Alternative titles; symbols
HGNC Approved Gene Symbol: ZNF445
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:44,431,705-44,477,670 (from NCBI)
ZNF445 is a zinc finger transcription factor (Luo et al., 2006) that functions as a primary regulator of genomic imprinting (Takahashi et al., 2019).
By RT-PCR, Luo et al. (2006) cloned human ZNF445. The deduced ZNF445 protein contains 1,031 amino acids and has a calculated molecular mass of 119 kD. ZNF445 has a leucine-rich SCAN domain and a Kruppel-associated box (KRAB) domain at its N terminus and 14 C2H2 zinc fingers at its C terminus. Northern blot analysis detected a 9.1-kb ZNF445 transcript in adult human testis, skeletal muscle, uterus, thymus, small intestine, colon, pancreas, and peripheral blood leukocytes. Immunofluorescence analysis showed that ZNF445 localized to nuclei of transfected HeLa cells. Bioinformatic analysis revealed that ZNF445 is an evolutionarily conserved member of the SCAN-KRAB-zinc finger gene family.
Luo et al. (2006) determined that the ZNF445 gene contains 8 exons and spans approximately 36.8 kb.
By database analysis, Luo et al. (2006) mapped the ZNF445 gene to chromosome 3p21.32.
Using a luciferase reporter gene, Luo et al. (2006) showed that ZNF445 was a transcriptional repressor. Overexpression of ZNF445 in HEK293T cells activated AP1 (165160) and serum response element (SRE) transcriptional activities, and deletion studies suggested that the SCAN domain of ZNF445 was likely involved in this activity. Expression of ZNF445 increased the phosphorylation of several proteins involved in mitogen-activated protein kinase (MAPK; see 176948) signal transduction pathways.
Using chromatin immunoprecipitation assays, Takahashi et al. (2019) showed that ZNF445 bound at imprinting control regions (ICRs) in human and mouse embryonic stem cells (ESCs). Mouse Zfp445 and Zfp57 (612192) were required to maintain imprint methylation in vivo, as the 2 proteins cooperated to protect all but 1 ICR during mouse embryonic development. In contrast, only ZNF445 controlled expression of imprinted genes in human ESCs by recruiting histone H3 (see 602810) lys9 methylation at imprinted differentially methylated regions. Evolutionary analysis suggested that ZNF445 is highly conserved in therians and in the human population, likely evolving as the primary protector of imprints.
Associations Pending Confirmation
For discussion of a possible association between Temple syndrome (see 616222) and mutation in the ZNF445 gene, see 610508.0001.
This variant is classified as a variant of unknown significance because its contribution to Temple syndrome (see 616222) has not been confirmed.
In a Japanese girl with Temple syndrome, Kagami et al. (2021) identified homozygosity for a gln935-to-ter (Q935X) substitution in the ZNF445 gene. The mutation, which was identified by whole-exome sequencing, was found in the carrier state in the parents. Analysis in patient lymphoblastoid cells demonstrated that the mutant ZNF445 mRNA transcript did not undergo nonsense-mediated decay, and Western blot analysis demonstrated a truncated ZNF445 protein consistent with the loss of 2 of the 14 zinc finger domains. Genomewide methylation analysis in the patient demonstrated severe hypomethylation at the MEG3:TSS differentially methylated region (DMR) and moderate to mild hypomethylation at additional DMRs. Methylation analysis in the parents was normal. Kagami et al. (2021) concluded that because ZNF445 is known to bind to the DMRs identified in this patient, the Q935X mutation is likely responsible for her diagnosis of Temple syndrome. Kagami et al. (2019) reported that the patient had pre- and postnatal growth failure, relative macrocephaly at birth, hypotonia, feeding difficulty requiring tube feeding, small hands, and body asymmetry. Brain MRI, auditory brainstem response, and echocardiography showed no abnormalities. She received growth hormone for short stature from 3 years of age, but at age 4 years and 5 months, her height was -4.4 SD, weight -7.8 SD, and OFC -2.0 SD. She still required tube feeding and had developmental delay with a developmental quotient of 66.
Kagami, M., Hara-Isono, K., Matsubara, K., Nakabayashi, K., Narumi, S., Fukami, M., Ohkubo, Y., Saitsu, H., Takada, S., Ogata, T. ZNF445: a homozygous truncating variant in a patient with Temple syndrome and multilocus imprinting disturbance. Clin. Epigenet. 13: 119, 2021. [PubMed: 34039421] [Full Text: https://doi.org/10.1186/s13148-021-01106-5]
Kagami, M., Yanagisawa, A., Ota, M., Matsuoka, K., Nakamura, A., Matsubara, K., Nakabayashi, K., Takada, S., Fukami, M., Ogata, T. Temple syndrome in a patient with variably methylated CpGs at the primary MEG3/DLK1:IG-DMR and severely hypomethylated CpGs at the secondary MEG3:TSS-DMR. Clin. Epigenet. 11: 42, 2019. [PubMed: 30846001] [Full Text: https://doi.org/10.1186/s13148-019-0640-2]
Luo, K., Yuan, J., Shan, Y., Li, J., Xu, M., Cui, Y., Tang, W., Wan, B., Zhang, N., Wu, Y., Yu, L. Activation of transcriptional activities of AP1 and SRE by a novel zinc finger protein ZNF445. Gene 367: 89-100, 2006. [PubMed: 16368201] [Full Text: https://doi.org/10.1016/j.gene.2005.09.023]
Takahashi, N., Coluccio, A., Thorball, C. W., Planet, E., Shi, H., Offner, S., Turelli, P., Imbeault, M., Ferguson-Smith, A. C., Trono, D. ZNF445 is a primary regulator of genomic imprinting. Genes Dev. 33: 49-54, 2019. [PubMed: 30602440] [Full Text: https://doi.org/10.1101/gad.320069.118]