Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: ZNF335
Cytogenetic location: 20q13.12 Genomic coordinates (GRCh38): 20:45,948,660-45,972,203 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.12 | Microcephaly 10, primary, autosomal recessive | 615095 | Autosomal recessive | 3 |
The ZNF335 gene encodes a component of a vertebrate-specific, trithorax H3K4-methylation chromatin remodeling complex that regulates neuronal gene expression and cell fate (summary by Yang et al., 2012).
Nuclear hormone receptors activate gene transcription through ligand-dependent association with coactivators such as NCOA6 (605299), also known as NRC. Using a segment of NCOA6 as bait in a yeast 2-hybrid screen of a rat GH4C1 cell cDNA library, Mahajan et al. (2002) isolated a partial rat cDNA. By screening a human teratoma phage library with the rat cDNA, followed by EST database searching and PCR, they cloned full-length ZNF335, which they called NIF1. The deduced 1,342-amino acid NIF1 protein contains 6 predicted C2H2 zinc fingers, of which the first 3 comprise a BED finger DNA-binding domain; an LXXLL motif; a C-terminal leucine zipper region; an N-terminal 35-amino acid region enriched in acidic residues; and putative protein kinase A and tyrosine kinase phosphorylation sites. By EST database analysis, Mahajan et al. (2002) identified a predicted 783-amino acid alternatively spliced isoform, NIF2, that lacks a region of NIF1 (amino acids 184-743) including zinc fingers 1-4. Northern blot analysis detected an approximately 5-kb NIF1 transcript with high expression in human skeletal muscle, thymus, placenta, and blood, moderate expression in colon, spleen, kidney, and lung, and lower expression in small intestine, heart, liver, and brain. Overexposure of the Northern blot detected a 2.5-kb transcript, consistent with the NIF2 isoform, in heart and skeletal muscle, and at lower levels in thymus, spleen, kidney, liver, placenta, and blood. The NIF2 isoform was not detected in small intestine or colon. Using fluorescence microscopy, Mahajan et al. (2002) localized NIF1 exclusively to the nucleus in COS-1 cells.
Using Northern blot analysis, Yang et al. (2012) found widespread expression of the ZNF335 gene in human developing embryo and adult tissues, including brain. Znf335 was expressed in the developing mouse brain at the height of cortical neurogenesis from E13 to E15. At E8.5, Znf335 was found in the ventricular and subventricular zones and in the developing cortical plate. At P5 to P30, Znf335 showed low levels of expression in the adult cerebral cortex, hippocampus, and cerebellum, possibly linked to neuronal maturation. Immunoreactivity was consistent with nuclear localization to DNA, suggesting a possible role in gene expression.
Using yeast 2-hybrid analysis and GST pull-down binding studies, Mahajan et al. (2002) identified the interaction domains between NIF1 and NCOA6: a 97-amino acid C-terminal region of NIF1 containing zinc finger-6, and amino acids 849-995 of NCOA6. The LXXLL1 receptor interaction motif of NCOA6 did not appear to be required for interaction with NIF1. Mahajan et al. (2002) found that NIF1, when expressed in HeLa cells, did not directly interact with ligand-bound nuclear hormone receptors, including ESR1 (133430), THRA (190120), RARA (180240), and GCCR (138040), but markedly enhanced their ligand-dependent transcriptional activation. Like NCOA6, NIF1 also enhanced the transcriptional activity of endogenous AP1 (see 165160), JUN (165160), and FOS (164810) in HeLa cells. Mahajan et al. (2002) showed that expression of NIF1 or NCOA6 alone increased transcriptional activation 3- to 5-fold, whereas their coexpression resulted in a 12-fold increase. Mahajan et al. (2002) concluded that NIF1 acts as a regulator or cotransducer of NCOA6 coactivator function.
Mahajan et al. (2002) determined that the ZNF335 gene contains 6 exons.
By genomic sequence analysis, Mahajan et al. (2002) mapped the ZNF335 gene to chromosome 20.
