Alternative titles; symbols
HGNC Approved Gene Symbol: CEP152
Cytogenetic location: 15q21.1 Genomic coordinates (GRCh38) : 15:48,729,083-48,811,069 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q21.1 | Microcephaly 9, primary, autosomal recessive | 614852 | Autosomal recessive | 3 |
| Seckel syndrome 5 | 613823 | Autosomal recessive | 3 |
CEP152 is a core protein of the centrosome, a major microtubule-organizing center of animal cells that influences cell shape, polarity, and motility, and has a crucial function in cell division (Andersen et al., 2003).
By sequencing clones obtained from a size-fractionated brain cDNA library, followed by RT-PCR, Nagase et al. (1998) cloned CEP152, which they designated KIAA0912. The transcript contains a repetitive element in its 3-prime end, and the deduced 1,209-amino acid protein shares significant similarity with Xenopus Numa protein (NUMA1; 164009). RT-PCR ELISA detected variable expression of CEP152 in all tissues examined, with highest expression in brain, lung, kidney, pancreas, testis, and ovary, and lowest expression in spleen.
Using mass spectrometry to identify proteins associated with centrosomes purified from the KE-37 human lymphoblastic cell line, followed by database analysis, Andersen et al. (2003) identified CEP152. The deduced protein contains 8 coiled-coil domains and has a calculated molecular mass of 151.5 kD. Fluorescence-tagged CEP152 associated with centrosomes in transfected U2OS cells, and salt extraction experiments revealed that it is a core centrosomal protein.
By RT-PCR analysis, Guernsey et al. (2010) detected Cep152 expression in fetal mouse brain at embryonic day 12.5 and embryonic day 14.5, but in situ hybridization studies showed no signal, suggesting a low level of Cep152 expression in embryonic mouse brain.
By database analysis, Sonnen et al. (2013) identified 4 isoforms of CEP152. The full-length 1,710-amino acid CEP152 isoform has a calculated molecular mass of 196 kD. Smaller isoforms are C-terminally truncated and/or have an in-frame deletion in the N- or C-terminal end. Immunoelectron microscopy detected both long and short isoforms of CEP152 confined to the proximal halves of mature mother centrioles during G1 phase. CEP152 remained confined to the proximity of centrioles throughout mitosis.
Firat-Karalar et al. (2014) stated that full-length CEP152 has an N-terminal conserved region, 2 central coiled-coiled regions, and a C-terminal conserved region.
By radiation hybrid analysis, Nagase et al. (1998) mapped the CEP152 gene to chromosome 15.
Matyas et al. (2007) noted that the CEP152 gene maps to chromosome 15q21.1, neighboring the FBN1 gene (134797).
By comparison of the human CEP152 gene with other primate and vertebrate orthologs, Guernsey et al. (2010) found evidence that the CEP152 gene was subject to positive selection, consistent with adaptive evolution. Eight sites in the protein were specifically identified to be under positive selection.
Dzhindzhev et al. (2010) demonstrated that the centriolar protein 'Asterless' (Asl) (CEP152) provides a conserved molecular platform, the amino terminus of which interacts with the cryptic Polo box of Plk4 (605031) whereas the carboxy terminus interacts with the centriolar protein Sas4 (CPAP; 609279). Drosophila Asl and human CEP152 are required for the centrosomal loading of Plk4 in Drosophila and CPAP in human cells, respectively. Depletion of Asl or CEP152 caused failure of centrosome duplication; their overexpression led to de novo centriole formation in Drosophila eggs, duplication of free centrosomes in Drosophila embryos, and centrosome amplification in cultured Drosophila and human cells. Overexpression of a Plk4 binding-deficient mutant of Asl prevented centriole duplication in cultured cells and embryos. However, this mutant protein was able to promote microtubule organizing center formation in both embryos and oocytes. Such microtubule organizing centers had pericentriolar material and the centriolar protein Sas4, but no centrioles at their core. Formation of such acentriolar microtubule organizing centers could be phenocopied by overexpression of Sas4 in oocytes or embryos. The findings of Dzhindzhev et al. (2010) identified independent functions for Asl as a scaffold for Plk4 and Sas4 that facilitates self-assembly and duplication of the centriole and organization of pericentriolar material.
Kalay et al. (2011) showed that impaired CEP152 function leads to accumulation of genomic defects resulting from replicative stress through enhanced activation of ATM (607585) signaling and increased H2AX (601772) phosphorylation.
