Alternative titles; symbols
HGNC Approved Gene Symbol: GLI2
Cytogenetic location: 2q14.2 Genomic coordinates (GRCh38): 2:120,735,868-120,992,653 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q14.2 | Culler-Jones syndrome | 615849 | Autosomal dominant | 3 |
| Holoprosencephaly 9 | 610829 | Autosomal dominant | 3 |
The GLI2 gene encodes a vertebral transcription factor involved in SHH (600725) signal transduction (Roessler et al., 2003).
The GLI gene (165220) was discovered and so-named by reason of its amplification in gliomas of the brain. Sequencing of GLI cDNA clones showed the presence of 5 tandem zinc fingers connected by histidine-cysteine links, which indicated that the gene belongs to the family of zinc finger genes related to Kruppel (Kr). The Drosophila gene Kr is a member of the gap class of segmentation genes; thoracic and anterior abdominal segments fail to form in Kr mutant embryos. This suggested to Ruppert et al. (1988) that other genes of this class might prove important in normal or disease states. Indeed, other genes important in neoplasia, such as NMYC (164840), LMYC (164850), HER2 (164870), and NRAS (164790), have been identified partly by their homology to previously identified oncogenes. Therefore, Ruppert et al. (1988) used a GLI cDNA fragment encoding the zinc finger region to isolate related human sequences. Six distinct loci were identified in this manner. Partial sequencing revealed that each open reading frame was capable of encoding fingers with H-C links. Most of these sequences were found to be expressed in several adult tissues. Using DNA from human-rodent hybrid panels in hybridization studies with probes representing each of 6 distinct loci (identified as distinct by patterns of RNA expression and species conservation), Ruppert et al. (1988) demonstrated that the 6 loci are located on 5 different chromosomes: GLI2 was concordant with NMYC on chromosome 2; GLI3 (165240) with epidermal growth factor receptor (131550) on chromosome 7; HKR1 (165250) and HKR2 (165260) with APOE (107741) on chromosome 19; HKR3 (165270) with NRAS on chromosome 1; and HKR4 (165280) with MYC (190080) on chromosome 8.
Roessler et al. (2005) showed that human GLI2 contains a previously undescribed 5-prime sequence, extending the N terminus by an additional 328 amino acids. The full-length GLI2 protein contains 1,586 amino acids. In vitro transcriptional activity of full-length GLI2 was up to 30 times lower than that of GLI2-delta-N (previously thought to represent the entire GLI2 protein), revealing the presence of an N-terminal repressor domain, encoded by 4 exons. GLI2-delta-N contains 1,258 amino acids and lacks the N-terminal repressor domain.
Roessler et al. (2005) determined that the GLI2 gene contains at least 13 exons.
Ruppert et al. (1988) mapped the GLI2 gene to chromosome 2. By fluorescence in situ hybridization, Matsumoto et al. (1996) refined the assignment of the GLI2 gene to chromosome 2q14.
Roessler et al. (2005) showed that GLI2-delta-N exhibited potent transcriptional activity in vivo: overexpression in mouse skin led to the formation of hedgehog-independent epithelial downgrowths resembling basal cell carcinomas, which in humans are associated with constitutive hedgehog signaling. On the basis of the functional domains affected by known human GLI2 mutations, mutant GLI2 proteins exhibited either loss-of-function or dominant-negative activity. Moreover, deletion of the N terminus abrogated dominant-negative activity of mutant GLI2, revealing that this domain may be required for transcriptional repressor activity of pathogenic GLI2. Roessler et al. (2005) concluded that the N-terminal transcriptional repressor domain may play a critical role in modulating the function of wildtype GLI2 and may be essential for dominant-negative activity of a GLI2 mutant associated with human disease.
Zhao et al. (2017) found that Gli2, the major Hedgehog pathway transcriptional effector, acts within mouse mammary stromal cells to direct a hormone-responsive niche signaling program by activating expression of factors that regulate epithelial stem cells as well as receptors for the mammatrophic hormones estrogen and growth hormone (GH1; 139250). Whereas prior studies implicated stem cell defects in human disease, the work of Zhao et al. (2017) showed that niche dysfunction may also cause disease, with possible relevance for human disorders and in particular the breast growth pathogenesis associated with combined pituitary hormone deficiency (see 613038).
