Alternative titles; symbols
HGNC Approved Gene Symbol: ANKRD17
Cytogenetic location: 4q13.3 Genomic coordinates (GRCh38) : 4:73,073,376-73,258,798 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q13.3 | Chopra-Amiel-Gordon syndrome | 619504 | Autosomal dominant | 3 |
ANKRD17 is a downstream effector of cyclin E (CCNE1; 123837)/CDK2 (116953) and positively regulates cell cycle progression (Deng et al., 2009). ANKRD17 also interacts with molecules that mediate immune responses to bacteria and viruses (Wang et al., 2012; Menning and Kufer, 2013).
Using TAP tag purification, Deng et al. (2009) identified ANKRD17 as a substrate of CCNE1/CDK2. The predicted 2,352-amino acid ANKRD17 protein contains clusters of 15 and 10 ankyrin repeats in its N-terminal half, followed by a nuclear export signal, a nuclear localization signal, a KH domain, and an RxL motif. RT-PCR analysis detected ubiquitous expression in human tissues. Immunoblot analysis showed nuclear expression and chromatin binding in human cells. Mass spectrometric analysis identified serine phosphorylation sites at positions 1791, 1794, and 2150.
Using an in vitro kinase assay, Deng et al. (2009) showed that phosphorylation of ANKRD17 was mediated by CCNE1/CDK2. Overexpression of ANKRD17 promoted cell cycle progression in human U2OS cells. Treatment with short interfering RNA (siRNA) blocked U2OS cells from entering S phase and prevented loading of CDC6 (602627) and PCNA (176740) onto chromatin. Immunoprecipitation analysis of transfected 293T cells revealed that ANKRD17 also interacted with proteins involved in DNA replication, including MCM3 (602693), MCM5 (602696), MCM7 (600592), CDC6, and PCNA. Deng et al. (2009) concluded that ANKRD17 is an important downstream effector of CCNE1/CDK2 that positively regulates G1/S transition.
RIGI (DDX58; 609631)-like receptors (RLRs) are intracellular molecules that sense viral RNAs and trigger immune responses. Wang et al. (2012) found that ANKRD17 interacted with the RLRs RIGI, MDA5 (606951), and VISA (MAVS; 609676). Overexpression of ANKRD17 enhanced signaling of these molecules and activation of IRF3 (603734) and NFKB (164011) and transcription of IFNB (147640) in transfected 293T cells. Knockdown of ANKRD17 impaired RLR signaling. Wang et al. (2012) concluded that ANKRD17 is a positive regulator of the RLR signaling pathway.
Menning and Kufer (2013) showed that the ANKRD17 N-terminal domain bound NOD2 (605956) in human cells. Knockdown and overexpression analyses revealed that ANKRD17 was functionally involved in NOD2- and NOD1 (605980)-mediated responses to bacteria in different human cell lines. Menning and Kufer (2013) concluded that ANKRD17 functions in innate antibacterial immune pathways.
Deng et al. (2009) stated that the ANKRD17 gene maps to chromosome 4q13.3.
In a patient (individual 6) with Chopra-Amiel-Gordon syndrome (CAGS; 619504), Chopra et al. (2021) identified a de novo heterozygous 1.16-Mb deletion encompassing 7 genes, including ANKRD17, by array CGH. The other 6 genes in the region were associated with an autosomal recessive pattern of disease inheritance when mutated (ADAMTS3, 605011; ALB, 103600; AFP, 104150) or were not known to be associated with a disease (COX18, 610428; AFM, 104150; RASSF6, 612620). Chopra et al. (2021) therefore considered ANKRD17 to be the most likely candidate gene underlying the patient's phenotype.
In 34 patients from 32 families with Chopra-Amiel-Gordon syndrome, Chopra et al. (2021) identified heterozygous mutations in the ANKRD17 gene (see, e.g., 615929.0001-615929.0005). The mutations included 21 truncating or canonical splice site mutations, 9 missense mutations, 1 in-frame indel, and 1 heterozygous microdeletion including additional genes. The mutations were shown to be de novo in 29 patients, inherited from an affected parent in 1 patient (615929.0004), and inherited from a parent with low-level mosaicism for an ANKRD17 mutation in 1 patient. Parental inheritance was not determined in 3 patients. One pair of monozygotic twins, who were heterozygous for a missense mutation (A377T), had a discordant phenotype. Molecular modeling suggested that most of the missense mutations disrupted the stability of ankyrin repeats.
