Gene Section GLIS2 (GLIS family zinc finger 2) in Oncology and Haematology

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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
Gene Section
Short Communication
GLIS2 (GLIS family zinc finger 2)
Clarisse Thiollier
Gustave Roussy Institute, Villejuif, France (CT)
Published in Atlas Database: April 2013
Online updated version :
DOI: 10.4267/2042/51534
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology
In human: GLIS2 mRNA is highly expressed in kidney,
low level in heart, lung and placenta (Zhang and Jetten,
Other names: NKL, NPHP7
HGNC (Hugo): GLIS2
Location: 16p13.3
Nuclear localization (Zhang et al., 2002); the 3rd Zinc
Finger motif contains a region required for the nuclear
localization (Vasanth et al., 2011).
Size: 7383 b; 6 coding exons.
Krüppel-like zinc finger family proteins can act as
activator or repressor of gene transcription. They are
involved in regulation of embryonic development and
various physiological mechanisms in adults (Dang et
al., 2000). Kang and colleagues described the
regulation of gene expression by Glis1-3 through the
interaction with transcriptional mediators that are
recruited by specific repressor and activation domains
within the respective Glis protein. According to cell
context, Glis2 can thus act as a transcriptional activator
or repressor. Glis2 is especially implicated in the
maintenance of normal kidney structure and function;
both activation and repression roles are involved during
embryonic development and adult kidney (Zhang et al.,
2002; Attanasio et al., 2007). GLIS2 has also been
described as NKL (neuronal Krüppel-like protein):
NKL is broadly expressed in the neural tube and
peripheral nervous system when neural precursors are
differentiating. NKL is implicated in neurogenesis,
promoting neuronal differentiation (Lamar et al., 2001).
In mice, Zhang and colleagues (Zhang et al., 2002)
highlighted the presence of an activation domain
located between Gly71 and Gly137. Two repressor
domains were identified: one is located between Ser148
and Arg171 and the other is located within the first zinc
finger motif. CtBP1 (C-terminal binding protein 1) and
HDAC3 (histone deacetylase 3) are two co-repressor
recruited by Glis2 for its repression activity, though a
repression complex (Kim et al., 2005).
2 transcripts: 3,7 kb RNA and 4,469 kb RNA
524 amino acids; molecular weight: 55,688 kD.
Member of the Krüppel-like zinc finger proteins
family, forming a subfamily with Glis1 and Glis3
closely related to Gli and Zic protein families.
Similarly to Gli and Zic proteins, Glis2 contains 5
Cys2-His2 zinc finger motifs separated by a conserved
consensus region T/SGEKPY/FX (Zhang et al., 2002).
In mouse tissues: high expression level of Glis2 in
kidney, moderate level in heart, lung, low level in
prostate, brain, colon (Zhang et al., 2002). In rat
embryos: high expression in embryonic kidneys
(particularly within the ureteric bud in 16-dpc and 19dpc rat). Expression of Glis2 detected in caudal somites
and in the neural tubes of 13-dpc in rat embryos (Zhang
et al., 2002); high expression level in neural tube in
Xenopus, mouse and chick embryos (Lamar et al.,
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(10)
GLIS2 (GLIS family zinc finger 2)
Thiollier C
nervy homology
GLI proteins are homologous of Cubitus interruptus
(Ci) in Drosophila melanogaster which plays an
important role in wing development. Ci and GLI are
involved in Sonic-Hedgehog pathway in Dosophila and
vertebrates. (Zhang and Jetten, 2001).
Glis2 shows high homologies with Gli and Zic
Krüppel-like protein families.
In mice highest homology is observed in the zinc finger
motifs: 57%, 56%, 56% and 49% homology with Gli1,
Gli2, Gli3 and Zic1 respectively. 3rd and 5th zinc finger
domains show the highest homology with Gli proteins
(70 and 88% homology) (Zhang et al., 2002).
In human: highest homology is observed with GLI1:
58% between Zinc Finger domains. 3rd, 4th and 5th Zinc
Finger show the highest homology: 65-80% homology
when compared to those of GLI and ZIC proteins
(Zhang and Jetten, 2001).
This suggests that Glis2 interacts with DNA in the way
Gli and Zic proteins do (Zhang et al., 2002).
