* 604043

NIMA-RELATED KINASE 2; NEK2


Alternative titles; symbols

NEVER IN MITOSIS GENE A-RELATED KINASE 2


HGNC Approved Gene Symbol: NEK2

Cytogenetic location: 1q32.3     Genomic coordinates (GRCh38): 1:211,658,256-211,675,621 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1q32.3 ?Retinitis pigmentosa 67 615565 AR 3

TEXT

Cloning and Expression

The Aspergillus nidulans protein-serine/threonine kinase nimA (never in mitosis A) is required for entry into mitosis. Cells with a nimA mutation arrest in G2, while overexpression of nimA induces mitosis. By PCR of human promyelocytic leukemia cell cDNA with degenerate primers corresponding to various portions of the protein sequence of the nimA catalytic domain, Schultz and Nigg (1993) isolated partial cDNAs representing 41 distinct protein kinases. Three of these kinases, PKs 20, 21, and 36, were related to NimA. The predicted PK21 and -36 proteins were designated NEK2 (nimA-related kinase 2) and NEK3 (604044), respectively. The authors suggested that the short partial PK20 cDNA might encode the human homolog of mouse Nek1. Schultz et al. (1994) isolated additional NEK2 cDNAs and reported that the deduced 445-amino acid protein contains all the characteristic features of protein kinases. Like nimA and Nek1, NEK2 has an N-terminal catalytic domain and a very basic C-terminal region. Overall, NEK2 shares 36 to 38% sequence identity with nimA, Nek1, and human NEK3. Using Western blots of extracts of synchronized HeLa cells, the authors found that NEK2 protein was almost undetectable during G1, but accumulated progressively throughout S phase, reaching maximal levels in late G2. Schultz et al. (1994) stated that the similarities between NEK2 and nimA in structure and expression suggest that NEK2 may also function in cell cycle control, particularly at the G2-M transition. Northern blot analysis revealed that NEK2 is expressed as 2.4- and 4.7-kb mRNAs in several human cell lines.

Arama et al. (1998) isolated a mouse nek2 cDNA and compared its patterns of expression during both gametogenesis and embryogenesis to those of nek1. Both genes were highly expressed in developing germ cells, albeit in distinct patterns.

Hames and Fry (2002) identified NEK2B, a variant of NEK2 that uses an alternative polyadenylation signal within intron 7. NEK2B encodes a deduced 384-amino acid protein with a calculated molecular mass of 44.9 kD. It diverges from the longer isoform, NEK2A, following amino acid 370 and lacks a number of important regulatory motifs in the extreme C terminus of NEK2A. RT-PCR detected both NEK2A and NEK2B in human U2OS and HeLa cells. Western blot analysis detected NEK2A and NEK2B at apparent molecular masses of 48 and 44 kD, respectively, in all human cell lines tested and in peripheral T lymphocytes. The 2 isoforms exhibited distinct patterns of cell cycle-dependent expression in U2OS cells. Both were present in low amounts in the G1 phase and exhibited increased abundance in the S and G2 phases. However, NEK2A disappeared in prometaphase-arrested cells, whereas NEK2B remained elevated.

Noguchi et al. (2004) found that the C terminus of NEK2A, but not that of NEK2B, has a nucleolar targeting/retention activity.


Gene Structure

Hames and Fry (2002) determined that the NEK2 gene contains 8 coding exons. Alternate polyadenylation signals are located in intron 7 and exon 8.


Mapping

By fluorescence in situ hybridization, Schultz et al. (1994) detected NEK2 signals on both 1q32.2-q41 and 14q12. They suggested that the human genome harbors either a NEK2 pseudogene or a second, closely related functional gene.

By somatic cell hybrid analysis and sequence analysis, Hames and Fry (2002) mapped the functional NEK2 gene to chromosome 1. They identified intronless NEK2-like pseudogenes on chromosomes 2, 14, and 22.


Gene Function

By both immunofluorescence microscopy and subcellular fractionation, Fry et al. (1998) found that human NEK2 localizes to the centrosome throughout the cell cycle. Overexpression of active NEK2 induces a splitting of centrosomes, whereas prolonged expression of either active or inactive NEK2 leads to dispersal of centrosomal material and loss of a focused microtubule-nucleating activity. The authors stated that centrosome dispersal may result from titration or competitive displacement of a NEK2-interacting protein and is unlikely to directly reflect a physiologic event, while centrosome splitting probably results from the phosphorylation of centrosomal proteins by NEK2. They concluded that NEK2 is important for centrosome integrity and may play a role in the regulation of centrosome separation.

