Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: ZMYM2
Cytogenetic location: 13q12.11 Genomic coordinates (GRCh38): 13:19,863,840-20,089,115 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q12.11 | Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities | 619522 | Autosomal dominant | 3 |
ZMYM2 contains a DUF3504 domain, related to the tyrosine recombinase (YR) element of Crypton DNA transposons present in lower organisms. The DUF3504 domain is derived from the YR element of Cryptons but lacks the complete catalytic tetrad essential for YR activity. Proteins that contain a DUF3504 domain function as transcriptional activators or repressors (Kojima and Jurka, 2011).
Xiao et al. (1998) identified the ZNF198 gene as a translocation partner of the fibroblast growth factor receptor-1 gene (FGFR1; 136350) in the 8p11 myeloproliferative syndrome (613523), also known as stem cell leukemia/lymphoma (SCLL) syndrome, caused by a specific chromosome translocation, t(8;13)(p11;q11-12) (see CYTOGENETICS). The ZNF198 cDNA sequence predicted an 87.1-kD protein with 4 atypical zinc fingers. Northern blot analysis revealed ubiquitous expression of a 4.5-kb transcript, with most tissues also expressing 7.5- and 10-kb transcripts.
Smedley et al. (1998) also identified the ZNF198 gene, which they called RAMP, and found that the predicted protein exhibits strong homology with the DXS6673E gene product (ZMYM3; 300061).
Popovici et al. (1998) found that full-length ZNF198, which they called FIM, encodes a deduced 1,379-amino acid protein that is largely hydrophilic.
Reiter et al. (1998) found that full-length ZNF198 encodes a deduced protein of 1,377 amino acids with a calculated molecular mass of 155 kD. It shares significant homology with the DXS6673E and KIAA0425 gene products. Alignment of these 3 proteins revealed a novel conserved zinc finger-related motif, the MYM domain, that was repeated 5 times in each protein. ZNF198 also has a proline-rich region located C-terminal to the last MYM domain. Kunapuli et al. (2006) noted that full-length ZNF198 has a C-terminal acidic domain containing a putative nuclear localization signal.
Using RT-PCR, Kulkarni et al. (1999) detected several ZNF198 splice variants resulting from the use of alternative promoters, skipping of noncoding exons 2 and/or 3, and alternative splicing within exon 4 that reduces the length of the predicted protein by 87 amino acids.
Inoue et al. (2004) found that Fim mRNA and protein were ubiquitously expressed in mouse embryonic tissues. However, Fim mRNA and protein showed relatively low expression in hematopoietic cells of the aorta-gonad-mesonephros region, an area where definitive hematopoiesis first develops, on embryonic day 11.5.
Using database analysis to identify Crypton-related proteins, Kojima and Jurka (2011) identified ZMYM2. The deduced protein has a central MYM-type zinc finger domain, followed by a proline-rich region, and a C-terminal 313-amino acid DUF3504 domain. The DUF3504 domain of ZMYM2 is very similar to that of ZMYM3 (300061) and ZMYM4 (613568). Orthologs of ZMYM proteins were detected in vertebrates, and more distantly in chordates and invertebrates.
By mass spectrometric analysis, Hakimi et al. (2003) identified ZNF198 as a subunit of HDAC2 (605164)- and BHC110 (KDM1A; 609132)-containing repressor complexes isolated from HeLa cell nuclear extracts. Other proteins that immunopurified with both HDAC2 and BHC110 included KIAA0182 (GSE1; 616886), ZNF261 (ZMYM3; 300061), and TFII-I (GTF2I; 601679). The authors noted that these proteins are likely subunits of multiple distinct HDAC2- and BHC110-containing complexes.
