Alternative titles; symbols
HGNC Approved Gene Symbol: ZBTB20
SNOMEDCT: 726709001;
Cytogenetic location: 3q13.31 Genomic coordinates (GRCh38) : 3:114,314,500-115,147,288 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q13.31 | Primrose syndrome | 259050 | Autosomal dominant | 3 |
ZBTB20 is a member of the POK (POZ and Kruppel) family of transcriptional repressors that interact with DNA via their conserved C2H2 Kruppel-type zinc finger and BTB/POZ domains (Sutherland et al., 2009).
Using an EST with an incomplete ORF potentially encoding 4 C2H2 zinc finger motifs from a human dendritic cell cDNA library, followed by 5-prime RACE, Zhang et al. (2001) isolated a full-length cDNA clone of a novel zinc finger, ZNF288, which they called DPZF. The deduced 733-amino acid protein has a molecular mass of 80 kD and contains an N-terminal BTB/POZ domain and a C-terminal zinc finger domain with 4 typical Kruppel-type C2H2 motifs. Within the BTB/POZ domain, ZNF288 shares high homology with BCL6 (109565), a POK protein putatively involved in lymphopoiesis. Northern blot analysis detected expression of ZNF288 in spleen, lymph node, thymus, peripheral blood leukocytes, and fetal liver; no expression was found in bone marrow. Two transcripts of approximately 7.4 kb and 2.8 kb were present in most of the tissues, with the 2.8-kb transcript predominant in spleen, lymph node, and peripheral blood leukocytes. RT-PCR analysis detected expression in dendritic cells, monocytes, B cells, and T cells. Expression of a 100-kD ZNF288 protein was detectable in lymphoid neoplasm, especially B lymphoma. The authors suggested that ZNF288 may be a transcription factor closely related to BCL6 and may be involved in hematopoiesis, oncogenesis, and immune responses.
By subtractive cloning to identify mRNAs expressed in mouse oligodendrocytes, Mitchelmore et al. (2002) cloned 2 major splice variants of mouse Zbtb20, which they called Hofl and Hofs. The deduced proteins contain 741 and 668 amino acids, respectively, and are 97% identical to their human counterparts. Hofl and Hofs differ only at their N termini, with Hofs lacking the first 73 amino acids of Hofl. Mitchelmore et al. (2002) also sequenced 4 additional splice variants encoding the same protein as Hofl, and 2 additional splice variants encoding the same protein as Hofs. Western blot analysis of in vitro-translated Hofl resulted in proteins corresponding to both Hofl and Hofs, suggesting that the Hofl translational start site is suboptimal. Immunohistochemical analysis of developing mouse brain showed that Hofl and Hofs were specifically expressed in early hippocampal neurons, cerebellar granule cells, and gliogenic progenitors, as well as in differentiated glia. In developing cerebral cortex, Hof expression was restricted to the hippocampal subdivision, and expression coincided with early differentiation of presumptive CA1 and CA3 pyramidal neurons and dentate gyrus granule cells, with a sharp decline in expression at the CA1/subicular border. Hof expression was downregulated in differentiated hippocampal cells.
Mitchelmore et al. (2002) determined that the ZBTB20 gene contains 11 exons and may span up to 700 kb. Exons 8 and 10 have translational start sites.
By FISH and radiation hybrid analysis, Harboe et al. (2000) mapped the ZNF288 gene to chromosome 3q13.2.
The alpha-fetoprotein gene (AFP; 104150) is highly activated in fetal liver but is dramatically repressed shortly after birth. Using chromatin immunoprecipitation analysis and reporter gene assays, Xie et al. (2008) showed that mouse Zbtb20 bound to the Afp promoter and inhibited Afp transcription in a dose-dependent manner. Immunohistochemical analysis showed that Zbtb20 was expressed in the nucleus of adult mouse hepatocytes. Furthermore, RT-PCR and Western blot analysis demonstrated an inverse relationship in the expression of Zbtb20 and Afp in fetal and adult liver.
