Alternative titles; symbols
HGNC Approved Gene Symbol: GLI1
SNOMEDCT: 205135003; ICD10CM: Q69.1;
Cytogenetic location: 12q13.3 Genomic coordinates (GRCh38): 12:57,459,785-57,472,268 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.3 | Polydactyly, postaxial, type A8 | 618123 | Autosomal recessive | 3 |
| Polydactyly, preaxial I | 174400 | Autosomal recessive | 3 |
Kinzler et al. (1987) identified a gene, which they called glioma-associated oncogene (GLI), that is amplified more than 50-fold in a malignant glioma. The gene was expressed at high levels in the original tumor and its derived cell line. Kinzler et al. (1988) extended this work by cloning the GLI complementary DNA. Analysis of the nucleotide sequence demonstrated that the gene contains 5 repeats of the DNA-binding consensus sequence (zinc finger). The zinc fingers contain sequence elements that place the GLI gene product among the Kruppel (Kr) family of zinc finger proteins (see 165230). (The German word 'Kruppel' means 'cripple' or 'dwarf.') The Drosophila gene is a member of the gap class of segmentation genes; thoracic and anterior abdominal segments fail to form in Kr mutant embryos. Kr encodes a chromatin-associated phosphoprotein that contains 5 zinc fingers with a consensus sequence connecting the histidine of 1 finger to the cysteine of the next. Conservation of the contiguous stretch of nucleotides encoding this H-C link allowed cloning of Kruppel-related genes from D. melanogaster, mouse, and frog, by hybridization with Kr cDNA at low stringency. Each of these Kr family members were shown to be expressed in embryonic cells, suggesting a role for them in normal development. Northern analysis revealed that GLI is expressed in embryonal carcinoma cells but not in most adult tissue. A fragile site of the folic acid type has been described at 12q13. In addition, translocations involving this region of chromosome 12 have been described in myxoid liposarcoma (151900) and salivary gland tumors. Southern blot analysis with probes for INT1 (164820) and IGF1 (147440), both of which are located on chromosome 12, showed that these genes are not amplified in the malignant glioma.
Kinzler et al. (1987) localized the GLI gene to 12q13-q14.3 by Southern blot analysis of hybrid cell DNA and by in situ hybridization. By in situ hybridization, Arheden et al. (1989) localized the GLI1 gene to 12q13.3-q14.1. By in situ hybridization, Dal Cin et al. (1989) narrowed the assignment of GLI1 to the distal part of band 12q13 (12q13.2 or 12q13.3). The corresponding gene is located on mouse chromosome 10 (Justice et al., 1990).
Chung and Seizinger (1992) reviewed the molecular genetics of neurologic tumors, including the role of the GLI oncogene.
Using confocal microscopy, immunoprecipitation, and luciferase reporter analysis, Kogerman et al. (1999) demonstrated that a centrally located leucine-rich CRM1 (602559)-dependent nuclear export signal causes the 1,106-amino acid GLI1 protein to be retained in the cytoplasm, where it is colocalized with SUFU (607035). SUFU inhibits the transcriptional activity of GLI1.
Ahn and Joyner (2005) adopted an in vivo genetic fate-mapping strategy using Gli1 as a sensitive readout of Sonic hedgehog (Shh; 600725) activity to systematically mark and follow the fate of Shh-responding cells in the adult mouse forebrain. They showed that initially, only a small population of cells (including both quiescent neural stem cells and transit-amplifying cells) responds to Shh in regions undergoing neurogenesis. This population subsequently expands markedly to continuously provide new neurons in the forebrain. Ahn and Joyner (2005) concluded that their study of the behavior of quiescent neural stem cells provides in vivo evidence that they can self-renew for over a year and generate multiple cell types. Furthermore, Ahn and Joyner (2005) showed that the neural stem cell niches in the subventricular zone and dentate gyrus are established sequentially and not until late embryonic stages.
Basal cell carcinoma (604451) is the most prevalent cancer in the Western world and it is showing a rapid increase in incidence. Activation of the SHH/Patched (PTCH; 601309) signaling pathway because of PTCH1 inactivation is a key event in sporadic and familial basal cell carcinoma development and is associated with transcriptional activation of several target genes, including PTCH1 itself. These changes are analogous to the situation in Drosophila where hedgehog activates the zinc finger transcription factor Cubitus interruptus, leading to increased transcription of target genes. Nilsson et al. (2000) showed that mice ectopically expressing the human Cubitus interruptus homolog GLI1 in the skin developed tumors closely resembling human basal cell carcinomas as well as other hair follicle-derived neoplasias, such as trichoepitheliomas (601606), cylindromas (132700), and trichoblastomas. Examination of the tumors revealed wildtype p53 (191170) and HRAS (190020) genes. These findings firmly established that increased GLI1 expression is central and probably sufficient for tumor development and suggested that GLI1-induced tumor development does not depend on additional p53 or HRAS mutations.
