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Gene Review

GLI3  -  GLI family zinc finger 3

Homo sapiens

Synonyms: ACLS, GCPS, GLI3 form of 190 kDa, GLI3 full length protein, GLI3-190, ...
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Disease relevance of GLI3


Psychiatry related information on GLI3

  • These data show that GLI3 mutations in humans mimic functional effects of the Drosophila ci gene and correlate with the distinct effects of these mutations on human development [6].
  • The primary endpoints were the physical and mental health summary scores (PHS; MHS) of the MOS-HIV as well as a global visual analogue scale (VAS) score [7].
  • PHS updates smoking cessation guideline [8].
  • Here, we describe a family with two affected children manifesting severe PHS with mental retardation, behavioral problems, and intractable seizures [9].
  • The primary target criteria were self-assessment of pain tolerability prior to the start of acupuncture and after the end of treatment, and pain intensity (GCPS) over time [10].

High impact information on GLI3

  • PAPP-A is a new candidate marker of unstable angina and acute myocardial infarction [11].
  • PAPP-A levels correlated with levels of C-reactive protein and free IGF-I, but not with markers of myocardial injury (troponin I and the MB isoform of creatine kinase) [11].
  • This disorder is inherited as an autosomal dominant trait and has been mapped to 7p13 (S. Kang et al. Autosomal dominant Pallister-Hall syndrome maps to 7p13. Am. J. Hum. Genet. 59, A81 (1996)), co-localizing the PHS locus and the GLI3 zinc finger transcription factor gene [12].
  • These data implicate mutations in GLI3 as the cause of autosomal dominant PHS, and suggest that frameshift mutations of the GLI3 transcription factor gene can alter the development of multiple organ systems in vertebrates [12].
  • Mutation in GLI3 in postaxial polydactyly type A [13].

Chemical compound and disease context of GLI3


Biological context of GLI3

  • A previously identified fragment of GLI3 genomic DNA was used to localize GLI3 to chromosome 7p13 and to isolate cDNA clones [17].
  • Point mutations in human GLI3 cause Greig syndrome [18].
  • However, cyclopamine failed to decrease Gli1 and Gli2 expression and branching morphogenesis in Gli3-deficient embryonic kidney tissue [19].
  • GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome [12].
  • These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis [20].

Anatomical context of GLI3

  • Two additional cell lines both having one methylated SMO allele and expressing mutant SMO did not express GLI3 [5].
  • Here we report a child with agenesis of the corpus callosum and severe retardation, both cardinal features of ACS and rare in GCPS, who has a mutation in GLI3 [21].
  • Other recent studies verified the presence of PAPP-A mRNA in granulosa cells of humans, monkeys, cattle, mice, and pigs [22].
  • This protease activity has recently been ascribed to serine metalloprotease(s), including pregnancy-associated plasma protein-A (PAPP-A), which was first detected in human follicular fluid nearly 20 yr ago [22].
  • We confirmed the protease to be pregnancy-associated plasma protein A (PAPP-A) by immunoblotting with an antibody against human PAPP-A/proMBP (pro form of eosinophil major basic protein) complex [23].

Associations of GLI3 with chemical compounds

  • However, single or double residue substitutions generally have a modest effect on PAPP-A heparin binding assessed by chromatography, but cell surface adhesion was critically reduced by several of these substitutions, emphasizing the relevance of analysis by flow cytometry [24].
  • Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function [25].
  • Upon in vitro decidualization of endometrial stromal cells with progesterone, PAPP-A levels in CM increased nearly 9-fold without a concomitant change in proMBP [26].
  • PAPP-A was barely detectable in conditioned media (CM) from granulosa derived from </=9 mm androgen-dominant follicles, but was secreted by cultured granulosa from estrogen-dominant follicles >/=9 mm, coincident with dominant follicle selection, and by luteinizing granulosa [27].
  • An inhibitor of p38 activation (SB203580) had no effect on TNFalpha- or IL-1beta-stimulated PAPP-A expression [28].