Holoprosencephaly 9
In affected members of 2 families with a distinctive phenotype within the spectrum of holoprosencephaly (HPE9; 610829), Roessler et al. (2003) identified heterozygous truncating mutations in the GLI2 gene (W441X, 165230.0002 and a 1-bp del, 165230.0001). The primary clinical features included defective anterior pituitary formation and panhypopituitarism, with or without overt forebrain cleavage abnormalities, and HPE-like midfacial hypoplasia. GLI2 is 1 of 3 vertebrate transcription factors implicated as obligatory mediators of Sonic hedgehog (SHH; 600725) signal transduction. Diminished SHH signaling is associated with holoprosencephaly; mutations in the SHH gene cause HPE3 (142945). The secreted SHH protein acts as a crucial factor that patterns the ventral forebrain and is required for the division of the primordial eye field and brain into 2 distinct halves. Roessler et al. (2003) noted that the occasional pituitary hypoplasia and/or holoprosencephaly seen in patients with Pallister-Hall syndrome (PHS; 146510) caused by mutation in the GLI3 gene (165240) is consistent with the possibility that GLI3 also partakes in the mediation of the SHH signal in the ventral forebrain.
Roessler et al. (2005) reexamined the in vitro consequences of the mutations identified by Roessler et al. (2003) in light of the discovery of a previously unknown N-terminal repressor domain. Both mutations resulted in a loss of intrinsic transcriptional activity, consistent with loss of the C-terminal activator domain. However, 1 mutation (165230.0001) resulted in a dominant-negative effect when coexpressed with wildtype GLI2.
Rahimov et al. (2006) reported 4 patients with an HPE-like phenotype associated with heterozygous GLI2 missense mutations, including 1 girl who was double heterozygous for mutations in GLI2 (165230.0003) and PTCH1 (601309.0012). Because the mutation in the PTCH1 gene had been found in other patients with holoprosencephaly (HPE7; 610828), the causative nature of the mutation in the GLI2 gene in that patient was uncertain.
Bertolacini et al. (2012) reported 6 unrelated Brazilian patients with variable manifestations of HPE9 resulting from a heterozygous mutation in the GLI2 gene (see, e.g., 165230.0004-165230.0007). The patients were identified from 110 individuals with diverse craniofacial anomalies who were specifically screened for mutations in the GLI2 gene. The phenotype in patients with GLI2 mutations showed a wide range, from isolated cleft lip/palate with polydactyly, to branchial arch anomalies, to semilobar holoprosencephaly. Some patients had marked involvement of the temporomandibular joint and derivatives of the first branchial arch. Only 1 patient had neurodevelopmental delay. Three of the mutations were inherited from a mother with very mild manifestations, and 1 mutation occurred de novo.
Culler-Jones Syndrome
In affected members of 3 unrelated families with variable manifestations of Culler-Jones syndrome (CJS; 615849), mainly postaxial polydactyly and hypopituitarism, Franca et al. (2010) identified 3 different heterozygous frameshift or truncating mutations in the GLI2 gene (165230.0009-165230.0011). Several mutation carriers were mildly affected or unaffected, indicating incomplete penetrance and variable expressivity. All patients with hypopituitarism had at least growth hormone deficiency and an ectopic posterior pituitary lobe. More severely affected individuals had deficiencies of other pituitary hormones, including ADH in 1 patient. Most mutation carriers had postaxial polydactyly; none of the patients had evidence of HPE. Franca et al. (2010) suggested that the incomplete penetrance and highly variable expressivity observed in this phenotype result from a complex pattern of inheritance combining multiple environmental and genetic factors, such as variants at other loci or digenic inheritance.
Grachtchouk et al. (2000) showed that transgenic mice overexpressing Gli2 in cutaneous keratinocytes, or Gli2(tg) mice, develop multiple basal cell carcinomas (BCCs). These results established Gli2 as a potent oncogene in skin and suggested a pivotal role for this transcription factor in the development of human BCC. Furthermore, they found that overexpression of Gli2 in skin resulted in activation of multiple Sonic hedgehog target genes, a feature of human BCCs. They proposed that irrespective of the genetic alteration eliciting uncontrolled SHH signaling in human BCCs, GLI2 has a central role in the genesis of these tumors.
DePianto et al. (2010) found that expression of keratin-17 (KRT17; 148069) was induced before the onset of lesions in the epidermis of Gli2(tg) mice. Deletion of Krt17 in Gli2(tg) mice reduced the inflammatory response and the frequency of mitotically active cells, and it resulted in better preservation of skin barrier function. Absence of Krt17 in Gli2(tg) Krt17 -/- skin correlated with reduction in T-helper-1 (Th1) proinflammatory and Th17 antimicrobial T cells and induction of Th2 antiinflammatory markers. Deletion of Krt17 also downregulated BCC-related matrix metalloproteases (e.g., MMP3; 185250) and normalized altered cytokine expression. Phorbol ester treatment enhanced proliferation of Gli2(tg) cells, but not Gli2(tg) Krt17 -/- cells. DePianto et al. (2010) concluded that KRT17 has a role in modulating the immune response in hedgehog-driven basaloid skin tumors.