Using small interfering RNA, Sonnen et al. (2013) found that CEP192 (616426) was required for centrosomal localization of CEP152, CEP63 (614724), and CPAP and reduced the centrosomal content of PLK4 in U2OS cells. CEP192 interacted directly with CEP152 and PLK4, but not with CEP63 or CPAP. Codepletion of CEP192 and CEP152 completely prevented association of PLK4 with centrosomes and also impaired centriole duplication in U2OS cells. Sonnen et al. (2013) did not observe ternary or quaternary CEP152 complexes comprising both CEP192 and either CEP63 or CPAP, suggesting that CEP152 and CEP192 likely form multiple complexes.
Using a proximity interaction assay with U2OS cells, Firat-Karalar et al. (2014) confirmed that CEP152 interacted with several major centriolar proteins, including CPAP, CEP63, and CCDC67 (DEUP1; 617148). The assay also showed an interaction with CDK5RAP2 (608201). Coimmunoprecipitation analysis of transfected HEK293T cells revealed a direct interaction between the C-terminal conserved region of CEP152 and CDK5RAP2. Depletion of CEP152 reduced centrosome localization of CDK5RAP2, whereas depletion of CDK5RAP2 had no effect on CEP152 localization.
Using mass spectrometric analysis, Gudi et al. (2014) identified CEP152 as a centrobin (CNTROB; 611425)-interacting protein, with the N-terminal region of centrobin binding to CEP152. Centrobin functioned downstream of CEP152 during centriole biogenesis, and its procentriole localization was dependent on CEP152. Knockdown analysis in HeLa cells revealed that centrobin and CPAP were recruited to procentrioles after CEP152.
Primary Microcephaly 9, Autosomal Recessive
In 3 unrelated patients from eastern Canada with primary microcephaly-9 (MCPH9; 614852), Guernsey et al. (2010) identified homozygous or compound heterozygous mutations in the CEP152 gene (613529.0001-613529.0002).
In affected members of a consanguineous Pakistani family (MCP43) with MCPH9, Sajid Hussain et al. (2013) identified 2 homozygous mutations in cis on the same CEP152 allele (613529.0008). The mutations, which were found by linkage analysis followed by Sanger sequencing of the candidate gene, segregated with the disorder in the family. The family was ascertained from a larger cohort of 57 consanguineous Pakistani families with autosomal recessive microcephaly who underwent linkage analysis to known MCPH loci. Three families showed linkage to CEP152, but mutations were only identified in 1 family.
Seckel Syndrome 5
Kalay et al. (2011) sequenced the CEP152 gene in affected members of 3 Turkish families segregating Seckel syndrome mapping to chromosome 15q21.1-q21.2 (SCKL5; 613823) and identified a homozygous splice site mutation in intron 4 (613529.0003), which cosegregated with the founder haplotype. Through the use of an exome sequencing strategy, Kalay et al. (2011) identified the same mutation in an affected French individual of Turkish origin, who was born to consanguineous parents. By sequence analysis, they identified compound heterozygous mutations in the CEP152 gene in affected individuals of different ethnic origins (613529.0004-613529.0007).
Associations Pending Confirmation
D'Alessandro et al. (2016) performed whole-exome sequencing in 81 unrelated probands with atrioventricular septal defect (AVSD; see 606215) to identify potential causal variants in a comprehensive set of 112 genes with strong biological relevance to AVSD. A significant enrichment of rare and rare damaging variants was identified in the gene set, compared with controls (odds ratio (OR) 1.52; 95% confidence interval (CI), 1.35-1.71; p = 4.8 x 10(-11)). The enrichment was specific to AVSD probands, compared with a cohort without AVSD with tetralogy of Fallot (OR 2.25; 95% CI, 1.84-2.76; p = 2.2 x 10(-16)). Six genes, including the syndrome-associated gene CEP152, were enriched for rare variants in AVSD compared with controls. The findings were confirmed in a replication cohort of 81 AVSD probands. D'Alessandro et al. (2016) concluded that mutations in genes with strong biological relevance to AVSD, including syndrome-associated genes, can contribute to AVSD, even in those with isolated heart disease. Eight rare nonsynonymous variants in CEP152 occurred in 9.7% of AVSD cases compared with 4.3% of controls from the Exome Variant Server (EVS) (OR 2.4; p = 0.03). One variant was novel, the rest rare. None of the patients had features of Seckel syndrome (SCKL5; 613823) or microcephaly (MCPH9; 614852).