Physical interactions of GLI3


Regulatory relationships of GLI3

  • PHS mutant protein (GLI3-PHS) localizes to the nucleus and represses GLI3-activated PTCH1 expression, which is similar to Ci75 [6].
  • Since FBXW11 is relatively highly expressed in fetal brain and is directly involved in proteolytic processing of GLI3, we propose FBXW11 as the most likely candidate gene for the HPE and prexial polydactyly phenotype [30].

Other interactions of GLI3

  • By contrast, treatment of embryonic kidney explants with cyclopamine decreased GLI1 and/or GLI2 binding, and induced binding of GLI3 [19].
  • GLI1 and GLI2 are primarily transcriptional activators of Hedgehog target genes, while GLI3 is primarily a transcriptional repressor of Hedgehog targets [31].
  • Moreover, a strong repression of both basal and induced PTCH1 transcription was observed following expression of a truncated version of GLI3 [32].
  • We have been able to show hemizygosity for the genes of INHBA, IGFBP1 and GLI3 in both patients and therefore can give the chromosomal assignment 7p12.3-p13 [33].
  • Our results suggest that expression of wild-type SMO is required for expression of GLI3 by a mechanism that is independent of conventional Hedgehog signalling [5].

Analytical, diagnostic and therapeutic context of GLI3

  • Sequence analysis of these clones and identification of the GLI3 protein by using polyclonal antisera demonstrated that GLI3 encodes a protein of 1,596 amino acids and an apparent molecular mass of 190 kilodaltons [17].
  • Binding to the unknown, natural cell surface receptor of PAPP-A, assessed by flow cytometry, also depends on residues of these three basic clusters [24].
  • Using heparin affinity chromatography, commonly employed in such studies, we define three clusters of arginines and lysines of CCP3, which are important for the interaction of PAPP-A with heparin [24].
  • Based on site-directed mutagenesis, we here delineate the PAPP-A GAG-binding site in the C-terminal modules CCP3 and CCP4 [24].
  • Cultured first and second trimester human trophoblasts (n = 5) secreted PAPP-A into CM with mean +/- SEM levels of 172.4 +/- 32.8 mIU/liter.10(5) cells, determined by specific ELISA [26].


