Alternative titles; symbols
HGNC Approved Gene Symbol: CEP57
Cytogenetic location: 11q21 Genomic coordinates (GRCh38): 11:95,790,498-95,832,693 (from NCBI)
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
---|---|---|---|---|
11q21 | Mosaic variegated aneuploidy syndrome 2 | 614114 | Autosomal recessive | 3 |
The CEP57 gene encodes translokin, a protein that localizes to the centrosome and has a function in microtubular stabilization (Snape et al., 2011). CEP57 binds basic fibroblast growth factor (FGF2; 134920) and mediates its nuclear translocation and mitogenic activity (Bossard et al., 2003).
By sequencing clones obtained from a size-fractionated immature myeloid cell line cDNA library, Nagase et al. (1995) cloned translokin, which they designated KIAA0092. The deduced 474-amino acid protein contains transmembrane domains and shares about 17% identity with smooth muscle myosin (MYH11; 160745). Northern blot analysis detected expression in all tissues and cell lines examined.
Using the 18-kD isoform of FGF2 as bait in a yeast 2-hybrid screen, Bossard et al. (2003) cloned translokin from a placenta cDNA library. The deduced 500-amino acid protein shares about 88% sequence identity with the mouse and bovine homologs. Northern blot analysis detected a 3.2-kb transcript in all tissues examined. Other transcripts of about 2.6 and 2.2 kb were expressed at highest levels in heart and skeletal muscle, with lowest levels in lung. RT-PCR and Western blot analysis detected expression in all cell lines examined. The translokin protein showed an apparent molecular mass of about 55 kD. Epitope-tagged translokin localized to the cytoplasm of transfected COS-7 cells in a distribution that completely overlapped with microtubules.
Secondary structure prediction suggested that the CEP57 protein is composed of 2 alpha-helical coiled-coil domains connected by a flexible linker region. The N-terminal coiled-coil domain is within a region required for localization of CEP57 to the centrosome and for multimerization of the protein. The C-terminal half of CEP57, including the second coiled-coil domain, is required for nucleating, bundling, and anchoring microtubules to the centrosomes within basket-like structures (summary by Snape et al., 2011).
By analysis of human-rodent hybrid cell lines, Nagase et al. (1995) mapped the translokin gene to chromosome 11.
By yeast 2-hybrid assay and ELISA using recombinant proteins, Bossard et al. (2003) determined that translokin specifically interacts with the 18-kD form of FGF2 and interacts only minimally with the 24-kD form. It did not interact with FGF1 (131220) or several other FGF family members. Exogenously added FGF2 and translokin coprecipitated from translokin-transfected mouse fibroblasts. Using FGF1-FGF2 chimeras, Bossard et al. (2003) identified 2 regions of FGF2 required to mediate binding with translokin. Mutations that suppressed the interaction did not alter several FGF2 signaling pathways in bovine aortic endothelial cells, but they interfered with nuclear translocation of FGF2 and the ability of FGF2 to stimulate proliferation. Inhibition of translokin expression by RNA interference also reduced intracellular translocation of FGF2.
By exome sequencing, Snape et al. (2011) identified compound heterozygous mutations in the CEP57 gene (607951.0001 and 607951.0002) in 2 Mexican sibs with autosomal recessive mosaic variegated aneuploidy-2 (MVA2; 614114) and growth retardation (Garcia-Castillo et al., 2008). Subsequent molecular analysis of 18 patients from 13 families with MVA without mutations in the BUB1B gene (602860) identified 2 additional unrelated patients with homozygous truncating mutations in the CEP57 gene (607951.0003, 607951.0004). All of the mutations were predicted to result in a loss of function. The findings confirmed the causative role of CEP57 in predisposition to aneuploidy. None of the 4 patients had a malignancy.
Aziz et al. (2018) generated knockin mice homozygous for the 915_925dup11 frameshift mutation (607951.0002) in the Cep57 gene, which results in a truncated protein. Some homozygous mutant mice died in utero, and those born alive were smaller than heterozygous and wildtype mice. Newborn homozygous mutant mice had short curly tails, failed to feed, and died within 24 hours of birth. Histologic evaluation showed that vertebral bones in homozygous mutant pups were underdeveloped and lacked defined borders. Examination of bone tissue revealed that osteoblasts in lumbosacral vertebrae of homozygous mutant mice were deficient in Fgf2 (134920), suggesting Fgf signaling defects in bone of these mice. Embryonic fibroblasts of homozygous mutant mice had defects in centrosome maturation in G2 phase, as they displayed premature centriole disjunction, centrosome amplification, aberrant spindle formation, and high rates of chromosome missegregation. Further analysis demonstrated high aneuploidy rates throughout tissues and organs of homozygous mutant mice, which correlated with increased centrosome amplification. Mice heterozygous for the mutation had no apparent morphologic difference from wildtype mice, despite reduced Cep57 protein levels, but Cep57 insufficiency in these mice made them prone to aneuploidization and cancer.