Using protein pull-down assays, Mitchelmore et al. (2002) showed that mouse Hofl and Hofs interacted strongly in both homotypic and heterotypic interactions and that the BTB/POZ domain seemed to be the major interaction interface. Isolated Hof zinc fingers bound a DNA sequence that interacts with PLZF (ZBTB16; 176797).
In 8 patients with Primrose syndrome (PRIMS; 259050), Cordeddu et al. (2014) identified heterozygosity for de novo missense variants in the ZBTB20 gene (see, e.g., 606025.0001-606025.0004). Functional analysis showed strongly reduced DNA binding for all mutants compared to wildtype, and results were consistent with the mutations having a dominant-negative impact on the wildtype allele.
In a 4-year-old boy with Primrose syndrome, Mattioli et al. (2016) identified heterozygosity for 2 de novo missense mutations on the same allele of the ZBTB20 gene (606025.0005).
In a 14-year-old boy with Primrose syndrome, Grimsdottir et al. (2019) identified heterozygosity for a de novo missense mutation in the ZBTB20 gene (H600Q; 606025.0006).
In 2 unrelated patients with Primrose syndrome, Stellacci et al. (2018) identified de novo heterozygous mutations in the ZBTB20 gene: the first reported frameshift mutation (c.1024delC; 606025.0007) and a missense mutation (T644I; 606025.0008) in the third zinc finger motif of the protein. The authors noted that previously reported mutations occurred in the first and second zinc finger motifs. Functional data showed that both mutations result in stable but dysfunctional proteins characterized by impaired binding to DNA, consistent with a dominant-negative effect.
In a 2-year-old boy and an unrelated 27-year-old man with Primrose syndrome, Ferreira et al. (2019) identified heterozygous missense mutations in the ZBTB20 gene. The boy carried a de novo cys608-to-arg (C608R; 606025.0009) substitution, and the man carried a met625-to-val (M625V; 606025.0010) substitution. The mutations in both patients occurred in the last coding exon of the ZBTB20 gene and in the second zinc finger domain of the ZBTB20 protein. Neither variant was present in large population databases, including gnomAD.
By trio exome sequencing in 5 unrelated patients with Primrose syndrome, Cleaver et al. (2019) identified de novo missense mutations in the ZBTB20 gene. Consistent with previous reports, all 5 mutations occurred within the C2H2 zinc finger domains. Two of the patients (patients 4 and 5) had mutations in the third zinc finger domain (e.g., 606025.0011), where only 2 mutations had previously been identified. Mosaicism for the variant in blood and saliva was noted in patient 4.
Xie et al. (2008) created mice with Zbtb20 knockout directed to liver. These mice were born at the expected ratio and appeared normal, with livers of normal size and architecture. Mutant hepatocytes differentiated normally. RT-PCR showed that adult Zbtb20-knockout liver expressed Afp mRNA levels about 3,000-fold higher than normal adult liver. Afp mRNA was activated gradually in both wildtype and Zbtb20-knockout fetal liver, but only wildtype liver showed a precipitous decline in Afp expression in the first 4 weeks of life. Afp mRNA levels declined less than 5-fold and remained high in Zbtb20-knockout liver, suggesting a failure of transcriptional shutoff. Xie et al. (2008) concluded that ZBTB20 is a key regulator that blocks AFP expression in adult liver.
Sutherland et al. (2009) found that Zbtb20 -/- mice were born at mendelian frequencies, but that they exhibited growth retardation accompanied by hypoglycemia, and all died by 12 weeks of age. All tissues except hippocampus appeared normal. Comprehensive serum chemistry analysis revealed severe widespread metabolic dysfunction, including abnormal glucose homeostasis and hormonal responses. Zbtb20 -/- mice were hypoglycemic in both the fed and fasted states and showed almost complete absence of glycogen stores. Microarray analysis revealed significant changes in expression of transcripts involved in growth, glucose metabolism, and detoxification. Reexpression of Zbtb20 specifically in livers of Zbtb20 -/- mice resulted in no significant normalization of growth or glucose metabolism, but it significantly increased life span compared with Zbtb20 -/- mice. Sutherland et al. (2009) concluded that the phenotype of Zbtb20 -/- mice results from liver-dependent and liver-independent defects.
