Alternative titles; symbols
HGNC Approved Gene Symbol: ANKZF1
Cytogenetic location: 2q35 Genomic coordinates (GRCh38) : 2:219,229,806-219,236,679 (from NCBI)
ANKZF1 has a role in mitochondrial stress response (van Haaften-Visser et al., 2017).
The deduced 726-amino acid human ANKZF1 protein has an N-terminal zinc finger motif and 2 C-terminal ankyrin domains (van Haaften-Visser et al., 2017).
Van Haaften-Visser et al. (2017) found that human ANKZF1 interacted with VCP (601023) in the cytoplasm and that the complex translocated toward mitochondria following H2O2-induced oxidative stress. Knockdown of ANKZF1 in U2OS human osteosarcoma cells via short hairpin RNA reduced mitochondrial integrity and respiration under H2O2-induced stress, with decreased ATP production and elevated glycolytic activity. Depletion of ANKZF1 did not alter mitochondrial integrity under basal conditions. Human ANKZF1 functionally rescued yeast lacking Vms1, the yeast ortholog of ANKZF1, suggesting evolutionary conservation.
Release of nascent chains from aberrant NC-tRNA/60S ribosome-nascent chain (NC) complexes (60S RNCs) complexes arising from interrupted translation is a prerequisite for their subsequent degradation and is therefore a key step in the RQC pathway. Kuroha et al. (2018) reconstituted the mammalian RQC pathway in vitro and showed that ubiquitinated and nonubiquitinated NCs were released from 60S subunits by ANKZF1 and PTRH1 (621047), respectively, but the mode of release and the composition of released products differed fundamentally. ANKZF1 did not function as a peptidyl-tRNA hydrolase. Instead, it induced specific cleavage in the acceptor arm of 60S-bound P site tRNA releasing proteasome-degradable NCs linked to a 4-nucleotide 3-prime-terminal portion of tRNA. Nonubiquitinated NCs were released in the free form from 60S RNCs and 80S stalled ribosomes following PTRH1-mediated hydrolysis of the NC-tRNA ester bond. In addition, the authors found that TCF25 (612326) promoted preferential formation of the K48 ubiquitin linkage during Listerin (LTN1; 613083)-mediated ubiquitination.
Hartz (2017) mapped the ANKZF1 gene to chromosome 2q35 based on an alignment of the ANKZF1 sequence (GenBank AK001277) with the genomic sequence (GRCh38).
Associations Pending Confirmation
Using homozygosity mapping and exome sequencing, Van Haaften-Visser et al. (2017) identified a homozygous missense variant in the ANKZF1 gene, arg585-to-gln (R585Q), in a patient with infantile-onset inflammatory bowel disease (IBD; e.g., 612567). They subsequently sequenced the ANKZF1 gene in 12 other patients with infantile-onset IBD and found an individual who was compound heterozygous for variants glu152-to-lys (E152K) and val32_gln87del. They also identified 2 patients who were heterozygous for an ANKZF1 variant. Functional studies of the ANKZF1 R585Q variant showed reduced mRNA and protein expression, as well as reduced stress-induced mitochondrial translocation. EBV-transformed lymphocytes from both patients showed decreased proliferation due to apoptosis. ANKF1 protein carrying either E585Q or E152K was unable to rescue the loss in yeast of Vms1, the homolog of ANKZF1. Hamosh (2024) noted that the R585Q variant was present in gnomAD (v4.0) in 74 homozygotes and in 11,961 of 1,614,034 total alleles (allele frequency 7.4 x 10(-3)), making it extremely unlikely that this variant is responsible for a severe early-onset disorder.
In a Chinese patient with IBD presenting at age 17, Huang et al. (2023) identified a heterozygous leu415-to-val (L415V) variant in ANKZF1 by exome sequencing. Hamosh (2024) noted that the L415V variant was present, in heterozygosity only, in 46 of 1,613,732 alleles in gnomAD (v4.0), with the highest frequency (39/1,613,732, allele frequency 0.0008691) in East Asians, suggesting that this variant is not the sole cause of IBD.
Hamosh, A. Personal Communication. Baltimore, Md. 03/12/2024.
Hartz, P. A. Personal Communication. Baltimore, Md. June 19, 2017.
Huang, H., Yang, X., Tao, L., Xiang, R., Yang, H. Identification of a de novo heterozygous mutation of ANKZF1 in a Chinese patient with inflammatory bowel disease. Quart. J. Med. 116: 463-465, 2023. [PubMed: 36857589] [Full Text: https://doi.org/10.1093/qjmed/hcad030]
Kuroha, K., Zinoviev, A., Hellen, C. U. T., Pestova, T. V. Release of ubiquitinated and non-ubiquitinated nascent chains from stalled mammalian ribosomal complexes by ANKZF1 and Ptrh1. Molec. Cell 72: 286-302, 2018. [PubMed: 30244831] [Full Text: https://doi.org/10.1016/j.molcel.2018.08.022]
van Haaften-Visser, D. Y., Harakalova, M., Mocholi, E., van Montfrans, J. M., Elkadri, A., Rieter, E., Fiedler, K., van Hasselt, P. M., Triffaux, E. M. M., van Haelst, M. M., Nijman, I. J., Kloosterman, W. P., Nieuwenhuis, E. E. S., Muise, A. M., Cuppen, E., Houwen, R. H. J., Coffer, P. J. Ankyrin repeat and zinc-finger domain-containing 1 mutations are associated with infantile-onset inflammatory bowel disease. J. Biol. Chem. 292: 7904-7920, 2017. [PubMed: 28302725] [Full Text: https://doi.org/10.1074/jbc.M116.772038]