In 2 Mexican sibs with mosaic variegated aneuploidy syndrome-2 (MVA2; 614114), Snape et al. (2011) identified compound heterozygosity for 2 mutations in the CEP57 gene: a 2-bp deletion (520delGA) in exon 5, and an 11-bp duplication in exon 9 (915_925dup11; 607951.0002). The patients were originally reported by Garcia-Castillo et al. (2008). The patients had poor growth and mildly dysmorphic facial features, but showed normal development, no abnormalities of the brain or major organ systems, and no evidence of malignancy. Cultured lymphocytes had approximately 50% aneuploidies involving all chromosome pairs during metaphase and structural chromosomal abnormalities in about 15% of cells. Only the girl had about 14% premature chromatid separation; studies of parental chromosomes were normal. The mutations were identified through exome sequencing.
In a boy with mosaic variegated aneuploidy syndrome-2 (MVA2; 614114), originally reported by Lane et al. (2002), Snape et al. (2011) identified a homozygous 11-bp duplication in exon 9 (915_925dup11) of the CEP57 gene. He had poor growth with growth hormone deficiency, mild mental retardation, asymptomatic small ventricular septal defect and mild subaortic stenosis, hearing deficit, hypothyroidism, rhizomelic shortening, and mild dysmorphic features. He died of sleep apnea at age 15 years. Lymphocyte culture at metaphase showed 24% hyperdiploid chromosome complements with no chromosome breakage.
Snape et al. (2011) also identified this mutation in compound heterozygosity with a 2-bp deletion (607951.0001) in 2 Mexican sibs with MVA2.
Pinson et al. (2014) identified homozygosity for this mutation in a 4-year-old Moroccan girl with MVA. Her unaffected consanguineous parents were heterozygous for the mutation.
In a male infant, born of consanguineous Caucasian parents, with mosaic variegated aneuploidy syndrome-2 (MVA2; 614114), Snape et al. (2011) identified a homozygous 241C-T transition in exon 3 of the CEP57 gene, resulting in an arg81-to-ter (R81X) substitution. Each unaffected parent was heterozygous for the mutation. The boy had low birth weight, growth retardation, and mild dysmorphic features, mainly temporal bossing and deep-set eyes with short palpebral fissures. He had several congenital defects, including atrial septal defect, atrioventricular septal defect, aortic coarctation, abnormal lung lobation, duodenal atresia, mild rhizomelic shortening of the upper limbs, and fifth finger clinodactyly. Developmental delay included hypotonia. He died of surgery-related complications at age 3 weeks. Cytogenetic analysis showed random aneuploidy of about 35% of cells with no evidence of premature chromatid separation.
Aziz, K., Sieben, C. J., Jeganathan, K. B., Hamada, M., Davies, B. A., Velasco, R. O. F., Rahman, N., Katzmann, D. J., van Deursen, J. M. Mosaic-variegated aneuploidy syndrome mutation or haploinsufficiency in Cep57 impairs tumor suppression. J. Clin. Invest. 128: 3517-3534, 2018. [PubMed: 30035751] [Full Text: https://doi.org/10.1172/JCI120316]
Bossard, C., Laurell, H., Van den Berghe, L., Meunier, S., Zanibellato, C., Prats, H. Translokin is an intracellular mediator of FGF-2 trafficking. Nature Cell Biol. 5: 433-439, 2003. [PubMed: 12717444] [Full Text: https://doi.org/10.1038/ncb979]
Garcia-Castillo, H., Vasquez-Velasquez, A. I., Rivera, H., Barros-Nunez, P. Clinical and genetic heterogeneity in patients with mosaic variegated aneuploidy: delineation of clinical subtypes. Am. J. Med. Genet. 146A: 1687-1695, 2008. [PubMed: 18548531] [Full Text: https://doi.org/10.1002/ajmg.a.32315]
Lane, A. H., Aijaz, N., Galvin-Parton, P., Lanman, J., Mangano, R., Wilson, T. A. Mosaic variegated aneuploidy with growth hormone deficiency and congenital heart defects. Am. J. Med. Genet. 110: 273-277, 2002. [PubMed: 12116237] [Full Text: https://doi.org/10.1002/ajmg.10462]
Nagase, T, Miyajima, N, Tanaka, A., Sazuka, T., Seki, N., Sato, S., Tabata, S., Ishikawa, K., Kawarabayashi, Y., Kotani, H., Nomura, N. Prediction of the coding sequences of unidentified human genes. III. The coding sequences of 40 new genes (KIAA0081-KIAA0120) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 2: 37-43, 1995. [PubMed: 7788527] [Full Text: https://doi.org/10.1093/dnares/2.1.37]
Pinson, L., Mannini, L., Willems, M., Cucco, F., Sirvent, N., Frebourg, T., Quarantotti, V., Collet, C., Schneider, A., Sarda, P., Genevieve, D., Puechberty, J., Lefort, G., Musio, A. CEP57 mutation in a girl with mosaic variegated aneuploidy syndrome. Am. J. Med. Genet. 164A: 177-181, 2014. [PubMed: 24259107] [Full Text: https://doi.org/10.1002/ajmg.a.36166]
Snape, K., Hanks, S., Ruark, E., Barros-Nunez, P., Elliott, A., Murray, A., Lane, A. H., Shannon, N., Callier, P., Chitayat, D., Clayton-Smith, J., FitzPatrick, D. R., and 9 others. Mutations in CEP57 cause mosaic variegated aneuploidy syndrome. Nature Genet. 43: 527-529, 2011. [PubMed: 21552266] [Full Text: https://doi.org/10.1038/ng.822]