Inoue et al. (2004) showed that forced expression of Fim in the embryonic mouse aorta-gonad-mesonephros region had no significant effect on survival of adherent cells, but it almost completely inhibited the emergence of Cd45 (PTPRC; 151460)-positive hematopoietic cells. The results suggested that FIM may negatively control differentiation from hemangioblasts to hematopoietic cells. Inoue et al. (2004) proposed that the leukemia-associated t(8;13) translocation may result in loss of the negative regulatory domain of FIM, in addition to activating the tyrosine kinase domain of FGFR1.
By yeast 2-hybrid analysis of a human fetal brain cDNA library, followed by coimmunoprecipitation analysis, Kunapuli et al. (2006) found that ZNF198 was covalently modified by SUMO1 (601912). Confocal microscopy showed that a proportion of ZNF198 colocalized with SUMO1 and PML (102578) in PML nuclear bodies, and coimmunoprecipitation analysis revealed that all 3 proteins resided in a protein complex. Mutation of lys963 within the SUMO1-binding site of ZNF198 resulted in degradation of ZNF198, nuclear dispersal of PML, and loss of punctate PML nuclear bodies. Kunapuli et al. (2006) found that the MDA-MB-157 breast cancer cell line, which has a deletion in chromosome 13q11 encompassing the ZNF198 gene, lacked PML nuclear bodies, although PML protein levels appeared normal. The fusion protein ZNF198/FGFR1, which lacks the SUMO1-binding site of ZNF198, could dimerize with wildtype ZNF198 and disrupt its function. Expression of ZNF198/FGFR1 disrupted PML sumoylation and nuclear body formation and resulted in cytoplasmic localization of SUMO1. Kunapuli et al. (2006) concluded that sumoylation of ZNF198 is required for PML nuclear body formation. They hypothesized that abrogation of sumoylation of ZNF198 in ZNF198/FGFR1-expressing cells may be an important mechanism in cellular transformation.
A transcriptional corepressor complex containing LSD1 (KDM1A), COREST (RCOR; 607675), and HDAC1 (601241) represses transcription by removing histone modifications associated with transcriptional activation. Gocke and Yu (2008) found that ZNF198 and REST (600571) interacted with LSD1/COREST/HDAC1 in a mutually exclusive manner in human cell lines. ZNF198 was required for repression of E-cadherin (CDH1; 192090), but not REST-responsive genes. ZNF198 interacted with chromatin and stabilized the LSD1/COREST/HDAC1 complex on chromatin. Interaction of ZNF198 with chromatin required the proline/valine-rich region of ZNF198, but multiple regions of ZNF198 contributed to the interaction. The MYM domain of ZNF198 mediated interaction of ZNF198 with LSD1/COREST/HDAC1. Sumoylation of HDAC1 by SUMO2 (603042) enhanced its binding to ZNF198 via a noncovalent mechanism, but it also weakened the interaction between HDAC1 and COREST.
Kulkarni et al. (1999) determined that the ZNF198 gene contains 27 exons, including alternative first exons 1a and 1b, which contain alternative promoters. Exon 4 contains the initiation codon, and introns 8 and 17 contain repetitive elements. Kulkarni et al. (1999) identified noncanonical GC donor splice sites for introns 11, 12, and 13.
Independently, Xiao et al. (1998), Smedley et al. (1998), Popovici et al. (1998), and Reiter et al. (1998) identified the ZNF198 gene on chromosome 13q11-q12.
Kulkarni et al. (1999) determined that the ZNF198 gene on chromosome 13q12 is oriented from telomere to centromere.
Kojima and Jurka (2011) determined that the ancestral gene of Drosophila Woc and mammalian ZMYM genes originated in the common ancestor of all bilaterians more than 910 million years ago, and represents the third-oldest transposon domestication event known, following those that generated TERT (187270) and PRP8 (607300). The ZMYM2, ZMYM3, and ZMYM4 genes were duplicated from a single gene during 2 rounds of whole-genome duplication in the early evolution of vertebrates, before the split between agnathans and jawed vertebrates.