In affected members of an Arab Israeli family with autosomal recessive severe primary microcephaly-10 (MCPH10; 615095), Yang et al. (2012) identified a homozygous mutation in the ZNF335 gene (610827.0001). The mutation was identified by linkage analysis followed by candidate gene sequencing. The mutation caused both a missense change (R1111H) and a splice site defect, resulting in a hypomorphic allele. Patient lymphoblasts showed decreased growth and decreased ZNF335 binding to Ki-67 (176741). Cellular studies indicated that ZNF335 interacts with a chromatin-remodeling complex involving H3K4 methyltransferases, which regulates the expression of specific genes in a variety of pathways; the complex was analogous to the TrxG (trithorax) complex in Drosophila. ZNF335 bound to the promoter of the known neuronal progenitor cell master regulator REST (600571), resulting in its regulation. Patient cell lines showed decreased mRNA levels of REST and decreased H3K4me3 marks at the REST promoter, as well as decreased REST mRNA levels. Finally, in vitro and in vivo mouse models showed that knockdown of Znf335 caused a small brain with absent cortex and disrupted the proliferation and proper differentiation of neuronal cells. The study identified ZNF335 as an essential link between H3K4 complexes and REST, and showed that this pathway regulates human neurogenesis and neuronal differentiation.
In a 33-month-old girl, born to nonconsanguineous Japanese parents, with MCPH10, Sato et al. (2016) identified compound heterozygous missense mutations in the ZNF335 gene (C467R, 610827.0002 and Y504C, 610827.0003). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Each parent was heterozygous for one of the mutations.
In 2 unrelated boys with MCPH10, Stouffs et al. (2018) identified biallelic ZNF335 mutations. One boy, born to consanguineous parents of North African descent, was homozygous for the previously reported C467R mutation. The other boy, born to nonconsanguineous parents of Caucasian European descent, was compound heterozygous for deletion (610827.0004) and missense (610827.0005) mutations.
Yang et al. (2012) found that knockdown of the Znf335 ortholog in mice (Zfp335) resulted in early embryonic lethality at day E7.5. Conditional knockdown of Znf335 in mouse cortical cells resulted in a small brain with essentially absent cortex lacking cortical neurons. Knockdown of Znf335 in mouse neuronal progenitor cells caused decreased proliferation and self-renewal due to premature cell cycle exit. Similar findings were observed in an in vivo embryonic mouse model using in utero electroporation to target Znf335 in cortical progenitor cells. Znf335 depletion resulted in abnormal neuronal cell orientation and radial glia with disorganized dendritic outgrowth. Znf335 also appeared to play a role in neuronal differentiation. The defects could be rescued by wildtype Znf335. Microarray analysis of neurons with decreased Znf335 expression showed decreased expression of genes important for brain development. Cellular studies indicated that ZNF335 interacts with a chromatin-remodeling complex involving H3K4 methyltransferases, which regulates the expression of specific genes in a variety of pathways; the complex was analogous to the TrxG (trithorax) complex in Drosophila. ZNF335 bound to the promoter of the known neuronal progenitor cell master regulator REST, and knockdown of ZNF335 caused decreased levels of REST mRNA. The study identified ZNF335 as an essential link between H3K4 complexes and REST, and showed that this pathway regulates human neurogenesis and neuronal differentiation.
Using ethylnitrosourea mutagenesis in mice, Han et al. (2014) identified a hypomorphic mutation, termed 'bloto,' in Zfp335. The mutation resulted in an arg1092-to-trp (R1092W) substitution in the Zfp335 protein. Mice homozygous for bloto exhibited a naive T-cell deficiency due to an intrinsic developmental defect that first manifested in thymus and then spread into the periphery to affect T cells that had recently egressed from the thymus. Altered thymic selection, proliferation, and Bcl2 (151430)-dependent survival were ruled out as causes of this defect. Restoring expression of Ankle2 (616062), a Zfp335 target gene, partially restored T-cell maturation. Han et al. (2014) concluded that ZNF335 is a transcription factor and essential regulator of late-stage intrathymic and postthymic T-cell maturation.
In affected members of an Arab Israeli family with autosomal recessive primary microcephaly-10 (MCPH10; 615095), Yang et al. (2012) identified a homozygous 3332G-A transition in exon 20 of the ZNF335 gene, predicted to result in an arg1111-to-his (R1111H) substitution at a conserved residue in the 13th zinc finger domain. The mutation occurs at the final position of the splice donor site, which disrupted normal splicing, resulting in an abnormally larger transcript including introns 19 and 20 and predicting premature termination. Patient cells showed severely reduced ZNF335 protein, but some residual transcript was identified. The mutation, which was identified by linkage analysis followed by candidate gene sequencing, was not found in 100 control individuals or in 2,700 control exomes.
In a 33-month-old girl, born of nonconsanguineous Japanese parents, with primary microcephaly-10 (MCPH10; 615095), Sato et al. (2016) performed exome sequencing of ZNF335 and identified compound heterozygosity for 2 missense mutations in exon 9: a c.1399T-C transition, resulting in a cys467-to-arg (C467R) substitution, and a c.1505A-G transition, resulting in a tyr502-to-cys (Y502C; 610827.0003) substitution. Both mutations occurred at conserved residues in the zinc finger domain. The mutations, which were found by exome sequencing, were confirmed by Sanger sequencing. The mutations were transmitted individually from her father and mother, respectively. The c.1399T-C variant was not present in the 1000 Genomes Project, Human Genetic Variation, or dbSNP databases, whereas the c.1505A-G variant was seen in 1 of 121,412 alleles in dbSNP (build 144). No functional studies were reported.
