Alternative titles; symbols
HGNC Approved Gene Symbol: ZNF143
Cytogenetic location: 11p15.4 Genomic coordinates (GRCh38) : 11:9,461,012-9,528,524 (from NCBI)
Transcriptional regulatory proteins containing tandemly repeated zinc finger domains are thought to be involved in both normal and abnormal cellular proliferation and differentiation. One abundant class of such transcriptional regulators resembles the Drosophila Kruppel segmentation gene product due to the presence of repeated Cys2-His2 (C2H2) zinc finger domains that are connected by conserved sequences, called H/C links. See ZNF91 (603971) for general information on zinc finger proteins.
ZNF143 is a transcriptional activator involved in regulation of coding and noncoding genes (summary by Pupavac et al., 2016).
Vertebrate small nuclear RNA (snRNA) gene promoters are among the most active known in growing cultured cells. Both proximal and distal sequence elements (PSE and DSE, respectively) in these promoters play a major role in transcription efficiency. The DSE, located approximately 200 bp upstream of the transcription start site, contains 2 adjacent elements, 1 of which is often an SPH motif. Schuster et al. (1995) isolated Staf (selenocysteine tRNA gene transcription-activating factor), a Xenopus transcription factor that binds to the SPH motifs present in the selenocysteine tRNA gene (TRSP; 165060) promoter and activates the RNA polymerase III (pol III) promoter of the TRSP gene. Staf contains 7 zinc fingers and a separate acidic activation domain. Schaub et al. (1997) demonstrated that activation of the majority of vertebrate snRNA and snRNA-type genes, transcribed by RNA polymerase II (pol II) and pol III, also requires Staf. Schuster et al. (1998) reported that Staf can also stimulate expression from a pol II mRNA promoter. Staf contains 2 physically distinct activation domains: a 93-amino acid domain with 4 repeated units activates mRNA promoters, and an 18-amino acid segment acts specifically on pol II and pol III snRNA and snRNA-type promoters.
By screening a human insulinoma cDNA library with a degenerate oligonucleotide corresponding to the H/C linker sequence, Tommerup et al. (1993) isolated cDNAs potentially encoding zinc finger proteins. Tommerup and Vissing (1995) performed sequence analysis on a number of these cDNAs and identified several zinc finger protein genes, including ZNF143. The ZNF143 cDNA predicts a protein that is a GLI (165220)-type member of the Kruppel family of zinc finger proteins.
By searching an EST database for human sequences related to Staf, Myslinski et al. (1998) found that 2 previously identified zinc finger proteins, ZNF76 (194549) and ZNF143 (Tommerup and Vissing, 1995), had homology to Staf. The predicted 626-amino acid ZNF143 protein shared 84% identity with Staf, while ZNF76 was only 64% identical, leading Myslinski et al. (1998) to conclude that ZNF143 is the human ortholog of Staf. Like Staf, both ZNF76 and ZNF143 contain 7 zinc fingers and an activation domain with the mRNA and snRNA activation regions. Both proteins bound Staf-responsive elements in vitro. When expressed in Drosophila cells, both activated transcription from an mRNA promoter through the Staf binding site. Chimeric ZNF76 and ZNF143 proteins activated a pol II mRNA promoter and snRNA pol II and pol III promoters in Xenopus oocytes. Northern blot analysis revealed that the 3.5-kb ZNF143 mRNA was expressed in all tissues tested, with the strongest expression in ovary. Independently, Rincon et al. (1998) isolated cDNAs encoding ZNF143, or SBF (SPH-binding factor). They found that antibodies against SBF inhibited assembly of native SBF-DNA complexes. In vitro, SBF stimulated transcription by pol III from a U6 (180692) snRNA gene promoter containing an SPH element.
By fluorescence in situ hybridization, Tommerup and Vissing (1995) mapped the ZNF143 gene to 11p15.4-p15.3.
Associations Pending Confirmation
For discussion of a possible association between mutation in the ZNF143 gene and a disorder of cobalamin metabolism, see 603433.0001 and 603433.0002.
This variant is classified as a variant of unknown significance because its contribution to a disorder of cobalamin metabolism has not been confirmed.