In an Algerian woman (individual 1) with Chopra-Amiel-Gordon syndrome (CAGS; 619504), Chopra et al. (2021) identified a de novo heterozygous c.1958-2A-C transition (c.1958-2A-C, NM_032217.4) in intron 11 of the ANKRD17 gene, predicted to result in a splicing abnormality. The mutation was identified by trio whole-exome sequencing and confirmed by Sanger sequencing. The mutation was not present in the gnomAD database. Functional studies were not performed.
In a 4-year-old Indian boy (individual 2) with Chopra-Amiel-Gordon syndrome (CAGS; 619504), Chopra et al. (2021) identified a de novo heterozygous c.4091G-C transversion (c.4091G-C, NM_032217.4) in exon 22 of the ANKRD17 gene, resulting in a gly1364-to-ala (G1364A) substitution at a conserved residue in the ankyrin repeats. The mutation was identified by trio whole-exome sequencing and confirmed by Sanger sequencing. The mutation was not present in the gnomAD database. Functional studies were not performed.
In a 5-year-old girl (individual 3) with Chopra-Amiel-Gordon syndrome (CAGS; 619504), Chopra et al. (2021) identified a de novo heterozygous 4-bp deletion (c.4341_4344del, NM_032217.4) in exon 24 of the ANKRD17 gene, predicted to result in a frameshift and premature termination (Gln1448LeufsTer12). The mutation was identified by trio whole-exome sequencing and was not present in the gnomAD database. Functional studies were not performed.
In a mother and son (individuals 11 and 12) with Chopra-Amiel-Gordon syndrome (CAGS; 619504), Chopra et al. (2021) identified heterozygosity for a c.2623G-T transversion (2623G-T, NM_032217.4) in exon 15 of the ANKRD17, resulting in a glu875-to-ter (E875X) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies were not performed.
In a patient (individual 14) with Chopra-Amiel-Gordon Syndrome (CAGS; 619504), Chopra et al. (2021) identified a de novo heterozygous 1-bp duplication (c.5756dup, NM_032217.4) in exon 29 of the ANKRD17 gene, predicted to result in a frameshift and premature termination (Ala1920SerfsTer). The mutation was identified by trio whole-exome sequencing and confirmed by Sanger sequencing. The mutation was not present in the gnomAD database. Functional studies were not performed.
Chopra, M., McEntagart, M., Clayton-Smith, J., Platzer, K., Shukla, A., Girisha, K. M., Kaur, A., Kaur, P., Pfundt, R., Veenstra-Knol, H., Mancini, G. M. S., Capuccio, G., and 72 others. Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism. Am. J. Hum. Genet. 108: 1138-1150, 2021. [PubMed: 33909992] [Full Text: https://doi.org/10.1016/j.ajhg.2021.04.007]
Deng, M., Li, F., Ballif, B. A., Li, S., Chen, X., Guo, L., Ye, X. Identification and functional analysis of a novel cyclin E/Cdk2 substrate Ankrd17. J. Biol. Chem. 284: 7875-7888, 2009. [PubMed: 19150984] [Full Text: https://doi.org/10.1074/jbc.M807827200]
Menning, M., Kufer, T. A. A role for the ankyrin repeat containing protein Ankrd17 in Nod1- and Nod2-mediated inflammatory responses. FEBS Lett. 587: 2137-2142, 2013. [PubMed: 23711367] [Full Text: https://doi.org/10.1016/j.febslet.2013.05.037]
Wang, Y., Tong, X., Li, G., Li, J., Deng, M., Ye, X. Ankrd17 positively regulates RIG-I-like receptor (RLR)-mediated immune signaling. Europ. J. Immun. 42: 1304-1315, 2012. [PubMed: 22328336] [Full Text: https://doi.org/10.1002/eji.201142125]