Alternative titles; symbols
HGNC Approved Gene Symbol: GLIS2
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38) : 16:4,314,761-4,339,595 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.3 | Nephronophthisis 7 | 611498 | Autosomal recessive | 3 |
GLIS2 is a zinc finger protein implicated in transcriptional regulation (Ramachandran et al., 2016).
By searching an EST database for sequences similar to mouse Glis2, followed by RT-PCR of human kidney RNA, Zhang and Jetten (2001) cloned full-length GLIS2. The deduced 525-amino acid protein contains 5 tandem C2H2 zinc finger motifs and has a calculated molecular mass of 55.7 kD. Human and mouse GLIS2 share 93% amino acid identity. GLIS2 is most closely related to members of the GLI (see 165220) and ZIC (see 600470) subfamilies of Kruppel-like finger proteins. Northern blot analysis detected a 3.7-kb transcript expressed most abundantly in kidney and weakly in heart, lung, and placenta.
Zhang et al. (2002) cloned Glis2 from mouse kidney RNA. The deduced 521-amino acid protein has a calculated molecular mass of 55.8 kD. Northern blot analysis detected highest expression in kidney. RT-PCR detected highest expression in kidney, moderate expression in heart and lung, and low expression in prostate, colon, and brain. Fluorescence-tagged Glis2 transfected into simian kidney cells showed a speckled nuclear localization, with exclusion from nucleoli. In situ hybridization showed rodent Glis2 expressed in developing somites and neural tube. During metanephric development, Glis2 predominantly localized to the ureteric bud, precursor of the collecting duct, and inductor of nephronic tubule formation.
Using immunofluorescence analysis, Ramachandran et al. (2016) found that human GLIS2 localized almost exclusively to nuclei of transfected HEK293T cells.
By 1-hybrid analysis using deletion mutants, Zhang et al. (2002) identified a novel activation domain at the N terminus of mouse Glis2. Activation of transcription through this domain was completely suppressed by 2 repressor functions just downstream from the activator domain. The authors localized one of the repressor functions within the first zinc finger motif. The level of transcriptional activation and repression varied with the cell line tested, likely due to differences in cell type-specific expression of coactivators and corepressors. Zhang et al. (2002) concluded that Glis2 behaves as a bifunctional transcriptional regulator.
Attanasio et al. (2007) found that Glis2 localized to both nuclei and primary cilia in canine renal epithelial cells with expression along the ciliary axoneme in a punctate pattern. In 8-week-old mouse kidney, Attanasio et al. (2007) detected Glis2 expression in the inner stripe of the outer medulla, in all renal tubule segments and epithelial cells of Bowman capsule, but not in glomerular, mesenchymal, or endothelial cells.
Zhang and Jetten (2001) determined that the GLIS2 gene contains 6 exons and spans more than 7.5 kb. Zhang et al. (2002) determined that the mouse Glis2 gene also contains 6 exons and spans more than 7.5 kb.
By genomic sequence analysis, Zhang and Jetten (2001) mapped the GLIS2 gene to chromosome 16p13.3. Zhang et al. (2002) mapped the mouse Glis2 gene to chromosome 16A3-B1.
By positional cloning, Attanasio et al. (2007) identified the GLIS2 gene as a cause of nephronophthisis (NPHP7; 611498). Three affected members of a consanguineous Canadian Oji-Cree kindred with autosomal recessive nephronophthisis had a homozygous splice site mutation in the GLIS2 gene (608539.0001).
In a Turkish patient with isolated NPHP7, Halbritter et al. (2013) identified a homozygous mutation in the GLIS2 gene (C175R; 608539.0002). The patient was ascertained from a larger cohort of 1,056 individuals with nephronophthisis-related disorders who underwent genetic analysis. Functional studies of the variant were not performed.
Associations Pending Confirmation
For discussion of a possible association between NPHP7 and an in-frame deletion in the GLIS2 gene, see 608539.0003.