In an 8-year-old girl with Primrose syndrome (PRIMS; 259050), Cordeddu et al. (2014) identified heterozygosity for a de novo c.1787A-G transition in exon 3 of the ZBTB20 gene, resulting in a his596-to-arg (H596R) substitution at a highly conserved residue, located in the first zinc finger, that coordinates the Zn(2+) ion. Transient transfection experiments in HEK293T cells showed nuclear localization of the mutant, although a distinctive nonhomogeneous distribution pattern suggestive of protein aggregation was observed. Treatment with CSK buffer indicated that the H596R mutant loosely interacted with chromatin, in contrast to wildtype protein. DNA-binding assays demonstrated strongly reduced DNA binding for the H596R mutant, which correlated with strongly reduced ability to repress transcription of a reporter gene. Reduced levels of DNA-bound ZBTB20 and less efficient AFP promoter repression were also observed in cells coexpressing the wildtype protein and the H596R mutant, consistent with a dominant-negative effect of the mutant on the wildtype allele.
In a 26-year-old man with Primrose syndrome (PRIMS; 259050), originally reported by Carvalho and Speck-Martins (2011), Cordeddu et al. (2014) identified heterozygosity for a de novo c.1861C-T transition in exon 4 of the ZBTB20 gene, resulting in a leu621-to-phe (L621F) substitution at a highly conserved residue in the second zinc finger. Assays in transfected HEK293T cells demonstrated strongly reduced DNA binding for the L621F mutant, which correlated with strongly reduced ability to repress transcription of a reporter gene. Reduced levels of DNA-bound ZBTB20 and less efficient AFP promoter repression were also observed in cells coexpressing the wildtype protein and the L621F mutant, consistent with a dominant-negative effect of the mutant on the wildtype allele.
In a 31-year-old man with Primrose syndrome (PRIMS; 259050), originally reported by Posmyk et al. (2011), Cordeddu et al. (2014) identified heterozygosity for a de novo c.1768A-C transversion in exon 3 of the ZBTB20 gene, resulting in a lys590-to-gln (K590Q) substitution at a highly conserved residue in the first zinc finger. Transient transfection experiments in HEK293T cells showed nuclear localization of the mutant, although a distinctive nonhomogeneous distribution pattern suggestive of protein aggregation was observed. Treatment with CSK buffer indicated that the K590Q mutant loosely interacted with chromatin, in contrast to wildtype protein. DNA-binding assays demonstrated strongly reduced DNA binding for the K590Q mutant, which correlated with strongly reduced ability to repress transcription of a reporter gene. Reduced levels of DNA-bound ZBTB20 and less efficient AFP promoter repression were also observed in cells coexpressing the wildtype protein and the K590Q mutant, consistent with a dominant-negative effect of the mutant on the wildtype allele.
In a 43-year-old man with Primrose syndrome (PRIMS; 259050), Cordeddu et al. (2014) identified heterozygosity for a de novo c.1805G-C transversion in exon 4 of the ZBTB20 gene, resulting in a gly602-to-ala (G602A) substitution at a highly conserved residue in the linker between the first and second zinc finger motifs. Assays in transfected HEK293T cells demonstrated strongly reduced DNA binding for the G602A mutant, which correlated with strongly reduced ability to repress transcription of a reporter gene. Reduced levels of DNA-bound ZBTB20 and less efficient AFP promoter repression were also observed in cells coexpressing the wildtype protein and the G602A mutant, consistent with a dominant-negative effect of the mutant on the wildtype allele.
In a 4-year-old boy with Primrose syndrome (PRIMS; 259050), Mattioli et al. (2016) identified heterozygosity for 2 de novo missense mutations located on the same allele of the ZBTB20 gene: c.1847C-T (c.1847C-T, NM_001164342.1) and c.2221G-A (c.2221G-A, NM_001164342.1) transitions in the last coding exon, resulting in ser616-to-phe (S616F) and gly741-to-arg (G741R) substitutions, respectively, at highly conserved residues within the C2H2 zinc finger domain. Neither mutation was present in his unaffected parents, and allele-specific amplification confirmed that the mutations were in cis.