Xiao et al. (1998) demonstrated that the aberrant transcripts resulting from the translocation t(8;13)(p11;q11-12) in patients with 8p11 myeloproliferative syndrome (613523) fused predicted zinc finger domains of the ZNF198 gene on chromosome 13 to the tyrosine-kinase domain of the FGFR1 gene on chromosome 8. Transient expression studies showed that the ZNF198/FGFR1 fusion transcript directed the synthesis of an approximately 87-kD polypeptide that localized predominantly to the cytoplasm.
Smedley et al. (1998) also determined that the 8p11;13q11-12 translocation results in the fusion of FGFR1, at 8p11, to the ZNF198 gene, which they designated RAMP, at 13q11-q12. RT-PCR detected only 1 of the 2 possible fusion transcripts, encoding a product in which the N-terminal 641 amino acids of ZNF198 became joined to the tyrosine kinase domain of FGFR1. Smedley et al. (1998) proposed that the ZNF198/FGFR1 fusion product contributed to progression of the myeloproliferative disorder by constitutive activation of tyrosine kinase function.
Popovici et al. (1998) described the molecular characterization of the t(8;13) translocation involving the FGFR1 gene and the ZNF198 gene, which they tentatively named FIM. The 2 reciprocal fusion transcripts, ZNF198/FGFR1 and FGFR1/ZNF198, were expressed in malignant cells. The ZNF198/FGFR1 fusion protein contained the ZNF198 putative zinc finger motifs and the catalytic domain of FGFR1, and the authors showed that the protein has a constitutive tyrosine kinase activity.
Reiter et al. (1998) detected an identical ZNF198/FGFR1 fusion in 3 patients with SCLL and t(8;13) for whom RNA was available; reciprocal FGFR1/ZNF198 transcripts were not detected. The fusion included the 5 MYM domains of ZNF198 and the intracellular tyrosine kinase domain of FGFR1. Reiter et al. (1998) hypothesized that this fusion leads to constitutive activation of the FGFR1 tyrosine kinase in a manner analogous to the activation of ABL by BCR in chronic myeloid leukemia.
Kulkarni et al. (1999) determined that the common t(8;13)(p11;q12) translocation results in a consistent fusion between ZNF198 exon 17 and FGFR1 exon 9. However, amplification of genomic DNA from 6 patients with t(8;13) revealed patient-specific products, suggesting clustering of several breakpoints. An additional patient showed a breakpoint within ZNF198 exon 18.
In 19 patients from 15 unrelated families with neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities (NECRC; 619522), Connaughton et al. (2020) identified heterozygous frameshift, nonsense, or splice site mutations in the ZMYM2 gene (see, e.g., 602221.0001-602221.0006). Mutations in the first few families were found by whole-exome sequencing; subsequent families were identified through the GeneMatcher Program. The mutations, which occurred throughout the gene, mostly occurred de novo, although some were inherited from an affected parent. There was at least 1 instance of mosaicism. All the mutations were predicted to result in nonsense-mediated mRNA decay with a loss of function. In vitro functional expression studies in HEK293 cells transfected with a subset of the predicted truncated proteins showed altered ZMYM2 intracellular localization compared to wildtype, with retention primarily or entirely within the cytoplasm and decreased or absent nuclear localization. Three truncated proteins tested had impaired interaction with FOXP1 (605515) and FOXP2 (605317) compared to wildtype. Although the findings were most consistent with haploinsufficiency, the authors could not exclude a dominant-negative effect for some of the ZMYM2 variants.
Connaughton et al. (2020) found that complete knockdown of the zmym2 gene in X. tropicalis resulted in impaired pronephric development that could not be rescued by expression of the truncated mutations tested. In addition, mutant animals developed craniofacial abnormalities. CRISPR-Cas9 technology was used to generate a heterozygous mutant mouse recapitulating a human frameshift Zmym2 mutation (602221.0003). Mutant mice showed a spectrum of CAKUT-like defects including hydroureter, duplex kidneys, simplex kidneys, and vesicoureteral reflux. No additional phenotypes were observed in heterozygous mutant mice. Overall, the findings suggested a role for ZMYM2 in renal and perhaps craniofacial development.
