Alternative titles; symbols
HGNC Approved Gene Symbol: CENPF
SNOMEDCT: 1187120008;
Cytogenetic location: 1q41 Genomic coordinates (GRCh38): 1:214,603,195-214,664,571 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q41 | Stromme syndrome | 243605 | Autosomal recessive | 3 |
The CENPF gene encodes a protein that is dynamically expressed throughout the cell cycle and is associated with the kinetochore and mitotic spindles (summary by Waters et al., 2015).
Rattner et al. (1993) identified a human kinetochore protein with a molecular weight of approximately 400 kD. Designated centromeric protein F, it was only transiently associated with kinetochores from the onset of mitosis to metaphase.
Liao et al. (1995) reported the cDNA sequence of CENPF. The predicted structure of the 367-kD CENPF protein consists of two 1,600-amino acid-long coil domains that flank a central flexible core.
Waters et al. (2015) found that CENPF localized to the basal body in ciliated fibroblasts and at the subdistal appendages of the motor centriole in mouse inner medullary collecting duct cells.
Waters et al. (2015) stated that the CENPF gene consists of 20 coding exons that encode at least 2 protein-coding transcripts.
Using CENPF cDNA in fluorescence in situ hybridization, Testa et al. (1994) mapped the CENPF gene to chromosome 1q32-q41.
Gross (2016) mapped the CENPF gene to chromosome 1q41 based on an alignment of the CENPF sequence (GenBank U19769) with the genomic sequence (GRCh38).
By interspecific backcross analysis, Fowler et al. (1998) mapped the mouse Cenpf gene to the distal region of chromosome 1.
Liao et al. (1995) reported the expression and localization patterns of CENPF at different stages of the HeLa cell cycle. CENPF is a protein of the nuclear matrix that gradually accumulates during the cell cycle until it reaches peak levels in G2- and M-phase cells and is rapidly degraded upon completion of mitosis. CENPF is first detected at the prekinetochore complex during late G2, and by prophase is clearly detectable as paired foci that correspond to all the centromeres. During mitosis, CENPF is associated with kinetochores from prometaphase until early anaphase and then is detected at the spindle midzone throughout the remainder of anaphase. By telophase, CENPF is concentrated within the intracellular bridge at either side of the midbody.
Waters et al. (2015) found that CENPF colocalized with IFT88 (600595) and KIF3B (603754) at the centrosome and along ciliary axonemes. The findings indicated that CENPF has a role in ciliogenesis.
Kabeche et al. (2018) described an unexpected role of ATR (601215) in mitosis. Acute inhibition or degradation of ATR in mitosis induces whole-chromosome missegregation. The effect of ATR ablation is not due to altered cyclin-dependent kinase-1 (CDK1; 116940) activity, DNA damage responses, or unscheduled DNA synthesis, but to loss of an ATR function at centromeres. In mitosis, ATR localizes to centromeres through Aurora A (603072)-regulated association with CENPF, allowing ATR to engage replication protein A (RPA; see 179835)-coated centromeric R loops. As ATR is activated at centromeres, it stimulates Aurora B (604970) through Chk1, preventing formation of lagging chromosomes. Thus, a mitosis-specific and R loop-driven ATR pathway acts at centromeres to promote faithful chromosome segregation, revealing functions of R loops and ATR in suppressing chromosome instability.
In 4 affected fetuses from a nonconsanguineous Caucasian family with a ciliopathy phenotype consistent with Stromme syndrome (STROMS; 243605), Waters et al. (2015) identified compound heterozygous mutations in the CENPF gene (600236.0001 and 600236.0002). The mutations were found by whole-exome sequencing. Exome sequencing of the CENPF gene in 1,000 patients with microcephaly further identified 1 patient who was compound heterozygous for 2 truncating mutations (600236.0001 and 600236.0003).
In 2 sets of sibs from 2 unrelated and nonconsanguineous families of European descent with Stromme syndrome, Filges et al. (2016) identified compound heterozygous truncating mutations in the CENPF gene (600236.0001; 600236.0004-600236.0006). The mutations were found by whole-exome sequencing. One of the families had previously been reported by Stromme et al. (1993). The phenotype was highly variable. The 2 sisters reported by Stromme et al. (1993) were alive in their early twenties with minimal impairment. The 2 sibs in the second family had multiple organ involvement; one died early in life and one was severely affected in utero necessitating termination of the pregnancy. All mutations were predicted to result in complete loss of function, but functional studies of the variants and studies of patient cells were not performed. The findings indicated that Stromme syndrome can be considered a ciliopathy.