In a 14-year-old boy with Primrose syndrome (PRIMS; 259050), Grimsdottir et al. (2019) identified heterozygosity for a de novo c.1800C-G transversion (c.1800C-G, NM_001164342.1) in exon 4 of the ZBTB20 gene, resulting in a his600-to-gln (H600Q) substitution at a highly conserved residue in a zinc finger domain thought to be essential for protein stabilization. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was not present in his parents or healthy sibs or in the gnomAD database.
In an 8-year-old boy (patient 1) with Primrose syndrome (PRIMS; 259050), Stellacci et al. (2018) identified a de novo heterozygous 1-bp deletion (c.1024delC, NM_001164342.2) in exon 4 of the ZBTB20 gene, predicted to result in a frameshift and premature termination (Gln342SerfsTer42), with the mutant protein lacking the entire C-terminal ZNF domain and having disrupted DNA binding capacity. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing,
In a 3-year-old girl (patient 2) with Primrose syndrome (PRIMS; 259050), Stellacci et al. (2018) identified a de novo heterozygous c.1931C-T transition (c.1931C-T, NM_001164342.2) in exon 5 of the ZBTB20 gene, resulting in a thr644-to-ile (T644I) substitution at a highly conserved residue in the third ZNF motif. The mutation was found by trio exome sequencing and confirmed by Sanger sequencing. Functional data indicated that the mutation impairs proper binding to DNA, with a dominant-negative effect.
In a 2-year-old (SCV000899114) boy with Primrose syndrome (PRIMS; 259050), Ferreira et al. (2019) identified a heterozygous de novo c.1822T-C transition (c.1822T-C, NM_001164342.2) in exon 5 (coding exon 4) of the ZBTB20 gene, resulting in a cys608-to-arg (C608R) substitution in the second zinc finger domain. The variant was identified by trio exome sequencing and was absent from the gnomAD database. Functional studies of the variant were not performed.
By Sanger sequencing in a 28-year-old Brazilian man with Primrose syndrome (PRIMS; 259050), Ferreira et al. (2019) identified a heterozygous c.1873A-G transition (c.1873A-G, NM_001164342.2) in exon 5 (coding exon 4) of the ZBTB20 gene, resulting in a met625-to-val (M625V) substitution in the second zinc finger domain. The variant was not found in the patient's mother or healthy sibs; paternal DNA was unavailable. The variant was not present in population databases, including gnomAD. Functional studies of the variant were not performed.
In a 13-year-old boy with Primrose syndrome (PRIMS; 259050), Cleaver et al. (2019) identified a heterozygous de novo c.1967A-G transition in the ZBTB20 gene that resulted in a his656-to-arg (H656R) substitution in the third zinc finger domain. The mutation was found by trio-based exome sequencing. Functional studies of the variant were not performed.
Carvalho, D. R., Speck-Martins, C. E. Additional features of unique Primrose syndrome phenotype. Am. J. Med. Genet. 155A: 1379-1383, 2011. [PubMed: 21567911] [Full Text: https://doi.org/10.1002/ajmg.a.33955]
Cleaver, R., Berg, J., Craft, E., Foster, A., Gibbons, R. J., Hobson, E., Lachlan, K., Naik, S., Sampson, J. R., Sharif, S., Smithson, S., Deciphering Developmental Disorders Study, Parker, M. J., Tatton-Brown, K. Refining the Primrose syndrome phenotype: a study of five patients with ZBTB20 de novo variants and a review of the literature. Am. J. Med. Genet. 179A: 344-349, 2019. [PubMed: 30637921] [Full Text: https://doi.org/10.1002/ajmg.a.61024]