In 2 unrelated patients of Macedonian descent (A4730-21 and A1204-21) with neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities (NECRC; 619522), Connaughton et al. (2020) identified a heterozygous c.1618C-T transition (c.1618C-T, NM_197968.2) in exon 8 of the ZMYM2 gene, resulting in an arg540-to-ter (R540X) substitution. The mutation was shown to be de novo in individual A4730-21; segregation status could not be assessed in the other family. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. The mutation was predicted to result in nonsense-mediated mRNA decay, but studies of patient cells were not performed. Detailed in vitro cellular studies and studies of animal models indicated that the mutation caused a loss of function and haploinsufficiency. The patients were ascertained from a cohort of 551 patients with CAKUT.
In an Italian girl (SSC3-21) with neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities (NECRC; 619522), Connaughton et al. (2020) identified a heterozygous 1-bp deletion (c.1607delG, NM_197968.2) in exon 8 of the ZMYM2 gene, resulting in a frameshift and premature termination (Cys536LeufsTer13). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Parental DNA was not available, so segregation status was unclear. The mutation was predicted to result in nonsense-mediated mRNA decay, but studies of patient cells were not performed. Detailed in vitro cellular studies and studies of animal models indicated that the mutation caused a loss of function and haploinsufficiency. The patient was ascertained due to the presence of renal anomalies consistent with CAKUT. She also had mild intellectual disability.
In a boy (GM1-21) with neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities (NECRC; 619522), Connaughton et al. (2020) identified a de novo heterozygous 2-bp duplication (c.766_767dupGT, NM_197968.2) in exon 3 of the ZMYM2 gene, resulting in a frameshift and premature termination (Gly257Ter). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. The mutation was predicted to result in nonsense-mediated mRNA decay, but studies of patient cells were not performed. Detailed in vitro cellular studies and animal models indicated that the mutation caused a loss of function and haploinsufficiency. The patient had renal anomalies, bicuspid aortic valve, hypotonia, and developmental delay.
In 2 sibs (GM6-21 and GM6-22) with neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities (NECRC; 619522), Connaughton et al. (2020) identified a heterozygous 4-bp deletion (c.2434_2437delAAAG, NM_197968.2) in exon 13 of the ZMYM2 gene, resulting in a frameshift and premature termination (Lys812AspfsTer18). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. The mutation was predicted to result in nonsense-mediated mRNA decay, but studies of patient cells were not performed. Detailed in vitro cellular studies and animal models indicated that the mutation may cause a loss of function and haploinsufficiency, although a dominant-negative effect was also suggested. Both patients had normal renal ultrasounds. One had cardiac septal defects, microcephaly, and developmental delay, whereas the other only had speech delay.
In a mother and her 2 sons (family GM18) with neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities (NECRC; 619522), Connaughton et al. (2020) identified a heterozygous G-to-A transition (c.2494-1G-A, NM_197968.2) in intron 15 of the ZMYM2 gene, predicted to result in splicing abnormalities and a loss of function. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. All 3 patients had atrial septal defects and neurologic abnormalities, but none were noted to have renal involvement.
In a girl (GM7-21) with neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities (NECRC; 619522), Connaughton et al. (2020) identified a heterozygous 2-bp duplication (c.3130_3131dupAA, NM_197968.2) in exon 19 of the ZMYM2 gene, resulting in a frameshift and premature termination (Gly1045ArgfsTer33). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. The mutation was predicted to result in nonsense-mediated mRNA decay, but studies of patient cells were not performed. Detailed in vitro cellular studies and animal models indicated that the mutation caused a loss of function and haploinsufficiency. She had normal renal and cardiac imaging, but had neurologic involvement manifest as microcephaly, developmental delay, and hypotonia.