Peng et al. (2013) identified a population of multipotent cardiopulmonary mesoderm progenitors (CPPs) within the posterior pole of the heart that are marked by the expression of Wnt2 (147870), Gli1, and Isl1 (600366). Peng et al. (2013) showed that CPPs arise from cardiac progenitors before lung development. Lineage tracing and clonal analysis demonstrates that CPPs generate the mesoderm lineages within the cardiac inflow tract and lung, including cardiomyocytes, pulmonary vascular and airway smooth muscle, proximal vascular endothelium, and pericyte-like cells. CPPs are regulated by hedgehog expression from the foregut endoderm, which is required for connection of the pulmonary vasculature to the heart. Peng et al. (2013) concluded that taken together, their studies identified a novel population of multipotent cardiopulmonary progenitors that coordinates heart and lung codevelopment that is required for adaptation to terrestrial existence.
Zahreddine et al. (2014) identified a novel form of drug resistance to ribavirin and Ara-C, and observed that the GLI1 and UGT1A (see 191740) families of enzymes are elevated in resistant cells. UGT1As add glucuronic acid to many drugs, modifying their activity in diverse tissues. GLI1 alone is sufficient to drive UGT1A-dependent glucuronidation of ribavirin and Ara-C, and thus drug resistance. Resistance is overcome by genetic or pharmacologic inhibition of GLI1, revealing a potential strategy to overcome drug resistance in some patients.
Samanta et al. (2015) characterized the contribution to remyelination of a subset of adult neural stem cells, identified by their expression of Gli1. Samanta et al. (2015) showed that these cells are recruited from the subventricular zone to populate demyelinated lesions in the forebrain but never enter healthy white matter tracts. Unexpectedly, recruitment of this pool of neural stem cells, and their differentiation into oligodendrocytes, is significantly enhanced by genetic or pharmacologic inhibition of Gli1. Importantly, complete inhibition of canonical hedgehog signaling (see SHH, 600725) was ineffective, indicating that the role of Gli1 both in augmenting hedgehog signaling and in retarding myelination is specialized. Samanta et al. (2015) found that inhibition of Gli1 improves the functional outcome in a relapsing/remitting model of experimental autoimmune encephalomyelitis and is neuroprotective. The authors suggested that endogenous neural stem cells can be mobilized for the repair of demyelinated lesions by inhibiting Gli1.
Degirmenci et al. (2018) showed that subepithelial mesenchymal GLI1-expressing cells constitute the Wnt-producing stem cell niche in the colon, required to maintain epithelial homeostasis. Blocking Wnt secretion from GLI1-expressing cells prevents colonic stem cell renewal in mice: the stem cells are lost and, as a consequence, the integrity of the colonic epithelium is corrupted, leading to death. GLI1-expressing cells also play an important role in the maintenance of the small intestine, where they serve as a reserve Wnt source that becomes critical when Wnt secretion from epithelial cells is prevented. Degirmenci et al. (2018) suggested a mechanism by which the stem cell niche is adjusted to meet the needs of the intestine via adaptive changes in the number of mesenchymal GLI1-expressing cells.
Postaxial Polydactyly Type A8
In 8 patients from 3 unrelated families with postaxial polydactyly of the hands and/or feet (PAPA8; 618123), Palencia-Campos et al. (2017) identified homozygosity for nonsense mutations in the GLI1 gene (165220.0001-165220.0003).
Preaxial Polydactyly I
In a consanguineous Pakistani family in which 2 cousins exhibited bilateral preaxial polydactyly of the hands (PPD1; 174400), Ullah et al. (2019) identified homozygosity for a missense mutation in the GLI1 gene (L506Q; 165220.0004).
The secreted glycoprotein Sonic hedgehog (SHH) is thought to act as an endodermal signal that controls hindgut patterning and lung growth. In mice, 3 zinc finger transcription factors, Gli1, Gli2, and Gli3, have been implicated in the transduction of Shh signal. Motoyama et al. (1998) found that mutant mice lacking Gli2 function exhibit foregut defects, including stenosis of the esophagus and trachea, as well as hypoplasia and lobulation defects of the lung. A reduction of 50% in the gene dosage of Gli3 (165240) in a Gli2-/- background resulted in esophageal atresia with tracheoesophageal fistula and a severe disruption of lung development. Mutant mice lacking both Gli2 and Gli3 function did not form esophagus, trachea, or lung. These results indicated that Gli2 and Gli3 possess specific and overlapping functions in Shh signaling during foregut development, and suggested that mutations in GLI genes may be involved in human foregut malformations.
