcriptional activity of the mutant LHX3 [6].

Biological context of LHX3

  • Mutations of the proximal binding sites demonstrate their importance for LHX3 induction of the FSHbeta promoter and basal promoter activity in gonadotrope cells [7].
  • By comparative genomics using the human FSHbeta promoter, we demonstrate structural and functional conservation of promoter induction by LHX3 [7].
  • The patients with a LHX3 mutation display a CPHD phenotype, associated with a rigid cervical spine [4].
  • 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 [2].
  • In this study, we show that the LHX3 protein can be modified post-translationally by phosphorylation [8].

Anatomical context of LHX3

  • Using in situ hybridization, we show that LHX3 and LHX4 are expressed in the developing human pituitary and along the rostro-caudal length of the spinal cord; here, both transcripts are detected in the ventral part giving rise to motorneurons and interneurons [4].
  • LHX3 is a LIM homeodomain transcription factor with essential roles in pituitary and motor neuron development in mammals [8].
  • Characterization of the genomic organization and chromosomal localization of LHX3 will enable molecular evaluation and genetic diagnoses of pituitary diseases and central nervous system developmental disorders in humans [9].
  • In mice, the Lhx3 LIM homeodomain transcription factor is required for both structural development and cellular differentiation of the pituitary gland [1].
  • The determination of the somatotroph cell line is dependent on the transcription factors Lhx3, Prop-1, and Pit-1 [10].

Associations of LHX3 with chemical compounds


Physical interactions of LHX3

  • Six LHX3-binding sites were characterized within the FSHbeta promoter, including three within a proximal region that also mediates gene regulation by other transcription factors and activin [7].

Regulatory relationships of LHX3

  • We demonstrate that in both heterologous and pituitary gonadotrope cells, specific LHX3 isoforms activate the FSH beta-subunit promoter, but not the proximal LHbeta promoter [7].

Other interactions of LHX3

  • However, whereas LHX3 is expressed at all stages studied, LHX4 expression is transient, and, at 6 weeks of development, is stronger at the caudal than at the cervical level [4].
  • 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 [2].
  • LHX3 can serve as a substrate for protein kinase C and casein kinase II [8].
  • Here, using transient transfections combined with DNA/protein interaction assays, we have delineated cis-acting elements within the rat GnRH-R gene promoter that represent targets for the LIM-homeodomain (LIM-HD) proteins, Isl-1 and Lhx3 [11].

Analytical, diagnostic and therapeutic context of LHX3

  • Human patients and animal models with mutations in the LHX3 LIM-homeodomain transcription factor gene exhibit complex endocrine diseases, including reproductive disorders with loss of FSH [7].
  • Mobility shift assays demonstrated that the Lhx3 Y114C mutant is capable of binding DNA, although a decrease in the formation of a specific complex was observed [6].
  • Northern blot analysis of adult tissues showed that Lhx3 mRNA persists in the pituitary [12].
  • Immunohistochemistry revealed that Lhx3 was localized in fetal lung epithelial cells and pleiotrophin in the mesenchymal cells adjacent to the developing epithelium and blood vessel [13].


  1. Molecular analysis of LHX3 and PROP-1 in pituitary hormone deficiency patients with posterior pituitary ectopia. Sloop, K.W., Walvoord, E.C., Showalter, A.D., Pescovitz, O.H., Rhodes, S.J. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  2. LHX3 transcription factor mutations associated with combined pituitary hormone deficiency impair the activation of pituitary target genes. Sloop, K.W., Parker, G.E., Hanna, K.R., Wright, H.A., Rhodes, S.J. Gene (2001) [Pubmed]
  3. DNA recognition properties of the LHX3b LIM homeodomain transcription factor. Yaden, B.C., Savage, J.J., Hunter, C.S., Rhodes, S.J. Mol. Biol. Rep. (2005) [Pubmed]
  4. Pathophysiology of syndromic combined pituitary hormone deficiency due to a LHX3 defect in light of LHX3 and LHX4 expression during early human development. Sobrier, M.L., Attié-Bitach, T., Netchine, I., Encha-Razavi, F., Vekemans, M., Amselem, S. Gene Expr. Patterns (2004) [Pubmed]
  5. Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Netchine, I., Sobrier, M.L., Krude, H., Schnabel, D., Maghnie, M., Marcos, E., Duriez, B., Cacheux, V., Moers, A., Goossens, M., Grüters, A., Amselem, S. Nat. Genet. (2000) [Pubmed]
  6. A point mutation in the LIM domain of Lhx3 reduces activation of the glycoprotein hormone alpha-subunit promoter. Howard, P.W., Maurer, R.A. J. Biol. Chem. (2001) [Pubmed]
  7. Regulation of the follicle-stimulating hormone beta gene by the LHX3 LIM-homeodomain transcription factor. West, B.E., Parker, G.E., Savage, J.J., Kiratipranon, P., Toomey, K.S., Beach, L.R., Colvin, S.C., Sloop, K.W., Rhodes, S.J. Endocrinology (2004) [Pubmed]
  8. Serine/threonine/tyrosine phosphorylation of the LHX3 LIM-homeodomain transcription factor. Parker, G.E., West, B.E., Witzmann, F.A., Rhodes, S.J. J. Cell. Biochem. (2005) [Pubmed]
  9. Analysis of the human LHX3 neuroendocrine transcription factor gene and mapping to the subtelomeric region of chromosome 9. Sloop, K.W., Showalter, A.D., Von Kap-Herr, C., Pettenati, M.J., Rhodes, S.J. Gene (2000) [Pubmed]
  10. Genetic regulation of the embryology of the pituitary gland and somatotrophs. Cohen, L.E. Endocrine (2000) [Pubmed]
  11. The LIM-homeodomain proteins Isl-1 and Lhx3 act with steroidogenic factor 1 to enhance gonadotrope-specific activity of the gonadotropin-releasing hormone receptor gene promoter. Granger, A., Bleux, C., Kottler, M.L., Rhodes, S.J., Counis, R., Laverrière, J.N. Mol. Endocrinol. (2006) [Pubmed]
  12. Expression pattern of the murine LIM class homeobox gene Lhx3 in subsets of neural and neuroendocrine tissues. Zhadanov, A.B., Bertuzzi, S., Taira, M., Dawid, I.B., Westphal, H. Dev. Dyn. (1995) [Pubmed]
  13. Gene expression profiling identifies regulatory pathways involved in the late stage of rat fetal lung development. Weng, T., Chen, Z., Jin, N., Gao, L., Liu, L. Am. J. Physiol. Lung Cell Mol. Physiol. (2006) [Pubmed]
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