Connaughton, D. M., Dai, R., Owen, D. J., Marquez, J., Mann, N., Graham-Paquin, A. L., Nakayama, M., Coyaud, E., Laurent, E. M. N., St-Germain, J. R., Blok, L. S., Vino, A., and 87 others. Mutations of the transcriptional corepressor ZMYM2 cause syndromic urinary tract malformations. Am. J. Hum. Genet. 107: 727-742, 2020. [PubMed: 32891193] [Full Text: https://doi.org/10.1016/j.ajhg.2020.08.013]
Gocke, C. B., Yu, H. ZNF198 stabilizes the LSD1-CoREST-HDAC1 complex on chromatin through its MYM-type zinc fingers. PLoS One 3: E3255, 2008. Note: Electronic Article. [PubMed: 18806873] [Full Text: https://doi.org/10.1371/journal.pone.0003255]
Hakimi, M.-A., Dong, Y., Lane, W. S., Speicher, D. W., Shiekhattar, R. A candidate X-linked mental retardation gene is a component of a new family of histone deacetylase-containing complexes. J. Biol. Chem. 278: 7234-7239, 2003. [PubMed: 12493763] [Full Text: https://doi.org/10.1074/jbc.M208992200]
Inoue, H., Nobuhisa, I., Okita, K., Takizawa, M., Pebusque, M.-J., Taga, T. Negative regulation of hematopoiesis by the fused in myeloproliferative disorders gene product. Biochem. Biophys. Res. Commun. 313: 125-128, 2004. [PubMed: 14672707] [Full Text: https://doi.org/10.1016/j.bbrc.2003.11.097]
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Kunapuli, P., Kasyapa, C. S., Chin, S.-F., Caldas, C., Cowell, J. K. ZNF198, a zinc finger protein rearranged in myeloproliferative disease, localizes to the PML nuclear bodies and interacts with SUMO-1 and PML. Exp. Cell Res. 312: 3739-3751, 2006. [PubMed: 17027752] [Full Text: https://doi.org/10.1016/j.yexcr.2006.06.037]
Popovici, C., Adelaide, J., Ollendorff, V., Chaffanet, M., Guasch, G., Jacrot, M., Leroux, D., Birnbaum, D., Pebusque, M.-J. Fibroblast growth factor receptor 1 is fused to FIM in stem-cell myeloproliferative disorder with t(8;13)(p12;q12). Proc. Nat. Acad. Sci. 95: 5712-5717, 1998. [PubMed: 9576949] [Full Text: https://doi.org/10.1073/pnas.95.10.5712]
Reiter, A., Sohal, J., Kulkarni, S., Chase, A., Macdonald, D. H. C., Aguiar, R. C. T., Goncalves, C., Hernandez, J. M., Jennings, B. A., Goldman, J. M., Cross, N. C. P. Consistent fusion of ZNF198 to the fibroblast growth factor receptor-1 in the t(8;13)(p11;q12) myeloproliferative syndrome. Blood 92: 1735-1742, 1998. [PubMed: 9716603]
Smedley, D., Hamoudi, R., Clark, J., Warren, W., Abdul-Rauf, M., Somers, G., Venter, D., Fagan, K., Cooper, C., Shipley, J. The t(8;13)(p11;q11-12) rearrangement associated with an atypical myeloproliferative disorder fuses the fibroblast growth factor receptor 1 gene to a novel gene RAMP. Hum. Molec. Genet. 7: 637-642, 1998. [PubMed: 9499416] [Full Text: https://doi.org/10.1093/hmg/7.4.637]
Xiao, S., Nalabolu, S. R., Aster, J. C., Ma, J., Abruzzo, L., Jaffe, E. S., Stone, R., Weissman, S. M., Hudson, T. J., Fletcher, J. A. FGFR1 is fused with a novel zinc-finger gene, ZNF198, in the t(8;13) leukaemia/lymphoma syndrome. Nature Genet. 18: 84-87, 1998. [PubMed: 9425908] [Full Text: https://doi.org/10.1038/ng0198-84]