Hames and Fry (2002) found that NEK2A and NEK2B could form homo- and heterodimers. Both isoforms localized to the centrosome, but only NEK2A induced centrosome splitting upon overexpression.

Noguchi et al. (2004) found that the C terminus of NEK2A, but not that of NEK2B, associated with NEK11 (609779) at the nucleolus in human osteosarcoma cells. Noncatalytic regions of each kinase were involved in complex formation. The longer NEK11 isoform, NEK11L, interacted with phosphorylated NEK2A and showed weaker interaction with a kinase-inactive NEK2A mutant. Both NEK2A autophosphorylation activity and NEK11L-NEK2A complex formation increased in G1/S-arrested cells. NEK2 phosphorylated NEK11 in its C-terminal autoinhibitory domain and elevated NEK11 kinase activity by dissociating the autoinhibitory domain from the N-terminal catalytic domain.

Bahmanyar et al. (2008) found that stabilization of beta-catenin (CTNNB1; 116806), mimicking mutations found in cancer, induced centrosome splitting, similar to ectopic NEK2 activation. They identified beta-catenin as a substrate and binding partner for NEK2 in vitro and in vivo and found that beta-catenin colocalized with the NEK2 substrates rootletin (CROCC; 615776) and CNAP1 (CEP2; 609689) between centrosomes. CNAP1 and rootletin were required for localization of beta-catenin between centrosomes in interphase, whereas beta-catenin had rootletin-independent binding sites on chromosomes at mitotic spindle poles. In response to ectopic expression of active NEK2 in interphase cells, rootletin was reduced at interphase centrosomes and beta-catenin localized to rootletin-independent sites on centrosomes, an event required for centrosome separation in mitosis.

Fang et al. (2014) found that NEK2A phosphorylated the centrosomal proteins centlein (CNTLN; 611870) and CEP68 (616889) in vitro and caused their dissociation from centrosomes in U2OS cells, resulting in centrosome splitting.

Man et al. (2015) found that NEK2-dependent phosphorylation reduced CEP68 stability during mitosis in HeLa cells, leading to CEP68 dissociation from centrosomes. Degradation of phosphorylated CEP68 was dependent upon the F-box protein beta-TRCP (BTRC; 603482) and was reduced by proteasome inhibition, suggesting that NEK2-mediated phosphorylation targets CEP68 for ubiquitination and proteasome-mediated degradation.

Chen et al. (2015) found that CEP85 (618898) interacted and colocalized with NEK2A at the proximal ends of centrioles in transfected human cells. The interaction required the C-terminal region of NEK2A and a region of CEP85 that the authors termed the NEK2A-binding domain (NBD). NEK2A and CEP85 formed a granule meshwork encasing the proximal ends of both mother and daughter centrioles. CEP85 functioned as an antagonist of NEK2A and inhibited NEK2A kinase activity in centrosome disjunction. The NBD and centrosome localization domain of CEP85 were both required for efficient suppression of centrosome disjunction in human cells.

Hellmuth and Stemmann (2020) showed that human cells that enter mitosis with already active separase (ESPL1; 604143) rapidly undergo death in mitosis owing to direct cleavage of antiapoptotic MCL1 (159552) and BCLXL (600039) by separase. Cleavage not only prevents MCL1 and BCLXL from sequestering proapoptotic BAK (600516), but also converts them into active promoters of death in mitosis. The data strongly suggested that the deadliest cleavage fragment, the C-terminal half of MCL1, forms BAK/BAX (600040)-like pores in the mitochondrial outer membrane. MCL1 and BCLXL are turned into separase substrates only upon phosphorylation by NEK2A. Early mitotic degradation of this kinase is therefore crucial for preventing apoptosis upon scheduled activation of separase in metaphase. Speeding up mitosis by abrogation of the spindle assembly checkpoint (SAC) results in a temporal overlap of the enzymatic activities of NEK2A and separase and consequently in cell death. Hellmuth and Stemmann (2020) proposed that NEK2A and separase jointly check on SAC integrity and eliminate cells that are prone to chromosome missegregation owing to accelerated progression through early mitosis.