In a 16-month-old Hispanic boy with a disorder of cobalamin metabolism, Pupavac et al. (2016) identified compound heterozygous mutations in the ZNF143 gene: a c.851T-G transversion, resulting in a leu284-to-ter (L284X), and a c.1019C-T transition, resulting in a thr340-to-ile (T340I; 603433.0002) substitution. The mutations, which were identified by whole-exome sequencing, were confirmed by Sanger sequencing. Each parent was a carrier of one of the mutations. The L284X mutation was not present in the ExAC database and the T340I mutation was present once in heterozygous state. Sequencing of cDNA from patient fibroblasts showed decreased expression from the ZNF143 allele with the L284X mutation, suggesting that the mutation was subject to nonsense-mediated decay. Patient fibroblasts also had low expression of MMACHC (609831). Biotinylation proximity assays showed that HCFC1 (300019) was the most enriched in proximity to ZNF143. Functional studies in patient fibroblasts with labeled cyanocobalamin showed defective synthesis of both adenosylocobalamin and hydroxocobalamin. Transcobalamin-bound cyanocobalamin accumulated in the lysosomes of patient fibroblasts, indicating trapping in lysosomes. Clinical features in the patient included bilateral cleft palate, microcephaly, hypertelorism, hypospadias, and a ventricular septal defect at birth. He received a gastrostomy tube at 1 month of age. At 16 months of age, he had epilepsy, progressive encephalopathy, hypotonia, combined immunodeficiency, nystagmus, cortical blindness, hearing loss, and prolonged QT interval. Biochemical testing showed elevated urinary methylmalonic acid and increased serum methylmalonic acid and total homocysteine. He died at 26 months of age from hypercarbic respiratory failure.
This variant is classified as a variant of unknown significance because its contribution to a disorder of cobalamin metabolism has not been confirmed.
For discussion of the c.1019C-T transition in the ZNF143 gene, resulting in a thr340-to-ile (T340I), that was identified in compound heterozygous state in a patient with a disorder of cobalamin metabolism by Pupavac et al. (2016), see 603433.0001.
Myslinski, E., Krol, A., Carbon, P. ZNF76 and ZNF143 are two human homologs of the transcriptional activator Staf. J. Biol. Chem. 273: 21998-22006, 1998. [PubMed: 9705341] [Full Text: https://doi.org/10.1074/jbc.273.34.21998]
Pupavac, M., Watkins, D., Petrella, F., Fahiminiya, S., Janer, A., Cheung, W., Gingras, A. C., Pastinen, T., Muenzer, J., Majewski, J., Shoubridge, E. A., Rosenblatt, D. S. Inborn error of cobalamin metabolism associated with the intracellular accumulation of transcobalamin-bound cobalamin and mutations in ZNF143, which codes for a transcriptional activator. Hum. Mutat. 37: 976-982, 2016. [PubMed: 27349184] [Full Text: https://doi.org/10.1002/humu.23037]
Rincon, J. C., Engler, S. K., Hargrove, B. W., Kunkel, G. R. Molecular cloning of a cDNA encoding human SPH-binding factor, a conserved protein that binds to the enhancer-like region of the U6 small nuclear RNA gene promoter. Nucleic Acids Res. 26: 4846-4852, 1998. [PubMed: 9776743] [Full Text: https://doi.org/10.1093/nar/26.21.4846]
Schaub, M., Myslinski, E., Schuster, C., Krol, A., Carbon, P. Staf, a promiscuous activator for enhanced transcription by RNA polymerase II and III. EMBO J. 16: 173-181, 1997. [PubMed: 9009278] [Full Text: https://doi.org/10.1093/emboj/16.1.173]
Schuster, C., Krol, A., Carbon, P. Two distinct domains in Staf to selectively activate small nuclear RNA-type and mRNA promoters. Molec. Cell. Biol. 18: 2650-2658, 1998. [PubMed: 9566884] [Full Text: https://doi.org/10.1128/MCB.18.5.2650]
Schuster, C., Myslinski, E., Krol, A., Carbon, P. Staf, a novel zinc finger protein that activates the RNA polymerase III promoter of the selenocysteine tRNA gene. EMBO J. 14: 3777-3787, 1995. [PubMed: 7641696] [Full Text: https://doi.org/10.1002/j.1460-2075.1995.tb00047.x]
Tommerup, N., Aagaard, L., Lund, C. L., Boel, E., Baxendale, S., Bates, G. P., Lehrach, H., Vissing, H. A zinc-finger gene ZNF141 mapping at 4p16.3/D4S90 is a candidate gene for the Wolf-Hirschhorn (4p-) syndrome. Hum. Molec. Genet. 2: 1571-1575, 1993. [PubMed: 8268908] [Full Text: https://doi.org/10.1093/hmg/2.10.1571]
Tommerup, N., Vissing, H. Isolation and fine mapping of 16 novel human zinc finger-encoding cDNAs identify putative candidate genes for developmental and malignant disorders. Genomics 27: 259-264, 1995. [PubMed: 7557990] [Full Text: https://doi.org/10.1006/geno.1995.1040]