Mill et al. (2003) found that Gli2-null mice showed grossly normal epidermal differentiation, but like Shh-null mice, they exhibited arrested hair follicle development with reduced cell proliferation and Shh-responsive gene expression. A constitutively active form of Gli2, but not wildtype Gli2, activated Shh-responsive gene expression and promoted cell proliferation in Shh-null skin.
Using microarray analysis and in situ hybridization, Purcell et al. (2009) showed that Gli2 was expressed during development of the temporomandibular joint (TMJ) in mice, with specific expression in the condyle and the disk. Gli2 -/- mouse embryos displayed TMJ abnormalities, with missing TMJ disk and aberrant chondrogenic differentiation. Mice with conditional deletion of Smo (601500), another Hh signaling component expressed during TMJ development, from chondrocyte progenitors formed a complete disk with morphology similar to wildtype, but the resulting structure failed to separate from the condyle. The results suggested that Hh signaling is required at 2 distinct steps in TMJ disk formation: initiation of TMJ disk formation and disk-condyle separation after chondrogenic differentiation to form the lower joint cavity.
In affected members in 4 successive generations of a family with pituitary anomalies with holoprosencephaly-like features (HPE9; 610829), Roessler et al. (2003) identified heterozygosity for a 1-bp deletion at nucleotide 2274 in the GLI2 gene. The disorder was transmitted through unaffected mutation carriers. A deceased male in the first generation was reported to have had cleft lip and palate in addition to polydactyly. The proband in the fourth generation had midface hypoplasia, repaired cleft lip and palate, postaxial polydactyly, and absent pituitary on MRI associated with panhypopituitarism. Male twin brothers of the female proband had panhypopituitarism. One died at age 5 months with midline cleft lip and palate, hypotelorism, flat midface, absent pituitary, and partial agenesis of the corpus callosum. The father and paternal aunt of the proband (in the third generation) had normal intelligence and postaxial polydactyly that may represent a microform. The 1-bp deletion was identified in the proband, the surviving twin brother, the father, and the paternal aunt.
In vitro functional expression studies by Roessler et al. (2005) showed that the 2274del1 mutation resulted in a dominant-negative effect when coexpressed with wildtype GLI2.
Franca et al. (2010) referred to this mutation as Tyr1086fsTer42.
Franca et al. (2010) stated that this mutation is a trp441-to-ter (W441X) substitution.
In a male with pituitary anomalies with holoprosencephaly-like features (HPE9; 610829), Roessler et al. (2003) identified a heterozygous 339G-A transition in the GLI2 gene, resulting in a trp113-to-ter (W113X) mutation. The patient had bilateral cleft lip and palate, microcephaly, hypotelorism, single central incisor, postaxial hexadactyly, growth hormone deficiency associated with pituitary hypoplasia, and no other obvious forebrain anomalies. The patient's sister, whose DNA was unavailable for analysis, was found at autopsy to have hypotelorism, single nostril, hypoplastic palate and maxilla, normal digits, absent anterior lobe of the pituitary, alobar HPE, and hydrocephalus. The mutation was absent in both parents, consistent with mosaicism.
In vitro functional expression studies by Roessler et al. (2005) showed that the W113X mutation resulted in a loss of function, but no dominant-negative effect when coexpressed with wildtype GLI2. These findings suggested haploinsufficiency as the disease mechanism in this patient.
In a 5-year-old Brazilian girl with a holoprosencephaly-like phenotype (HPE9; 610829), Rahimov et al. (2006) identified double heterozygosity for a 451A-G transition in the GLI2 gene, resulting in an arg151-to-gly (R151G) substitution, and a 2171C-T transition in the PTCH1 gene, resulting in a thr728-to-met (T728M; 601309.0012) substitution. (The authors erroneously stated that the 2171C-T transition in the PTCH1 gene resulted in a T328M substitution.) The patient was the first child of unrelated parents. Pregnancy was unremarkable. Clinical examination showed large ears, hypoplastic anterior nasal spine, diminished frontonasal angle, hypotelorism, hypoplastic premaxilla, hypoplastic nose with flattened alae and nasal tip, poorly developed philtrum, bilateral cleft lip/palate, malocclusion, and normal neuropsychologic development. MRI demonstrated mild gyral asymmetry in the perisylvian areas. Because the mutation in the PTCH1 gene had been found in other patients with holoprosencephaly, the causative nature of the mutation in the GLI2 gene was uncertain.