Molecular Genetics

Nishiguchi et al. (2013) performed whole-genome sequencing in 16 unrelated RP patients from diverse ethnic backgrounds, and in 1 Japanese female patient, who did not have any clear-cut mutations in known RP genes, they identified a homozygous frameshift mutation in the NEK2 gene (604043.0001). By sequencing the NEK2 gene in a mixed cohort of 192 American and 64 Japanese RP patients, as well as in 13 patients with retinal degeneration who had previously shown linkage to the NEK2 region, they identified a Japanese male RP patient who was heterozygous for the same NEK2 frameshift mutation. However, he also carried a frameshift mutation in the known RP-associated RPGR gene (312610) that had previously been described as a sufficient cause of X-linked RP (see 300029) by Vervoort et al. (2000); studies in zebrafish suggested that the RPGR allele interacts in trans with the NEK2 locus to exacerbate photoreceptor defects.

Role in Left-Right Patterning

By high-resolution genotyping of 262 heterotaxy (see HTX1, 306955) subjects and 991 controls, Fakhro et al. (2011) identified a 2-fold excess of subjects with rare genic copy number variations (CNVs) in heterotaxy (14.5% vs 7.4%, p = 1.5 x 10(-4)). Although 7 of 45 heterotaxy CNVs were large chromosomal abnormalities, 38 smaller CNVs altered a total of 61 genes, 22 of which had Xenopus orthologs. In situ hybridization identified 7 of these 22 genes with expression in the ciliated left-right organizer, a marked enrichment compared with 40 of 845 previously studied genes (7-fold enrichment, p less than 10(-6)). Morpholino knockdown in Xenopus of heterotaxy candidate genes demonstrated that 5 genes (NEK2; ROCK2, 604002; TGFBR2, 190182; GALNT11, 615130; and NUP188, 615587) strongly disrupted both morphologic left-right development and expression of PITX2 (601542), a molecular marker of left-right patterning. These effects were specific, because 0 of 13 control genes from rare heterotaxy or control CNVs produced significant left-right abnormalities (p = 0.001).


Animal Model

Nishiguchi et al. (2013) generated Nek2 -/- morphant zebrafish and observed gross ocular defects, including microphthalmia and enlarged eye sockets at 5 days postfertilization. Histologic analysis of the photoreceptor layer showed a persistent decrease in the number of photoreceptors with large central domains of condensed chromatin in all morphant embryos and in none of the controls, suggesting a loss of rod photoreceptors specific to the suppression of Nek2. Immunohistochemical analysis demonstrated depletion of approximately 24% of rhodopsin-positive rod photoreceptors, and mislocalization of rod opsin throughout the photoreceptor cells was evident in the central retina of morphant specimens, consistent with the hypothesis that NEK2 is required for the appropriate trafficking of rhodopsin to the outer segments.


ALLELIC VARIANTS ( 1 Selected Example):

.0001 RETINITIS PIGMENTOSA 67 (1 patient)

NEK2, 8-BP DEL/1-BP INS, NT617
  
RCV000076909

In a Japanese woman with retinitis pigmentosa (RP67; 615565) who was born of consanguineous parents, Nishiguchi et al. (2013) identified homozygosity for an 8-bp deletion/1-bp insertion (c.617_624delTGTATGAGinsA) in the NEK2 gene, causing a frameshift (Leu206fs) predicted to result in nonsense-mediated mRNA decay. The mutation was not found in 1,273 Japanese or 95 North American controls. In addition, Nishiguchi et al. (2013) identified a Japanese male patient who was heterozygous for the same NEK2 frameshift mutation, but who also carried a frameshift mutation in the known RP-associated RPGR gene (312610.0026) that had previously been described as a sufficient cause of X-linked RP (see 300029) by Vervoort et al. (2000); studies in zebrafish suggested that the RPGR allele interacts in trans with the NEK2 locus to exacerbate photoreceptor defects.