Cordeddu, V., Redeker, B., Stellacci, E., Jongejan, A., Fragale, A., Bradley, T. E. J., Anselmi, M., Ciolfi, A., Cecchetti, S., Muto, V., Bernardini, L., Azage, M., and 15 others. Mutations in ZBTB20 cause Primrose syndrome. Nature Genet. 46: 815-817, 2014. [PubMed: 25017102] [Full Text: https://doi.org/10.1038/ng.3035]
Ferreira, L. D., Borges-Medeiros, R. L., Thies, J., Schnur, R. E., Lam, C., de Oliveira, J. R. M. Expansion of the Primrose syndrome phenotype through the comparative analysis of two new case reports with ZBTB20 variants. Am. J. Med. Genet. 179A: 2228-2232, 2019. [PubMed: 31321892] [Full Text: https://doi.org/10.1002/ajmg.a.61297]
Grimsdottir, S., Hove, H. B., Kreiborg, S., Ek, J., Johansen, A., Darvann, T. A., Hermann, N. V. Novel de novo mutation in ZBTB20 in primrose syndrome in boy with short stature. Clin. Dysmorph. 28: 41-45, 2019. [PubMed: 30256248] [Full Text: https://doi.org/10.1097/MCD.0000000000000244]
Harboe, T. L., Tumer, Z., Hansen, C., Jensen, N. A., Tommerup, N. Assignment of the human zinc finger gene, ZNF288, to chromosome 3 band q13.2 by radiation hybrid mapping and fluorescence in situ hybridisation. Cytogenet. Cell Genet. 89: 156-157, 2000. [PubMed: 10965110] [Full Text: https://doi.org/10.1159/000015600]
Mattioli, F., Piton, A., Gerard, B., Superti-Furga, A., Mandel, J.-L., Unger, S. Novel de novo mutations in ZBTB20 in Primrose syndrome with congenital hypothyroidism. Am. J. Med. Genet. 170A: 1626-1629, 2016. [PubMed: 27061120] [Full Text: https://doi.org/10.1002/ajmg.a.37645]
Mitchelmore, C., Kjaerulff, K. M., Pedersen, H. C., Nielsen, J. V., Rasmussen, T. E., Fisker, M. F., Finsen, B., Pedersen, K. M., Jensen, N. A. Characterization of two novel nuclear BTB/POZ domain zinc finger isoforms: association with differentiation of hippocampal neurons, cerebellar granule cells, and macroglia. J. Biol. Chem. 277: 7598-7609, 2002. [PubMed: 11744704] [Full Text: https://doi.org/10.1074/jbc.M110023200]
Posmyk, R., Lesniewicz, R., Chorazy, M., Wolczynski, S. New case of Primrose syndrome with mild intellectual disability. Am. J. Med. Genet. 155A: 2838-2840, 2011. [PubMed: 21910247] [Full Text: https://doi.org/10.1002/ajmg.a.34257]
Stellacci, E., Steindl, K., Joset, P., Mercurio, L., Anselmi, M., Cecchetti, S., Gogoll, L., Zweier, M., Hackenberg, A., Bocchinfuso, G., Stella, L., Tartaglia, M., Rauch, A. Clinical and functional characterization of two novel ZBTB20 mutations causing Primrose syndrome. Hum. Mutat. 39: 959-964, 2018. [PubMed: 29737001] [Full Text: https://doi.org/10.1002/humu.23546]
Sutherland, A. P. R., Zhang, H., Zhang, Y., Michaud, M., Xie, Z., Patti, M.-E., Grusby, M. J., Zhang, W. J. Zinc finger protein Zbtb20 is essential for postnatal survival and glucose homeostasis. Molec. Cell. Biol. 29: 2804-2815, 2009. [PubMed: 19273596] [Full Text: https://doi.org/10.1128/MCB.01667-08]
Xie, Z., Zhang, H., Tsai, W., Zhang, Y., Du, Y., Zhong, J., Szpirer, C., Zhu, M., Cao, X., Barton, M. C., Grusby, M. J., Zhang, W. J. Zinc finger protein ZBTB20 is a key repressor of alpha-fetoprotein gene transcription in liver. Proc. Nat. Acad. Sci. 105: 10859-10864, 2008. [PubMed: 18669658] [Full Text: https://doi.org/10.1073/pnas.0800647105]
Zhang, W., Mi, J., Li, N., Sui, L., Wan, T., Zhang, J., Chen, T., Cao, X. Identification and characterization of DPZF, a novel human BTB/POZ zinc finger protein sharing homology to BCL-6. Biochem. Biophys. Res. Commun. 282: 1067-1073, 2001. [PubMed: 11352661] [Full Text: https://doi.org/10.1006/bbrc.2001.4689]