Attanasio et al. (2007) found that mice with targeted disruption of the Glis2 gene had no kidney developmental abnormalities at birth. However, from 4 weeks to 6 months, the mutant mice exhibited decreased size and weight compared to wildtype mice. Mutant mouse kidneys showed progressive atrophy and loss of corticomedullary junction differentiation beginning at age 4 weeks. By 8 weeks, the hallmarks of NPHP were present, including diffuse tubulointerstitial cell infiltration, interstitial fibrosis, and diffuse collagen deposition. There was also tubular basement membrane disintegration with tubular atrophy and cysts, similar to that observed in humans. Glomerular cysts were present, and there was apoptosis of renal tubular cells. Differential gene expression analysis showed that genes promoting the epithelial-to-mesenchymal transition of renal tubular cells and fibrosis were upregulated in the absence of Glis2. Attanasio et al. (2007) concluded that Glis2 plays an essential role in the maintenance of renal tissue architecture through prevention of apoptosis and fibrosis.
Mice with kidney-specific Kif3a (604683) knockout exhibit severe cystic kidney disease early in life and die at about 6 weeks of age. Lu et al. (2016) found that Glis2 knockout in kidney-specific Kif3a-knockout mice reduced kidney cyst growth and preserved renal function by reducing tubular cell proliferation and apoptosis. Kif3a-null kidney epithelial cells had cell-autonomous accelerated cell cycle and increased DNA damage and apoptosis, which were rescued by inactivation of Glis2. Moreover, Kif3a-null kidney epithelial cells were defective in G1/S cell cycle checkpoint in the presence of DNA damage, which was also rescued by inactivation of Glis2. Kif3a-null kidney epithelial cells and Glis2-null kidney epithelial cells displayed defective and excessive activation of p53 (TP53; 191170), respectively, suggesting that decreased proliferation associated with Glis2 knockout in kidney-specific Kif3a-knockout mice was related to activation of p53. The authors observed ectopic accumulation of cyclin B1 (CCNB1; 123836) and genomic instability in Kif3a-null kidney epithelial cells, consistent with defective p53 activation. Pharmacologic stabilization of p53 slowed cystic progression and prevented cell proliferation and apoptosis in Kif3a-null kidney. Loss of Glis2 induced senescence in kidney epithelial cells.
In 3 affected members of a consanguineous Canadian Oji-Cree kindred with autosomal recessive nephronophthisis-7 (NPHP7; 611498), Attanasio et al. (2007) identified a homozygous G-to-T transversion in intron 5 of the GLIS2 gene. A minigene assay indicated that the mutation interfered with normal splicing and resulted in a nonfunctional protein.
In a Turkish patient with isolated nephronophthisis (NPHP7; 611498), Halbritter et al. (2013) identified a homozygous c.523T-C transition in the first nucleotide of exon 4 of the GLIS2 gene, predicted to result in a cys175-to-arg (C175R) substitution, but also potentially affecting splicing. The patient was ascertained from a larger cohort of 1,056 individuals with nephronophthisis-related disorders who underwent genetic analysis. Functional studies of the variant were not performed.
Ramachandran et al. (2016) determined that the C175R mutation abolished the first zinc finger of GLIS2. The mutation did not disrupt interaction of GLIS2 with its binding partners, nor did it affect protein stability or ubiquitination. Instead, C175R abolished nuclear localization of GLIS2, as the mutant protein localized predominantly to the cytoplasm, thereby affecting GLIS2 transcriptional activity. Furthermore, the C175R mutation also affected DNA recognition and/or binding, as forced nuclear localization of the mutant protein did not reestablish GLIS2 transcriptional activity. In addition, expression of wildtype nphp7, but not mutant nphp7 corresponding to the human C175R mutation, prevented cyst formation caused by knockdown of nphp7 in zebrafish embryos.
This variant is classified as a variant of unknown significance because its contribution to nephronophthisis (see NPHP7; 611498) has not been confirmed.
