HGNC Approved Gene Symbol: ZNF341
Cytogenetic location: 20q11.22 Genomic coordinates (GRCh38): 20:33,731,996-33,792,269 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q11.22 | Hyper-IgE syndrome 3, autosomal recessive, with recurrent infections | 618282 | Autosomal recessive | 3 |
ZNF341 is a nuclear zinc finger transcription factor that regulates expression of STAT3 (102582), a central regulator of immune homeostasis (Frey-Jakobs et al., 2018; Beziat et al., 2018).
Frey-Jakobs et al. (2018) reported that human ZNF341 encodes 3 isoforms. The longest ZNF341 isoform contains 854 amino acids and has 12 C2H2 zinc finger domains and a putative nuclear localization signal (NLS). RT-PCR detected ZNF341 transcripts in all human cell lines and cell types tested, including peripheral blood mononuclear cells (PBMCs), Epstein-Barr virus (EBV)-transformed B cells, monocytes, CD3 (see 186740)-positive T cells, and granulocytes. Confocal microscopy showed that ZNF341 localized to nuclei in transfected HEK293T cells.
Beziat et al. (2018) reported that human ZNF341 encodes 2 main transcripts that differ by 21 in-frame nucleotides due to alternative splicing involving different acceptor sites at the 3-prime end of exon 6. The transcripts yield isoforms of 847 and 854 amino acids with calculated molecular masses of 92 and 93 kD, respectively. Both isoforms contain 12 predicted DNA-binding C2H2 zinc finger domains and 2 predicted NLSs. Database analysis indicated ubiquitous expression of ZNF341, and PCR detected ZNF341 expression in all cell types and cell lines tested, including EBV-transformed B cells, herpesvirus saimiri-transformed T cells, primary human umbilical vein endothelial cells (HUVECs), SV40-transformed fibroblasts, primary keratinocytes, and multiple hematopoietic and nonhematopoietic cancer cell lines. Western blot analysis detected both ZNF341 isoforms in nuclei of transfected HEK293T cells. Immunoprecipitation and immunoblot analysis suggested that both ZNF341 isoforms can homo- or hetero-oligomerize.
Frey-Jakobs et al. (2018) and Beziat et al. (2018) reported that the ZNF341 gene contains 15 exons.
Frey-Jakobs et al. (2018) stated that the ZNF341 gene maps to chromosome 20q11.22.
Using a reporter assay in transfected HEK293T cells, Frey-Jakobs et al. (2018) showed that ZNF341 activated a synthetic STAT3 promoter. Chromatin immunoprecipitation-sequencing (ChIP-seq) analysis revealed that ZNF341 bound directly to a specific sequence in the STAT3 promoter through several of its zinc finger domains.
Using ChIP-seq, computational, and pull-down analyses, Beziat et al. (2018) found that ZNF341 bound specifically to a bipartite motif present in the promoters of STAT1 (600555) and STAT3. Further analysis showed that the ZNF-like motif and the Sp1-like motif contained within the bipartite ZNF341-binding motif acted in synergy to ensure strong binding of ZNF341 to DNA. Overexpression of ZNF341 in HEK293T cells resulted in induction of STAT1 and STAT3 transcription via binding of ZNF341 to the bipartite motif in the STAT1 and STAT3 promoters.
In 11 patients from 4 unrelated consanguineous families with autosomal recessive hyper-IgE syndrome-3 with recurrent infections (HIES3; 618282), Frey-Jakobs et al. (2018) identified homozygous loss-of-function nonsense mutations in the ZNF341 gene (R302X, 618269.0001 and R386X, 618269.0002). The mutations, which were found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the families. In vitro functional expression studies and studies of patient cells showed that the mutations resulted in absence of the full-length ZNF341 protein, decreased STAT3 (102582) protein levels, decreased STAT3 Y705 phosphorylation, and impaired ZNF341 signaling and activation of STAT3 due to nuclear translocation failure or poor binding to chromatin. The clinical and cellular phenotype thus mimicked HIES1 (147060), which is caused by mutations in the STAT3 gene.
Simultaneously and independently, Beziat et al. (2018) identified homozygous loss-of-function mutations in the ZNF341 gene (618269.0001; 618269.0003-618269.0005) in 8 patients from 6 unrelated consanguineous families with HIES3. The mutations, which were found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Patient cells showed slightly higher mutant mRNA levels compared to controls, suggesting that the mutations do not cause nonsense-mediated mRNA decay. However, patient cells showed absence of the full-length ZNF341 protein. Mutant proteins showed variably impaired binding to the STAT3 promoter and showed decreased or absent ability to induce STAT3 expression compared to wildtype. Patient cells showed decreased levels of STAT3 protein and low levels of STAT3 phosphorylation and activation.