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  2. Acute lymphoblastic leukemia in a patient with Greig cephalopolysyndactyly and interstitial deletion of chromosome 7 del(7)(p11.2 p14) involving the GLI3 and ZNFN1A1 genes. Mendoza-Londono, R., Kashork, C.D., Shaffer, L.G., Krance, R., Plon, S.E. Genes Chromosomes Cancer (2005) [Pubmed]
  3. Boy with syndactylies, macrocephaly, and severe skeletal dysplasia: not a new syndrome, but two dominant mutations (GLI3 E543X and COL2A1 G973R) in the same individual. Sobetzko, D., Eich, G., Kalff-Suske, M., Grzeschik, K.H., Superti-Furga, A. Am. J. Med. Genet. (2000) [Pubmed]
  4. GLI3 is not mutated commonly in sporadic medulloblastomas. Erez, A., Ilan, T., Amariglio, N., Muler, I., Brok-Simoni, F., Rechavi, G., Izraeli, S. Cancer (2002) [Pubmed]
  5. Functional Smoothened is required for expression of GLI3 in colorectal carcinoma cells. Zhu, Y., James, R.M., Peter, A., Lomas, C., Cheung, F., Harrison, D.J., Bader, S.A. Cancer Lett. (2004) [Pubmed]
  6. GLI3 mutations in human disorders mimic Drosophila cubitus interruptus protein functions and localization. Shin, S.H., Kogerman, P., Lindström, E., Toftgárd, R., Biesecker, L.G. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  7. Quality of life outcomes of saquinavir, zalcitabine and combination saquinavir plus zalcitabine therapy for adults with advanced HIV infection with CD4 counts between 50 and 300 cells/mm3. Revicki, D.A., Swartz, C., Wu, A.W., Haubrich, R., Collier, A.C. Antivir. Ther. (Lond.) (1999) [Pubmed]
  8. PHS updates smoking cessation guideline. Morey, S.S. American family physician. (2001) [Pubmed]
  9. Gonadal mosaicism in severe Pallister-Hall syndrome. Ng, D., Johnston, J.J., Turner, J.T., Boudreau, E.A., Wiggs, E.A., Theodore, W.H., Biesecker, L.G. Am. J. Med. Genet. A (2004) [Pubmed]
  10. Long-term improvement in pain coping for cLBP and gonarthrosis patients following body needle acupuncture: a prospective cohort study. Kukuk, P., Lungenhausen, M., Molsberger, A., Endres, H.G. Eur. J. Med. Res. (2005) [Pubmed]
  11. Pregnancy-associated plasma protein A as a marker of acute coronary syndromes. Bayes-Genis, A., Conover, C.A., Overgaard, M.T., Bailey, K.R., Christiansen, M., Holmes, D.R., Virmani, R., Oxvig, C., Schwartz, R.S. N. Engl. J. Med. (2001) [Pubmed]
  12. GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Kang, S., Graham, J.M., Olney, A.H., Biesecker, L.G. Nat. Genet. (1997) [Pubmed]
  13. Mutation in GLI3 in postaxial polydactyly type A. Radhakrishna, U., Wild, A., Grzeschik, K.H., Antonarakis, S.E. Nat. Genet. (1997) [Pubmed]
  14. Mediator modulates gli3-dependent sonic hedgehog signaling. Zhou, H., Kim, S., Ishii, S., Boyer, T.G. Mol. Cell. Biol. (2006) [Pubmed]
  15. Serum screening for Down's syndrome between 8 and 14 weeks of pregnancy. International Prenatal Screening Research Group. Wald, N.J., George, L., Smith, D., Densem, J.W., Petterson, K. British journal of obstetrics and gynaecology. (1996) [Pubmed]
  16. Hemodynamic responses of broiler pulmonary vasculature to intravenously infused serotonin. Chapman, M.E., Wideman, R.F. Poult. Sci. (2002) [Pubmed]
  17. GLI3 encodes a 190-kilodalton protein with multiple regions of GLI similarity. Ruppert, J.M., Vogelstein, B., Arheden, K., Kinzler, K.W. Mol. Cell. Biol. (1990) [Pubmed]
  18. Point mutations in human GLI3 cause Greig syndrome. Wild, A., Kalff-Suske, M., Vortkamp, A., Bornholdt, D., König, R., Grzeschik, K.H. Hum. Mol. Genet. (1997) [Pubmed]
  19. GLI3-dependent transcriptional repression of Gli1, Gli2 and kidney patterning genes disrupts renal morphogenesis. Hu, M.C., Mo, R., Bhella, S., Wilson, C.W., Chuang, P.T., Hui, C.C., Rosenblum, N.D. Development (2006) [Pubmed]