REFERENCES

  1. Arama, E., Yanai, A., Kilfin, G., Bernstein, A., Motro, B. Murine NIMA-related kinases are expressed in patterns suggesting distinct functions in gametogenesis and a role in the nervous system. Oncogene 16: 1813-1823, 1998. [PubMed: 9583679, related citations] [Full Text]

  2. Bahmanyar, S., Kaplan, D. D., DeLuca, J. G., Giddings, T. H., Jr., O'Toole, E. T., Winey, M., Salmon, E. D., Casey, P. J., Nelson, W. J., Barth, A. I. M. Beta-catenin is a Nek2 substrate involved in centrosome separation. Genes Dev. 22: 91-105, 2008. [PubMed: 18086858, images, related citations] [Full Text]

  3. Chen, C., Tian, F., Lu, L., Wang, Y., Xiao, Z., Yu, C., Yu, X. Characterization of Cep85: a new antagonist of Nek2A that is involved in the regulation of centrosome disjunction. J. Cell Sci. 128: 3290-3303, 2015. Note: Erratum: J. Cell Sci. 128: 3837 only, 2015. [PubMed: 26220856, related citations] [Full Text]

  4. Fakhro, K. A., Choi, M., Ware, S. M., Belmont, J. W., Towbin, J. A., Lifton, R. P., Khokha, M. K., Brueckner, M. Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning. Proc. Nat. Acad. Sci. 108: 2915-2920, 2011. [PubMed: 21282601, images, related citations] [Full Text]

  5. Fang, G., Zhang, D., Yin, H., Zheng, L., Bi, X., Yuan, L. Centlein mediates an interaction between C-Nap1 and Cep68 to maintain centrosome cohesion. J. Cell Sci. 127: 1631-1639, 2014. [PubMed: 24554434, related citations] [Full Text]

  6. Fry, A. M., Meraldi, P., Nigg, E. A. A centrosomal function for the human Nek2 protein kinase, a member of the NIMA family of cell cycle regulators. EMBO J. 17: 470-481, 1998. [PubMed: 9430639, related citations] [Full Text]

  7. Hames, R. S., Fry, A. M. Alternative splice variants of the human centrosome kinase Nek2 exhibit distinct patterns of expression in mitosis. Biochem. J. 361: 77-85, 2002. [PubMed: 11742531, related citations] [Full Text]

  8. Hellmuth, S., Stemmann, O. Separase-triggered apoptosis enforces minimal length of mitosis. Nature 580: 542-547, 2020. [PubMed: 32322059, related citations] [Full Text]

  9. Man, X., Megraw, T. L., Lim, Y. P. Cep68 can be regulated by Nek2 and SCF complex. Europ. J. Cell Biol. 94: 162-172, 2015. [PubMed: 25704143, related citations] [Full Text]

  10. Nishiguchi, K. M., Tearle, R. G., Liu, Y. P., Oh, E. C., Miyake, N., Benaglio, P., Harper, S., Koskiniemi-Kuendig, H., Venturini, G., Sharon, D., Koenekoop, R. K., Nakamura, M., and 10 others. Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene. Proc. Nat. Acad. Sci. 110: 16139-16144, 2013. [PubMed: 24043777, images, related citations] [Full Text]

  11. Noguchi, K., Fukazawa, H., Murakami, Y., Uehara, Y. Nucleolar Nek11 is a novel target of Nek2A in G1/S-arrested cells. J. Biol. Chem. 279: 32716-32727, 2004. [PubMed: 15161910, related citations] [Full Text]

  12. Schultz, S. J., Fry, A. M., Sutterlin, C., Ried, T., Nigg, E. A. Cell cycle-dependent expression of Nek2, a novel human protein kinase related to the NIMA mitotic regulator of Aspergillus nidulans. Cell Growth Diff. 5: 625-635, 1994. [PubMed: 7522034, related citations] [Full Text]

  13. Schultz, S. J., Nigg, E. A. Identification of 21 novel human protein kinases, including 3 members of a family related to the cell cycle regulator nimA of Aspergillus nidulans. Cell Growth Diff. 4: 821-830, 1993. [PubMed: 8274451, related citations]

  14. Vervoort, R., Lennon, A., Bird, A. C., Tulloch, B., Axton, R., Miano, M. G., Meindl, A., Meitinger, T., Ciccodicola, A., Wright, A. F. Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa. Nature Genet. 25: 462-466, 2000. [PubMed: 10932196, related citations] [Full Text]