In a 24-month-old girl, born to consanguineous parents, with Stromme syndrome, Ozkinay et al. (2017) identified a homozygous frameshift mutation in the CENPF gene (600236.0007). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was also found in the DNA of the patient's deceased male sib who had died from sepsis in the newborn period after an operation for 'apple peel' jejunal atresia. The mutation was found in heterozygous state in their parents. Ozkinay et al. (2017) proposed that variability in clinical features in the 2 sibs with the same mutation suggested that other modifying factors may be at play, rather than the phenotype being dependent on the amount of protein produced.
Waters et al. (2015) found that morpholino knockdown of cenpf in zebrafish embryos resulted in decreased survival and a ciliopathy phenotype, including axis curvature defects, abnormal heart looping, hydrocephalus, and pronephric cysts. Mutant zebrafish also showed left-right patterning defects and shortened Kupffer vesicle cilia compared to controls.
In 4 affected fetuses from a nonconsanguineous Caucasian family with Stromme syndrome (STROMS; 243605), Waters et al. (2015) identified compound heterozygous mutations in the CENPF gene: a c.1744G-T transversion (c.1744G-T, NM_016343.3) in exon 12, resulting in a glu582-to-ter (E582X) substitution, and an A-to-C transversion in intron 5 (IVS5-2A-C; 600236.0002), predicted to abolish a splice acceptor site from exon 6. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and were not found in 200 control alleles or 200 control in-house exomes. The splice site mutation was predicted to either result in a 97-residue in-frame deletion affecting the MT-binding domain at the N terminus, or in a frameshift and premature termination (Lys191fsTer); however, RNA was not available for confirmation studies. Exome sequencing of the CENPF gene in 1,000 patients with microcephaly further identified 1 patient with microcephaly and mild to moderate learning disabilities who was compound heterozygous for E582X and a c.8692C-T transition, resulting in an arg2898-to-ter (R2898X; 600236.0003) substitution. Western blot analysis of this patient's cells showed decreased CENPF protein levels, possibly consistent with nonsense-mediated mRNA decay. Renal epithelial cells from the fetuses from the first family showed that the cilia were shortened compared to controls, consistent with defective ciliogenesis.
In 2 sibs, born of unrelated parents of northern European descent, with a severe form of Stromme syndrome, Filges et al. (2016) identified compound heterozygous truncating mutations in the CENPF gene: an E582X substitution and a c.9280C-T transition in exon 20, resulting in an arg3094-to-ter (R3094X; 600236.0006) substitution in the nuclear localization signal. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variants were found at very low frequencies in the ExAC database, and none has been reported in the homozygous state, which is compatible with a rare disease. The mutations were predicted to result in a complete loss of function, but functional studies of the variants and studies of patient cells were not performed.
For discussion of the IVS5-2A-C mutation (IVS5-2A-C, NM_016343.3) in the CENPF gene that was found in compound heterozygous state in fetuses with Stromme syndrome (STROMS; 243605) by Waters et al. (2015), see 600236.0001.
For discussion of the arg2898-to-ter (R2898X) (c.8692C-T, NM_016343.3) mutation in the CENPF gene that was found in compound heterozygous state in a patient with Stromme syndrome (STROMS; 243605) by Waters et al. (2015), see 600236.0001.
In 2 Norwegian sisters with Stromme syndrome (STROMS; 243605) originally reported by Stromme et al. (1993), Filges et al. (2016) identified compound heterozygous truncating mutations in the CENPF gene: a c.2734G-T transversion (c.2734G-T, NM_016343.3) in exon 12, resulting in a glu912-to-ter (E912X) substitution, and a 29-bp deletion (c.165_193del; 600236.0005) in exon 3, resulting in a frameshift and premature termination (Asn57LysfsTer11). The nonsense variant was found at a very low frequency in the ExAC database, but has not been reported in the homozygous state, which is compatible with a rare disease. The mutations were predicted to result in a complete loss of function, but functional studies of the variants and studies of patient cells were not performed.
For discussion of the 29-bp deletion (c.165_193del, NM_016343.3) in exon 3 of the CENPF gene, resulting in a frameshift and premature termination (Asn57LysfsTer11) that was found in compound heterozygous state in 2 sisters with Stromme syndrome (STROMS; 243605) by Filges et al. (2016), see 600236.0004.