  20. Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations. Johnston, J.J., Olivos-Glander, I., Killoran, C., Elson, E., Turner, J.T., Peters, K.F., Abbott, M.H., Aughton, D.J., Aylsworth, A.S., Bamshad, M.J., Booth, C., Curry, C.J., David, A., Dinulos, M.B., Flannery, D.B., Fox, M.A., Graham, J.M., Grange, D.K., Guttmacher, A.E., Hannibal, M.C., Henn, W., Hennekam, R.C., Holmes, L.B., Hoyme, H.E., Leppig, K.A., Lin, A.E., Macleod, P., Manchester, D.K., Marcelis, C., Mazzanti, L., McCann, E., McDonald, M.T., Mendelsohn, N.J., Moeschler, J.B., Moghaddam, B., Neri, G., Newbury-Ecob, R., Pagon, R.A., Phillips, J.A., Sadler, L.S., Stoler, J.M., Tilstra, D., Walsh Vockley, C.M., Zackai, E.H., Zadeh, T.M., Brueton, L., Black, G.C., Biesecker, L.G. Am. J. Hum. Genet. (2005) [Pubmed]
  21. De novo GLI3 mutation in acrocallosal syndrome: broadening the phenotypic spectrum of GLI3 defects and overlap with murine models. Elson, E., Perveen, R., Donnai, D., Wall, S., Black, G.C. J. Med. Genet. (2002) [Pubmed]
  22. Proteolytic degradation of insulin-like growth factor binding proteins by ovarian follicles: a control mechanism for selection of dominant follicles. Spicer, L.J. Biol. Reprod. (2004) [Pubmed]
  23. IGF-I differentially regulates IGF-binding protein expression in primary mammary fibroblasts and epithelial cells. Fleming, J.M., Leibowitz, B.J., Kerr, D.E., Cohick, W.S. J. Endocrinol. (2005) [Pubmed]
  24. Cell surface adhesion of pregnancy-associated plasma protein-A is mediated by four clusters of basic residues located in its third and fourth CCP module. Weyer, K., Overgaard, M.T., Laursen, L.S., Nielsen, C.G., Schmitz, A., Christiansen, M., Sottrup-Jensen, L., Giudice, L.C., Oxvig, C. Eur. J. Biochem. (2004) [Pubmed]
  25. Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. Haycraft, C.J., Banizs, B., Aydin-Son, Y., Zhang, Q., Michaud, E.J., Yoder, B.K. PLoS Genet. (2005) [Pubmed]
  26. Identification and regulation of the IGFBP-4 protease and its physiological inhibitor in human trophoblasts and endometrial stroma: evidence for paracrine regulation of IGF-II bioavailability in the placental bed during human implantation. Giudice, L.C., Conover, C.A., Bale, L., Faessen, G.H., Ilg, K., Sun, I., Imani, B., Suen, L.F., Irwin, J.C., Christiansen, M., Overgaard, M.T., Oxvig, C. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  27. Pregnancy-associated plasma protein-a is the insulin-like growth factor binding protein-4 protease secreted by human ovarian granulosa cells and is a marker of dominant follicle selection and the corpus luteum. Conover, C.A., Faessen, G.F., Ilg, K.E., Chandrasekher, Y.A., Christiansen, M., Overgaard, M.T., Oxvig, C., Giudice, L.C. Endocrinology (2001) [Pubmed]
  28. Stress-activated signaling pathways mediate the stimulation of pregnancy-associated plasma protein-A expression in cultured human fibroblasts. Resch, Z.T., Oxvig, C., Bale, L.K., Conover, C.A. Endocrinology (2006) [Pubmed]
  29. Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. Dai, P., Akimaru, H., Tanaka, Y., Maekawa, T., Nakafuku, M., Ishii, S. J. Biol. Chem. (1999) [Pubmed]
  30. Holoprosencephaly and preaxial polydactyly associated with a 1.24 Mb duplication encompassing FBXW11 at 5q35.1. Koolen, D.A., Herbergs, J., Veltman, J.A., Pfundt, R., van Bokhoven, H., Stroink, H., Sistermans, E.A., Brunner, H.G., Geurts van Kessel, A., de Vries, B.B. J. Hum. Genet. (2006) [Pubmed]
  31. Asymmetric expression of Gli transcription factors in Hensen's node. Granata, A., Quaderi, N.A. Gene Expr. Patterns (2005) [Pubmed]
  32. Expression of the PTCH1 tumor suppressor gene is regulated by alternative promoters and a single functional Gli-binding site. Agren, M., Kogerman, P., Kleman, M.I., Wessling, M., Toftgård, R. Gene (2004) [Pubmed]
  33. Localization of genes and anonymous DNA probes on the short arm of chromosome 7. Wagner, K., Kroisel, P.M., Rosenkranz, W. Mamm. Genome (1992) [Pubmed]
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