Alternative titles; symbols
HGNC Approved Gene Symbol: GZF1
SNOMEDCT: 1217372003;
Cytogenetic location: 20p11.21 Genomic coordinates (GRCh38): 20:23,361,127-23,373,062 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p11.21 | Joint laxity, short stature, and myopia | 617662 | Autosomal recessive | 3 |
GZF1 is a transcriptional regulator that binds to a 12-bp GZF1 response element (GRE) and represses gene transcription (Morinaga et al., 2005).
Using differential display analysis with TGW human neuroblastoma cell RNA to identify genes upregulated by GDNF (600837), followed by screening the TGW cell cDNA library, Fukuda et al. (2003) isolated GZF1. The deduced 711-amino acid protein has a calculated molecular mass of 80 kD. It has an N-terminal BTB/POZ domain, followed by a bipartite nuclear localization signal and 10 tandem C2H2-type zinc fingers. Fukuda et al. (2003) also cloned mouse Gzf1, and the deduced 706-amino acid mouse protein shares 84% identity with human GZF1. Northern blot analysis detected variable expression of a 4.8-kb GZF1 transcript in adult and fetal human tissues, with highest expression in adult heart, skeletal muscle, and kidney and in fetal brain and kidney. In adult mouse tissues, Gzf1 was highly expressed in liver, kidney, heart, brain, and testis, and it was expressed at all mouse embryonic stages examined. Western blot analysis of TGW cells revealed GZF1 proteins with apparent molecular masses of 95 and 115 kD, the smaller of which may be translated from an internal methionine. Only the 115-kD protein was detected in Neuro2a mouse neuroblastoma cells. Fractionation of transfected HEK293 cells revealed more fluorescence-tagged GZF1 in the nuclear fraction than in the cytosolic fraction. Immunohistochemical analysis of embryonic mouse kidney localized Gzf1 to nuclei and cytoplasm of uretic buds, with significantly decreased expression after birth.
Using immunofluorescence, Patel et al. (2017) observed strong localization of Gzf1 in the developing mouse eye and, to a lesser extent, in the mesenchyme of the developing mouse limb buds. The authors stated that the cytoplasmic and nuclear localization was consistent with previously published data by Fukuda et al. (2003).
Fukuda et al. (2003) stated that the GZF1 gene maps to chromosome 20 in human and to chromosome 2 in mouse.
Hartz (2011) mapped the GZF1 gene to chromosome 20p11.21 based on an alignment of the GZF1 sequence (GenBank AK025447) with the genomic sequence (GRCh37).
RET (164761) and its ligand, GDNF, are critical regulators of uretic bud and neuronal branching during development. Using Northern blot analysis, Fukuda et al. (2003) found that GDNF induced GZF1 mRNA in TGW human neuroblastoma cells, with expression peaks occurring at 1 hour and again at 24 to 48 hours. GZF1 protein was detected only 24 to 72 hours after stimulation. GZF1 fused to the GAL4 (LGALS4; 602518) DNA-binding domain repressed expression of a reporter gene following transfection in HEK293 cells. Mutation of asp32 and/or lys50 within the BTB/POZ domain of GZF1 reduced its suppressive activity. Knockdown of Gzf1 in isolated embryonic mouse metanephroi inhibited branching morphogenesis.
Morinaga et al. (2005) found that the isolated zinc finger domain of GZF1 bound the consensus sequence TGCGCN(T/G)(C/A)TATA in vitro. They named the most frequently occurring sequence, TGCGCGTCTATA, the GZF1 response element (GRE). Full-length GZF1 did not bind the GRE in vitro, suggesting that the N-terminal BTB/POZ domain of GZF1 interferes with DNA binding by the zinc finger domain. However, full-length GZF1 repressed translation of a reporter gene containing multiple copies of this GRE in both orientations. Mutation analysis revealed that zinc fingers 1 through 6 were sufficient to bind the GRE probe, and mutation of the 2 cysteines to arginines in any 1 of zinc fingers 2 through 5 abolished GRE binding. Morinaga et al. (2005) identified a GRE in the 5-prime regulatory region of both mouse and human HOX10 (CHX10; 142993). GZF1 suppressed expression of a reporter gene containing the HOX10 GRE in a dose-dependent manner.
Using immunoprecipitation analysis and mass spectrometry, Dambara et al. (2007) found that recombinant GZF1 bound to nucleolin (NCL; 164035) in HEK293T cell lysates. Deletion analysis revealed that zinc finger motifs 1 through 4 of GZF1 mediated the interaction. Deletion of GZF1 zinc finger motifs 1 through 4 or knockdown of nucleolin expression via short interfering RNA impaired GZF1 nuclear localization. Knockdown of GZF1 and nucleolin expression also impaired cell proliferation.