For discussion of the c.9280C-T transition (c.9280C-T, NM_016343.3) in exon 20 of the CENPF gene, resulting in an arg3094-to-ter (R3094X) substitution, that was found in compound heterozygous state in 2 sibs with Stromme syndrome (STROMS; 243605) by Filges et al. (2016), see 600236.0001.
In a brother and sister with Stromme syndrome (STROMS; 243605), Ozkinay et al. (2017) identified a 1-bp insertion (c.5912_5913insA, NM_016343.3) in exon 13 of the CENPF gene, resulting in a frameshift and a premature termination codon (Thr1974AsnfsTer9). The mutation occurred in the coiled-coil domain region. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the phenotype in the family.
Filges, I., Bruder, E., Brandal, K., Meier, S., Undlien, D. E., Waage, T. R., Hoesli, I., Schubach, M., de Beer, T., Sheng, Y., Hoeller, S., Schulzke, S., Rosby, O., Miny, P., Tercanli, S., Oppedal, T., Meyer, P., Selmer, K. K., Stromme, P. Stromme syndrome is a ciliary disorder caused by mutations in CENPF. Hum. Mutat. 37: 359-363, 2016. Note: Erratum: Hum. Mutat. 37: 711 only, 2016. [PubMed: 26820108] [Full Text: https://doi.org/10.1002/humu.22960]
Fowler, K. J., Saffery, R., Irvine, D. V., Trowell, H. E., Choo, K. H. A. Mouse centromere protein F (Cenpf) gene maps to the distal region of chromosome 1 by interspecific backcross analysis. Cytogenet. Cell Genet. 82: 180-181, 1998. [PubMed: 9858811] [Full Text: https://doi.org/10.1159/000015094]
Gross, M. B. Personal Communication. Baltimore, Md. 8/24/2016.
Kabeche, L., Nguyen, H. D., Buisson, R., Zou, L. A mitosis-specific and R loop-driven ATR pathway promotes faithful chromosome segregation. Science 359: 108-114, 2018. [PubMed: 29170278] [Full Text: https://doi.org/10.1126/science.aan6490]
Liao, H., Winkfein, R. J., Mack, G., Rattner, J. B., Yen, T. J. CENP-F is a protein of the nuclear matrix that assembles onto kinetochores at late G2 and is rapidly degraded after mitosis. J. Cell Biol. 130: 507-518, 1995. [PubMed: 7542657] [Full Text: https://doi.org/10.1083/jcb.130.3.507]
Ozkinay, F., Atik, T., Isik, E., Gormez, Z., Sagiroglu, M., Sahin, O. A., Corduk, N., Onay, H. A further family of Stromme syndrome carrying CENPF mutation. Am. J. Med. Genet. 173A: 1668-1672, 2017. [PubMed: 28407396] [Full Text: https://doi.org/10.1002/ajmg.a.38173]
Rattner, J. B., Rao, A., Fritzler, M. J., Valencia, D. W., Yen, T. J. CENP-F is a ca 400 kDa kinetochore protein that exhibits a cell-cycle dependent localization. Cell Motil. Cytoskeleton 26: 214-226, 1993. [PubMed: 7904902] [Full Text: https://doi.org/10.1002/cm.970260305]
Stromme, P., Dahl, E., Flage, T., Stene-Johansen, H. Apple peel intestinal atresia in siblings with ocular anomalies and microcephaly. Clin. Genet. 44: 208-210, 1993. [PubMed: 8261651] [Full Text: https://doi.org/10.1111/j.1399-0004.1993.tb03881.x]
Testa, J. R., Zhou, J., Bell, D. W., Yen, T. J. Chromosomal localization of the genes encoding the kinetochore proteins CENPE and CENPF to human chromosomes 4q24-q25 and 1q32-q41, respectively, by fluorescence in situ hybridization. Genomics 23: 691-693, 1994. [PubMed: 7851898] [Full Text: https://doi.org/10.1006/geno.1994.1558]
Waters, A. M., Asfahani, R., Carroll, P., Bicknell, L., Lescai, F., Bright, A., Chanudet, E., Brooks, A., Christou-Savina, S., Osman, G., Walsh, P., Bacchelli, C., and 21 others. The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes. J. Med. Genet. 52: 147-156, 2015. Note: Erratum: J. Med. Genet. 53: 845 only, 2016. [PubMed: 25564561] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102691]