In 2 unrelated patients from eastern Canada with autosomal recessive primary microcephaly-9 (MCPH9; 614852), Guernsey et al. (2010) identified a homozygous A-to-C transversion in the CEP152 gene, resulting in a gln265-to-pro (Q265P) substitution predicted to occur in a conserved residue in a coiled-coiled region important for organizing chromosomes for cell division. A third unrelated affected patient was compound heterozygous for the Q265P mutation and a C-to-T transition, resulting in an arg987-to-ter (R987X; 613529.0002) substitution that was predicted to result in a truncated protein missing 668 amino acids from the C terminus. In vitro functional expression studies in human osteosarcoma-derived cells showed that the R987X-mutant protein could not be detected in centrosomes, whereas the wildtype and Q265P-mutant proteins could both be detected.
For discussion of the arg987-to-ter (R987X) mutation in the CEP152 gene that was found in compound heterozygous state in patients with autosomal recessive primary microcephaly-9 (MCPH9; 614852) by Guernsey et al. (2010), see 613529.0001.
In affected members of 5 consanguineous Turkish families segregating Seckel syndrome-5 (SCKL5; 613823), Kalay et al. (2011) identified a homozygous splice site mutation in intron 4 of the CEP152 gene (261+1G-C). They identified the same mutation in an affected French patient of Turkish descent. The mutation completely disrupted the splice donor site, as shown through RT-PCR analysis of RNA from affected individuals. The mutation was not found in 250 healthy Turkish control individuals. Kalay et al. (2011) found 4 different aberrant transcripts likely to cause loss of protein function though partial functional activity of one mutant protein, val86_asn87del, which could not be excluded.
In a Seckel syndrome patient (SCKL5; 613823) of Italian origin living in Germany, Kalay et al. (2011) identified compound heterozygosity for 2 mutations in the CEP152 gene: a 2034T-G transversion resulting in a tyr678-to-ter mutation (Y678X) and a splice site mutation at intron 19 (613529.0005). The splice site mutation (2694+1G-T) led to retention of the entire intron 19 in the CEP152 mRNA (r.2694G_ins3581, Ile899LeufsX29).
For discussion of the splice site mutation (2694+1G-T) in the CEP152 gene that was found in compound heterozygous state in a patient with Seckel syndrome-5 (SCKL5; 613823) by Kalay et al. (2011), see 613529.0004.
In an individual from South Africa with Seckel syndrome-5 (SCKL5; 613823), Kalay et al. (2011) identified compound heterozygosity for 2 mutations in the CEP152 gene: a paternally inherited 2-bp deletion (4210_4211delGT; Val1404fsTer2) in exon 27 and a maternally inherited missense mutation (2000A-G; K667R; 613529.0007) in exon 15.
For discussion of the lys667-to-arg (K667R) mutation in the CEP152 gene that was found in compound heterozygous state in a patient with Seckel syndrome-5 (SCKL5; 613823) by Kalay et al. (2011), see 613529.0006.
In affected members of a consanguineous Pakistani family (MCP43) with autosomal recessive primary microcephaly-9 (MCPH9; 614852), Sajid Hussain et al. (2013) identified 2 in cis homozygous mutations in the CEP152 gene: a c.3149T-C transition in exon 20, resulting in a leu1050-to-pro (L1050P) substitution, and a 3-bp deletion (c.3676_3678delAAC), resulting in a deletion of Asn1226. The mutations, which were found by linkage analysis followed by Sanger sequencing of the candidate gene, segregated with the disorder in the family: affected individuals had 4 mutations and carriers had 2 mutations on 1 allele. The mutations were not found in 96 control individuals or public SNP databases. The mutations affected highly conserved residues in the C-terminal CPAP-binding domain. Functional studies were not performed.
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Gudi, R., Zou, C., Dhar, J., Gao, Q., Vasu, C. Centrobin-centrosomal protein 4.1-associated protein (CPAP) interaction promotes CPAP localization to the centrioles during centriole duplication. J. Biol. Chem. 289: 15166-15178, 2014. [PubMed: 24700465] [Full Text: https://doi.org/10.1074/jbc.M113.531152]
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Sonnen, K. F., Gabryjonczyk, A.-M., Anselm, E., Stierhof, Y.-D., Nigg, E. A. Human Cep192 and Cep152 cooperate in Plk4 recruitment and centriole duplication. J. Cell Sci. 126: 3223-3233, 2013. [PubMed: 23641073] [Full Text: https://doi.org/10.1242/jcs.129502]