In 5 affected members of 2 consanguineous Saudi families with joint laxity, short stature, and myopia (JLSM; 617662), Patel et al. (2017) identified homozygosity for a nonsense mutation (E289X; 613842.0001) and a frameshift mutation (613842.0002), respectively, in the GZF1 gene. Transcriptional analysis using patient lymphoblastoid cell lines revealed that among significantly dysregulated genes, 39 were involved in matrix remodeling. In addition, the P3H2 gene (610341), known to be associated with severe myopia and an elongated globe (see MCVD, 614292), was downregulated by approximately 8-fold in the patients compared to controls, and significant downregulation was confirmed by qRT-PCR. Patel et al. (2017) noted that although other genes might be indirectly involved in the phenotype, it seemed plausible that the eye phenotype was at least in part due to dysregulation of P3H2.
In a sister and brother with joint laxity, short stature, and myopia (JLSM; 617662), born of doubly consanguineous Saudi parents, Patel et al. (2017) identified homozygosity for a c.865G-T transversion (c.865G-T, NM_022482.4) in the GZF1 gene, resulting in a glu289-to-ter (E289X) substitution. The mutation, which was found by a combination of autozygome and exome sequencing and confirmed by Sanger sequencing, segregated fully with disease in the family and was not found in 2,379 Saudi exomes or the ExAC database. Both sibs exhibited multiple joint dislocations, and the sister had respiratory compromise due to severe kyphoscoliosis.
In 3 brothers from a consanguineous Saudi family with joint laxity, short stature, and myopia (JLSM; 617662), Patel et al. (2017) identified homozygosity for a 1-bp duplication (c.1054dup, NM_022482.4) in the GZF1 gene, causing a frameshift predicted to result in a premature termination codon (Thr352AsnfsTer50) within the second zinc finger motif. The mutation, which was found by a combination of autozygome and exome sequencing and confirmed by Sanger sequencing, segregated fully with disease in the family and was not found in 2,379 Saudi exomes or the ExAC database. In addition to severe myopia, 2 of the brothers had retinal detachment and iris and chorioretinal coloboma.
Dambara, A., Morinaga, T., Fukuda, N., Yamakawa, Y., Kato, T., Enomoto, A., Asai, N., Murakumo, Y., Matsuo, S., Takahashi, M. Nucleolin modulates the subcellular localization of GDNF-inducible zinc finger protein 1 and its roles in transcription and cell proliferation. Exp. Cell Res. 313: 3755-3766, 2007. [PubMed: 17674968] [Full Text: https://doi.org/10.1016/j.yexcr.2007.07.003]
Fukuda, N., Ichihara, M., Morinaga, T., Kawai, K., Hayashi, H., Murakumo, Y., Matsuo, S., Takahashi, M. Identification of a novel glial cell line-derived neurotrophic factor-inducible gene required for renal branching morphogenesis. J. Biol. Chem. 278: 50386-50392, 2003. Note: Erratum: J. Biol. Chem. 279: 3120 only, 2004. [PubMed: 14522971] [Full Text: https://doi.org/10.1074/jbc.M309629200]
Hartz, P. A. Personal Communication. Baltimore, Md. 3/18/2011.
Morinaga, T., Enomoto, A., Shimono, Y., Hirose, F., Fukuda, N., Dambara, A., Jijiwa, M., Kawai, K., Hashimoto, K., Ichihara, M., Asai, N., Murakumo, Y., Matsuo, S., Takahashi, M. GDNF-inducible zinc finger protein 1 is a sequence-specific transcriptional repressor that binds to the HOXA10 gene regulatory region. Nucleic Acids Res. 33: 4191-4201, 2005. [PubMed: 16049025] [Full Text: https://doi.org/10.1093/nar/gki734]
Patel, N., Shamseldin, H. E., Sakati, N., Khan, A. O., Softa, A., Al-Fadhli, F. M., Hashem, M., Abdulwahab, F. M., Alshidi, T., Alomar, R., Alobeid, E., Wakil, S. M., Colak, D., Alkuraya, F. S. GZF1 mutations expand the genetic heterogeneity of Larsen syndrome. Am. J. Hum. Genet. 100: 831-836, 2017. [PubMed: 28475863] [Full Text: https://doi.org/10.1016/j.ajhg.2017.04.008]