In both human and mouse, little homology with Gli and
Zic protein family is observed outside the zinc finger
domain, which show that Glis2 belongs to another
subfamily of Krüppel-like zinc finger proteins (Zhang
et al., 2002; Zhang and Jetten, 2001).
Nephronophthisis (NPHP)
Nephronophthisis, an autosomal recessive kidney
Mutation in GLIS2 gene: homozygous transversion
IVS5+1G>T that leads to an abrogation of the
obligatory splice site and to a non-functional protein.
This mutation defines a new cause of NPHP (Attanasio
et al., 2007).
Dang DT, Pevsner J, Yang VW. The biology of the mammalian
Krüppel-like family of transcription factors. Int J Biochem Cell
Biol. 2000 Nov-Dec;32(11-12):1103-21
Lamar E, Kintner C, Goulding M. Identification of NKL, a novel
Gli-Kruppel zinc-finger protein that promotes neuronal
differentiation. Development. 2001 Apr;128(8):1335-46
Zhang F, Jetten AM. Genomic structure of the gene encoding
the human GLI-related, Krüppel-like zinc finger protein GLIS2.
Gene. 2001 Dec 12;280(1-2):49-57
Zhang F, Nakanishi G, Kurebayashi S et al.. Characterization
of Glis2, a novel gene encoding a Gli-related, Krüppel-like
transcription factor with transactivation and repressor
functions. Roles in kidney development and neurogenesis. J
Biol Chem. 2002 Mar 22;277(12):10139-49
Implicated in
Acute megakaryoblastic leukemia
(AMKL, AML-M7 (FAB classification))
Kim SC, Kim YS, Jetten AM. Krüppel-like zinc finger protein
Gli-similar 2 (Glis2) represses transcription through interaction
with C-terminal binding protein 1 (CtBP1). Nucleic Acids Res.
CBFA2T3-GLIS2 or ETO2-GLIS2 fusion oncogene
(Thiollier et al., 2012; Gruber et al., 2012; Masetti et
al., 2013).
For the first time, GLIS2 has been implicated in the
haematological context. GLIS2 is indeed not expressed
in normal hematopoietic cells. Its fusion to CBFA2T3
leads to the expression of GLIS2 in blasts.
Worse overall survival at 5 years than other pediatric
AMKL patients.
The ETO2-GLIS2 fusion oncogene results from a
chromosomal inversion inv(16)(p13.3q24.3). This is a
cryptic inversion not visible by on a karyotype.
Abnormal protein
Different fusions points have been described: 1)
between exon 11 of CBFA2T3 and exon 3 of GLIS2
(most frequent); 2) between exon 10 of CBFA2T3 and
exon 2 of GLIS2; 3) between exon 12 of CBFA2T3 and
exon 1 of GLIS2. All fusion proteins are predicted to
contain the GLIS2 DNA binding C-terminal Zinc
Finger domains and the three CBFA2T3 N-terminal
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(10)
Attanasio M, Uhlenhaut NH, Sousa VH et al.. Loss of GLIS2
causes nephronophthisis in humans and mice by increased
apoptosis and fibrosis. Nat Genet. 2007 Aug;39(8):1018-24
Vasanth S, ZeRuth G, Kang HS, Jetten AM. Identification of
nuclear localization, DNA binding, and transactivating
mechanisms of Kruppel-like zinc finger protein Gli-similar 2
(Glis2). J Biol Chem. 2011 Feb 11;286(6):4749-59
Gruber TA, Larson Gedman A, Zhang J, Koss CS et al.. An
Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein
defines an aggressive subtype of pediatric acute
megakaryoblastic leukemia. Cancer Cell. 2012 Nov
Thiollier C, Lopez CK, Gerby B, Ignacimouttou C et al..
Characterization of novel genomic alterations and therapeutic
approaches using acute megakaryoblastic leukemia xenograft
models. J Exp Med. 2012 Oct 22;209(11):2017-31
Masetti R, Pigazzi M, Togni M, Astolfi A, Indio V et al..
CBFA2T3-GLIS2 fusion transcript is a novel common feature in
pediatric, cytogenetically normal AML, not restricted to FAB M7
subtype. Blood. 2013 Apr 25;121(17):3469-72
This article should be referenced as such:
Thiollier C. GLIS2 (GLIS family zinc finger 2). Atlas Genet
Cytogenet Oncol Haematol. 2013; 17(10):687-688.

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