In 2 affected individuals (patients 1 and 2) from a large multiply consanguineous Turkish pedigree with postaxial polydactyly of the hands and/or feet (PAPA8; 618123), Palencia-Campos et al. (2017) identified homozygosity for a c.2340G-A transition (c.2340G-A, NM_005269.2) in the last exon of the GLI1 gene, resulting in a trp780-to-ter (W780X) substitution and a protein lacking the transactivation domain. The proband had hexadactyly of the hands and feet, whereas the affected distant relative had hexadactyly only of the hands. Another distant relative with hand involvement (patient 3) was heterozygous for the mutation, which he inherited from his unaffected mother, and an older relative with a history of hand involvement that was surgically corrected in infancy did not carry the mutation. The authors suggested that patient 3 might carry hypomorphic variants in another gene, or that mutation in a different gene might be responsible for the phenotype in patients 3 and 4. Functional analysis in cell cultures and in vivo assays revealed severely impaired transcriptional activity of the W780X mutant compared to wildtype. In addition, reduced expression of the GLI1 target PTCH1 (601309) was observed in patient fibroblasts after chemical induction of the hedgehog (see 600725) pathway. The variant was not found in dbSNP, ExAC, EVS, gnomAD, 1000 Genomes Project, or Kaviar databases.
In 2 brothers (patients 5 and 6) from a consanguineous Turkish family with postaxial polydactyly of the hands and feet (PAPA8; 618123), Palencia-Campos et al. (2017) identified homozygosity for a c.1930C-T transition (c.1930C-T, NM_005269.2) in the last exon of the GLI1 gene, resulting in a gln644-to-ter (Q644X) substitution and a protein lacking the transactivation domain. The mutation was present in heterozygosity in 2 more brothers, 1 who exhibited postminimi polydactyly of the left hand and 1 who was unaffected, and another brother without polydactyly did not carry the mutation. The variant was not found in dbSNP, ExAC, EVS, gnomAD, 1000 Genomes Project, or Kaviar databases.
In 4 affected individuals from 2 sibships of a consanguineous Pakistani pedigree (patients 7 to 10) with postaxial polydactyly of the feet (PAPA8; 618123), 1 of whom also had postaxial polydactyly of the left hand, Palencia-Campos et al. (2017) identified homozygosity for a c.337C-T transition (c.337C-T, NM_005269.2) in exon 3 of the GLI1 gene, resulting in an arg113-to-ter (R113X) substitution, predicted to be subject to nonsense-mediated decay. The unaffected parents and an unaffected sib were heterozygous for the mutation. The variant was found in 1 of 246,242 alleles in the gnomAD database.
In a consanguineous Pakistani family in which 2 cousins exhibited bilateral preaxial polydactyly of the hands (PPD1; 174400), Ullah et al. (2019) identified homozygosity for a c.1517T-A transition in the GLI1 gene, resulting in a leu506-to-gln (L506Q) substitution at a highly conserved residue. The mutation segregated fully with disease in the family and was not found in 70 unrelated Pakistani controls, but was present in heterozygosity at low frequency in the gnomAD database (allele frequency, 0.0002109).
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Arheden, K., Ronne, M., Mandahl, N., Heim, S., Kinzler, K. W., Vogelstein, B., Mitelman, F. In situ hybridization localizes the human putative oncogene GLI to chromosome subbands 12q13.3-14.1. Hum. Genet. 82: 1-2, 1989. [PubMed: 2497059] [Full Text: https://doi.org/10.1007/BF00288260]
Bigner, S. H., Mark, J., Burger, P. C., Mahaley, M. S., Jr., Bullard, D. E., Muhlbaier, L. H., Bigner, D. D. Specific chromosomal abnormalities in malignant human gliomas. Cancer Res. 48: 405-411, 1988. [PubMed: 3335011]
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Dal Cin, P., Turc-Carel, C., Sandberg, A. A., Van den Berghe, H. More precise localization of GLI gene by in situ hybridization. (Abstract) Cytogenet. Cell Genet. 51: 982-983, 1989.