In a Brazilian girl with a mild variant of holoprosencephaly (HPE9; 610829), Bertolacini et al. (2012) identified a heterozygous 4663T-C transition in the GLI2 gene, resulting in a ser1555-to-pro (S1555P) substitution. The mutation was not found in 96 Brazilian controls. The patient had a flat face, maxillary hypoplasia, arched eyebrows, downslanting palpebral fissures, epicanthus inversus, large ears, low nasal bridge, flat nose, bilateral cleft lip/palate, hypoplastic columella and philtrum, and right hand preaxial polydactyly. Evaluation at age 28 months showed normal development for age, and brain CT scan was normal. The mutation was inherited from her mother, who had isolated hypotelorism with no other anomalies.
In a Brazilian girl with holoprosencephaly (HPE9; 610829), Bertolacini et al. (2012) identified a heterozygous 2-bp deletion (864delCC) in the GLI2 gene, resulting in a frameshift and premature termination (Pro288fsTer301). The mutation, which was not found in 96 Brazilian controls, was inherited from the mother, who had postaxial polydactyly. The child had microcephaly, a large cleft lip/palate involving partially the premaxilla, and bilateral postaxial polydactyly. Evaluation at age 8 years showed severe neurodevelopmental delay, and brain MRI showed semilobar holoprosencephaly.
In a Brazilian boy with holoprosencephaly (HPE9; 610829), Bertolacini et al. (2012) identified a heterozygous 1886G-A transition in the GLI2 gene, resulting in a glu629-to-lys (E629K) substitution. The mutation was not found in 96 Brazilian controls. At age 5 years, the boy had a high forehead, facial asymmetry with hypoplastic right side, right epibulbar dermoid, a thin and asymmetric nose, abnormal ears with preauricular skin tags, clefting, and short neck. Neurologic development and brain CT scan were normal. Radiographs of the mandible showed an abnormally developed right condyle and coronoid process, short right ramus with abnormal opening of the angle of the mandible, and short mandible body at right. A maternal cousin had preaxial polydactyly, but parents and relatives were not available for study.
In a Brazilian girl with holoprosencephaly (HPE9; 610829), Bertolacini et al. (2012) identified a de novo heterozygous 4558G-A transition in the GLI2 gene, resulting in an asp1520-to-asn (D1520N) substitution. The mutation was not found in 96 Brazilian controls. At age 5 months, the child had a high forehead, facial asymmetry with hypoplastic left side, left-sided anophthalmia, abnormal ears, preauricular skin tags, and clefting. Reevaluation at age 3.5 years showed normal neuropsychologic development and normal CT images of the mastoid bone and brain.
In affected members of a 3-generation family with variable manifestations of Culler-Jones syndrome (CJS; 615849), originally reported by Culler and Jones (1984), Roessler et al. (2005) identified a heterozygous c.3768C-T transition in the GLI2 gene, resulting in premature termination at residue 1256. In vitro functional expression studies showed that the mutation caused a loss of transcriptional activity and acted in a dominant-negative manner when coexpressed with wildtype GLI2.
In 9 affected members of a large Brazilian family with variable manifestations of Culler-Jones syndrome (CJS; 615849), Franca et al. (2010) identified a heterozygous 7-bp deletion (c.2362_2368del) in exon 13 of the GLI2 gene, resulting in a frameshift and premature termination (Leu788fsTer794) before the C-terminal activator domain. The proband had panhypopituitarism, seizures, delayed development, and polydactyly, whereas other mutation carriers had only polydactyly with no other anomalies or only some pituitary abnormalities. The mutation was not found in 184 control alleles. The transmission pattern was consistent with incomplete penetrance and variable expressivity.
In a 12-year-old boy with Culler-Jones syndrome (CJS; 615849), Franca et al. (2010) identified a heterozygous 4-bp deletion (c.2081_2084del) in exon 12 of the GLI2 gene, resulting in a frameshift and premature termination (Leu694fsTer722) before the C-terminal activator domain. A heterozygous c.1760C-T transition, resulting in a pro608-to-leu (P608L) substitution was also found; the P608L variant was not found in 224 control alleles. The patient's unaffected father carried both variants, indicating incomplete penetrance.
In a 1-year-old girl with Culler-Jones syndrome (CJS; 615849), Franca et al. (2010) identified a heterozygous c.1138G-T transversion in exon 7 of the GLI2 gene, resulting in a glu380-to-ter (E380X) substitution. The mutant protein was predicted to lack the zinc fingers responsible for DNA binding and the C-terminal activator domain. The mutation was not found in 204 control alleles, but was present in the unaffected mother. The girl had panhypopituitarism, including absence of the posterior pituitary on brain imaging and ADH deficiency resulting in diabetes insipidus.
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