In an 11-year-old girl, born of consanguineous Omani parents, with isolated nephronophthisis (see NPHP7; 611498), Al Alawi et al. (2021) identified a homozygous 15-bp in-frame deletion (c.560_574del, NM_032575.3) in exon 4 of the GLIS2 gene, predicted to result in the deletion of 5 residues (His188_Tyr192del) that are evolutionarily conserved and close to the zinc-finger C2H2-type DNA-binding domain. The authors described the mutation as c.562_576del in Figure 1 of the report. The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in the unaffected parents. The variant was not present in public databases, including gnomAD. Functional studies of the variant were not performed, but molecular modeling suggested that it could cause protein misfolding or a loss of function due to altered DNA-binding capacity. According to ACMG guidelines, Al Alawi et al. (2021) classified the c.560_574del allele as a variant of uncertain significance. The affected girl presented at 9 years of age with right hip injury and was found to be hypertensive with advanced chronic kidney disease and evidence of renal failure. Kidney ultrasound showed normal-sized but echogenic kidneys with loss of corticomedullary differentiation. Urinalysis did not show significant proteinuria. Renal biopsy showed tubular injury, dilated tubules, duplication of tubular basement membranes, tubulointerstitial nephritis, interstitial fibrosis, and tubular atrophy, consistent with NPHP. Immunofluorescence studies were negative. The kidney disease was progressive, and she reached end-stage renal disease by 10 years of age.
Al Alawi, I., Powell, L., Rice, S. J., Al Riyami, M. S., Al-Riyami, M., Al Salmi, I., Sayer, J. A. Case report: a novel in-frame deletion of GLIS2 leading to nephronophthisis and early onset kidney failure. Front. Genet. 12: 791495, 2021. [PubMed: 34917135] [Full Text: https://doi.org/10.3389/fgene.2021.791495]
Attanasio, M., Uhlenhaut, N. H., Sousa, V. H., O'Toole, J. F., Otto, E., Anlag, K., Klugmann, C., Treier, A.-C., Helou, J., Sayer, J. A., Seelow, D., Nurnberg, G., Becker, C., Chudley, A. E., Nurnberg, P., Hildebrandt, F., Treier, M. Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis. Nature Genet. 39: 1018-1024, 2007. [PubMed: 17618285] [Full Text: https://doi.org/10.1038/ng2072]
Halbritter, J., Porath, J. D., Diaz, K. A., Braun, D. A., Kohl, S., Chaki, M., Allen, S. J., Soliman, N. A., Hildebrandt, F., Otto, E. A., The GPN Study Group. Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy. Hum. Genet. 132: 865-884, 2013. [PubMed: 23559409] [Full Text: https://doi.org/10.1007/s00439-013-1297-0]
Lu, D., Rauhauser, A., Li, B., Ren, C., McEnery, K., Zhu, J., Chaki, M., Vadnagara, K., Elhadi, S., Jetten, A. M., Igarashi, P., Attanasio, M. Loss of Glis2/NPHP7 causes kidney epithelial cell senescence and suppresses cyst growth in the Kif3a mouse model of cystic kidney disease. Kidney Int. 89: 1307-1323, 2016. [PubMed: 27181777] [Full Text: https://doi.org/10.1016/j.kint.2016.03.006]
Ramachandran, H., Yakulov, T. A., Engel, C., Muller, B., Walz, G. The C175R mutation alters nuclear localization and transcriptional activity of the nephronophthisis NPHP7 gene product. Europ. J. Hum. Genet. 24: 774-778, 2016. [PubMed: 26374130] [Full Text: https://doi.org/10.1038/ejhg.2015.199]
Zhang, F., Jetten, A. M. Genomic structure of the gene encoding the human GLI-related, Kruppel-like zinc finger protein GLIS2. Gene 280: 49-57, 2001. [PubMed: 11738817] [Full Text: https://doi.org/10.1016/s0378-1119(01)00764-8]
Zhang, F., Nakanishi, G., Kurebayashi, S., Yoshino, K., Perantoni, A., Kim, Y.-S., Jetten, A. M. Characterization of Glis2, a novel gene encoding a Gli-related, Kruppel-like transcription factor with transactivation and repressor functions: roles in kidney development and neurogenesis. J. Biol. Chem. 277: 10139-10149, 2002. [PubMed: 11741991] [Full Text: https://doi.org/10.1074/jbc.M108062200]