Degirmenci, B., Valenta, T., Dimitrieva, S., Hausmann, G., Basler, K. GLI1-expressing mesenchymal cells form the essential Wnt-secreting niche for colon stem cells. Nature 558: 449-453, 2018. [PubMed: 29875413] [Full Text: https://doi.org/10.1038/s41586-018-0190-3]
Justice, M. J., Siracusa, L. D., Gilbert, D. J., Heisterkamp, N., Groffen, J., Chada, K., Silan, C. M., Copeland, N. G., Jenkins, N. A. A genetic linkage map of mouse chromosome 10: localization of eighteen molecular markers using a single interspecific backcross. Genetics 125: 855-866, 1990. [PubMed: 1975791] [Full Text: https://doi.org/10.1093/genetics/125.4.855]
Kinzler, K. W., Bigner, S. H., Bigner, D. D., Trent, J. M., Law, M. L., O'Brien, S. J., Wong, A. J., Vogelstein, B. Identification of an amplified, highly expressed gene in a human glioma. Science 236: 70-73, 1987. [PubMed: 3563490] [Full Text: https://doi.org/10.1126/science.3563490]
Kinzler, K. W., Ruppert, J. M., Bigner, S. H., Vogelstein, B. The GLI gene is a member of the Kruppel family of zinc finger proteins. Nature 332: 371-374, 1988. [PubMed: 2832761] [Full Text: https://doi.org/10.1038/332371a0]
Kogerman, P., Grimm, T., Kogerman, L., Krause, D., Unden, A. B., Sandstedt, B., Toftgard, R., Zaphiropoulos, P. G. Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of GLI-1. Nature Cell Biol. 1: 312-319, 1999. [PubMed: 10559945] [Full Text: https://doi.org/10.1038/13031]
Motoyama, J., Liu, J., Mo, R., Ding, Q., Post, M., Hui, C. Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus. Nature Genet. 20: 54-57, 1998. [PubMed: 9731531] [Full Text: https://doi.org/10.1038/1711]
Nilsson, M., Unden, A. B., Krause, D., Malmqwist, U., Raza, K., Zaphiropoulos, P. G., Toftgard, R. Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1. Proc. Nat. Acad. Sci. 97: 3438-3443, 2000. [PubMed: 10725363] [Full Text: https://doi.org/10.1073/pnas.97.7.3438]
Palencia-Campos, A., Ullah, A., Nevado, J., Yildirim, R., Unal, E., Ciorraga, M., Barruz, P., Chico, L., Piceci-Sparascio, F., Guida, V., De Luca, A., Kayserili, H., Ullah, I., Burmeister, M., Lapunzina, P., Ahmad, W., Morales, A. V., Ruiz-Perez, V. L. GLI1 inactivation is associated with developmental phenotypes overlapping with Ellis-van Creveld syndrome. Hum. Molec. Genet. 26: 4556-4571, 2017. [PubMed: 28973407] [Full Text: https://doi.org/10.1093/hmg/ddx335]
Peng, T., Tian, Y., Boogerd, C. J., Lu, M. M., Kadzik, R. S., Stewart, K. M., Evans, S. M., Morrisey, E. E. Coordination of heart and lung co-development by a multipotent cardiopulmonary progenitor. Nature 500: 589-592, 2013. [PubMed: 23873040] [Full Text: https://doi.org/10.1038/nature12358]
Ruppert, J. M., Kinzler, K. W., Wong, A. J., Bigner, S. H., Kao, F.-T., Law, M. L., Seuanez, H. N., O'Brien, S. J., Vogelstein, B. The GLI-Kruppel family of human genes. Molec. Cell. Biol. 8: 3104-3113, 1988. [PubMed: 2850480] [Full Text: https://doi.org/10.1128/mcb.8.8.3104-3113.1988]
Samanta, J., Grund, E. M., Silva, H. M., Lafaille, J. J., Fishell, G., Salzer, J. L. Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination. Nature 526: 448-452, 2015. [PubMed: 26416758] [Full Text: https://doi.org/10.1038/nature14957]
Ullah, A., Umair, M., Majeed, A. I., Abdullah, Jan, A., Ahmad, W. A novel homozygous sequence variant in GLI1 underlies first case of autosomal recessive pre-axial polydactyly. Clin. Genet. 95: 540-541, 2019. [PubMed: 30620395] [Full Text: https://doi.org/10.1111/cge.13495]
Zahreddine, H. A., Culjkovic-Kraljacic, B., Assouline, S., Gendron, P., Romeo, A. A., Morris, S. J., Cormack, G., Jaquith, J. B., Cerchietti, L., Cocolakis, E., Amri, A., Bergeron, J., Leber, B., Becker, M. W., Pei, S., Jordan, C. T., Miller, W. H., Jr., Borden, K. L. B. The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation. Nature 511: 90-93, 2014. [PubMed: 24870236] [Full Text: https://doi.org/10.1038/nature13283]