In a boy (patient A) with MCPH10, who was born to consanguineous parents of North African descent and died at age 5 days, Stouffs et al. (2018) identified homozygosity for the c.1399T-C variant (c.1399T-C, NM_022095.3) in the ZNF335 gene. The variant was not present in the gnomAD database. No functional studies were reported.
For discussion of the c.1505A-G transition in exon 9 of the ZNF335 gene, resulting in a tyr502-to-cys (Y502C) substitution in the ZNF335 gene, that was found in compound heterozygous state in a Japanese patient with autosomal recessive primary microcephaly-10 (MCPH10; 615095) by Sato et al. (2016), see 610827.0002.
In a 3-month-old boy (patient B), born to nonconsanguineous parents of Caucasian European descent, with autosomal recessive primary microcephaly-10 (MCPH10; 615095), Stouffs et al. (2018) identified compound heterozygous mutations in the ZNF335 gene: a 3-bp deletion (c.2171_2173delTCT, NM_022095.3) inherited from his father, predicted to result in deletion of phe724 (F724del), and a c.3998A-G mutation inherited from his mother, predicted to result in a glu1333-to-gly (E1333G; 610827.0005) substitution at a highly conserved residue. The latter mutation is predicted to activate a cryptic donor site. The F724del mutation was not present in the gnomAD database, and the E1333G mutation was present in heterozygous state in 31 of 138,000 individuals, with an allele frequency of 0.01119% (2016). No functional studies were reported.
For discussion of the c.3998A-G transition (c.3998A-G, NM_022095.3) in the ZNF335 gene, predicted to result in a glu1333-to-gly (E1333G) substitution, that was found in compound heterozygous state in a patient with autosomal recessive primary microcephaly-10 (MCPH10; 615095) by Stouffs et al. (2018), see 610827.0004.
Han, B. Y., Wu, S., Foo, C.-S., Horton, R. M., Jenne, C. N., Watson, S. R., Whittle, B., Goodnow, C. C., Cyster, J. G. Zinc finger protein Zfp335 is required for the formation of the naive T cell compartment. eLife 3: e03549, 2014. Note: Electronic Article. [PubMed: 25343476] [Full Text: https://doi.org/10.7554/eLife.03549]
Mahajan, M. A., Murray, A., Samuels, H. H. NRC-interacting factor 1 is a novel cotransducer that interacts with and regulates the activity of the nuclear hormone receptor coactivator NRC. Molec. Cell. Biol. 22: 6883-6894, 2002. [PubMed: 12215545] [Full Text: https://doi.org/10.1128/MCB.22.19.6883-6894.2002]
Sato, R., Takanashi, J., Tsuyusaki, Y., Kato, M., Saitsu, H., Matsumoto, N., Takahashi, T. Association between invisible basal ganglia and ZNF335 mutations: a case report. Pediatrics 138: e20160897, 2016. Note: Electronic Article. [PubMed: 27540107] [Full Text: https://doi.org/10.1542/peds.2016-0897]
Stouffs, K., Stergachis, A. B., Vanderhasselt, T., Dica, A., Janssens, S., Vandervore, L., Gheldof, A., Bodamer, O., Keymolen, K., Seneca, S., Liebaers, I., Jayaraman, D., Hill, H. E., Partlow, J. N., Walsh, C. A., Jansen, A. C. Expanding the clinical spectrum of biallelic ZNF335 variants. Clin. Genet. 94: 246-251, 2018. [PubMed: 29652087] [Full Text: https://doi.org/10.1111/cge.13260]
Yang, Y. J., Baltus, A. E., Mathew, R. S., Murphy, E. A., Evrony, G. D., Gonzalez, D. M., Wang, E. P., Marshall-Walker, C. A., Barry, B. J., Murn, J., Tatarakis, A., Mahajan, M. A., Samuels, H. H., Shi, Y., Golden, J. A., Mahajnah, M., Shenhav, R., Walsh, C. A. Microcephaly gene links trithorax and REST/NRSF to control neural stem cell proliferation and differentiation. Cell 151: 1097-1112, 2012. [PubMed: 23178126] [Full Text: https://doi.org/10.1016/j.cell.2012.10.043]