In 8 patients from 3 unrelated consanguineous Arab-Israeli families (families A, B, and C) from the same small village with autosomal recessive hyper-IgE syndrome-3 with recurrent infections (HIES3; 618282), Frey-Jakobs et al. (2018) identified a homozygous c.904C-T transition (c.904C-T, NM_001282933.1) in exon 6 of the ZNF341 gene, resulting in an arg302-to-ter (R302X) substitution upstream of the nuclear localization sequence. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. It was found at a low frequency in the heterozygous state in the dbSNP database (0.0017%). Patient cells showed absence of the full-length ZNF341 protein. In vitro functional expression studies showed that the mutant protein was unable to increase STAT3 expression compared to wildtype, consistent with a loss of function. The mutation R302X protein was unable to localize to the nucleus and remained in the cytoplasm, indicating that the nuclear localization sequence had been deleted.
Beziat et al. (2018) also found a homozygous R302X mutation in the ZNF341 gene in 4 patients from 3 unrelated consanguineous families (families A, B, and C), with HIES3. The mutations, which were found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The families were of Moroccan, Afro-Caribbean, and Iranian origin. Haplotype analysis did not suggest a founder effect; the recurrent mutation was believed to result from a hotspot. There were 2 R302X heterozygotes in the ExAC database. Patient cells showed absence of the full-length ZNF341 protein.
In 3 sisters, born of consanguineous Turkish parents (family D), with autosomal recessive hyper-IgE syndrome-3 with recurrent infections (HIES3; 618282), Frey-Jakobs et al. (2018) identified a homozygous c.1156C-T transition (c.1156C-T, NM_001282933.1) in exon 8 of the ZNF341 gene, resulting in an arg386-to-ter (R386X) substitution. The mutation, which was found by targeted next-generation sequencing, segregated with the disorder in the family. Patient cells showed absence of the full-length ZNF341 protein. The mutant R386X protein retained the ability to localize to the nucleus, but showed reduced binding to chromatin compared to wildtype.
In a girl, born of consanguineous Turkish parents (family D), with autosomal recessive hyper-IgE syndrome-3 with recurrent infections (HIES3; 618282), Beziat et al. (2018) identified a homozygous 1-bp deletion (c.1062delG) in the ZNF341 gene, resulting in a frameshift and premature termination (Lys355fs). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the ExAC database. Patient cells showed absence of the full-length ZNF341 protein. In vitro functional expression studies in HEK293 cells showed that the mutant protein did localize to the nucleus, but had impaired DNA binding and a decreased ability to homo- or hetero-oligomerize compared to wildtype.
In a boy, born of consanguineous Turkish parents (family E), with autosomal recessive hyper-IgE syndrome-3 with recurrent infections (HIES3; 618282), Beziat et al. (2018) identified a homozygous c.1626C-G transversion in the ZNF341 gene, resulting in a tyr542-to-ter (Y542X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the ExAC database. Patient cells showed absence of the full-length ZNF341 protein. In vitro functional expression studies in HEK293 cells showed that the mutant protein did localize to the nucleus, but had impaired DNA binding.
In a boy, born of consanguineous Lebanese parents (family F), with autosomal recessive hyper-IgE syndrome-3 with recurrent infections (HIES3; 618282), Beziat et al. (2018) identified a homozygous c.583C-T transition in the ZNF341 gene, resulting in a gln195-to-ter (Q195X) substitution upstream of the nuclear localization sequence. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the ExAC database. In vitro functional expression studies in HEK293 cells showed that the mutant protein was retained in the cytoplasm and did not localize to the nucleus.
Beziat, V., Li, J., Lin, J.-X., Ma, C. S., Li, P., Bousfiha, A., Pellier, I., Zoghi, S., Baris, S., Keles, S., Gray, P., Du, N., and 49 others. A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity. Sci. Immun. 3: eaat4956, 2018. Note: Electronic Article. [PubMed: 29907691] [Full Text: https://doi.org/10.1126/sciimmunol.aat4956]
Frey-Jakobs, S., Hartberger, J. M., Fliegauf, M., Bossen, C., Wehmeyer, M. L., Neubauer, J. C., Bulashevska, A., Proietti, M., Frobel, P., Noltner, C., Yang, L., Rojas-Restrepo, J., and 18 others. ZNF341 controls STAT3 expression and thereby immunocompetence. Sci. Immun. 3: eaat4941, 2018. Note: Electronic Article. [PubMed: 29907690] [Full Text: https://doi.org/10.1126/sciimmunol.aat4941]