Ada Hamosh - updated : 09/21/2020
Bao Lige - updated : 05/29/2020
Patricia A. Hartz - updated : 03/31/2016
Ada Hamosh - updated : 1/16/2014
Marla J. F. O'Neill - updated : 12/13/2013
Patricia A. Hartz - updated : 3/12/2008
Patricia A. Hartz - updated : 12/13/2005
Creation Date:
Rebekah S. Rasooly : 7/22/1999
carol : 03/01/2021
alopez : 09/21/2020
carol : 08/28/2020
mgross : 06/18/2020
mgross : 05/29/2020
mgross : 03/31/2016
carol : 10/6/2014
mgross : 5/14/2014
alopez : 1/16/2014
carol : 12/18/2013
carol : 12/17/2013
mcolton : 12/13/2013
mgross : 3/18/2008
terry : 3/12/2008
mgross : 12/13/2005
jlewis : 7/23/1999
jlewis : 7/23/1999
jlewis : 7/22/1999

* 604043

NIMA-RELATED KINASE 2; NEK2


Alternative titles; symbols

NEVER IN MITOSIS GENE A-RELATED KINASE 2


HGNC Approved Gene Symbol: NEK2

Cytogenetic location: 1q32.3     Genomic coordinates (GRCh38): 1:211,658,256-211,675,621 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1q32.3 ?Retinitis pigmentosa 67 615565 Autosomal recessive 3

TEXT

Cloning and Expression

The Aspergillus nidulans protein-serine/threonine kinase nimA (never in mitosis A) is required for entry into mitosis. Cells with a nimA mutation arrest in G2, while overexpression of nimA induces mitosis. By PCR of human promyelocytic leukemia cell cDNA with degenerate primers corresponding to various portions of the protein sequence of the nimA catalytic domain, Schultz and Nigg (1993) isolated partial cDNAs representing 41 distinct protein kinases. Three of these kinases, PKs 20, 21, and 36, were related to NimA. The predicted PK21 and -36 proteins were designated NEK2 (nimA-related kinase 2) and NEK3 (604044), respectively. The authors suggested that the short partial PK20 cDNA might encode the human homolog of mouse Nek1. Schultz et al. (1994) isolated additional NEK2 cDNAs and reported that the deduced 445-amino acid protein contains all the characteristic features of protein kinases. Like nimA and Nek1, NEK2 has an N-terminal catalytic domain and a very basic C-terminal region. Overall, NEK2 shares 36 to 38% sequence identity with nimA, Nek1, and human NEK3. Using Western blots of extracts of synchronized HeLa cells, the authors found that NEK2 protein was almost undetectable during G1, but accumulated progressively throughout S phase, reaching maximal levels in late G2. Schultz et al. (1994) stated that the similarities between NEK2 and nimA in structure and expression suggest that NEK2 may also function in cell cycle control, particularly at the G2-M transition. Northern blot analysis revealed that NEK2 is expressed as 2.4- and 4.7-kb mRNAs in several human cell lines.

Arama et al. (1998) isolated a mouse nek2 cDNA and compared its patterns of expression during both gametogenesis and embryogenesis to those of nek1. Both genes were highly expressed in developing germ cells, albeit in distinct patterns.

Hames and Fry (2002) identified NEK2B, a variant of NEK2 that uses an alternative polyadenylation signal within intron 7. NEK2B encodes a deduced 384-amino acid protein with a calculated molecular mass of 44.9 kD. It diverges from the longer isoform, NEK2A, following amino acid 370 and lacks a number of important regulatory motifs in the extreme C terminus of NEK2A. RT-PCR detected both NEK2A and NEK2B in human U2OS and HeLa cells. Western blot analysis detected NEK2A and NEK2B at apparent molecular masses of 48 and 44 kD, respectively, in all human cell lines tested and in peripheral T lymphocytes. The 2 isoforms exhibited distinct patterns of cell cycle-dependent expression in U2OS cells. Both were present in low amounts in the G1 phase and exhibited increased abundance in the S and G2 phases. However, NEK2A disappeared in prometaphase-arrested cells, whereas NEK2B remained elevated.

Noguchi et al. (2004) found that the C terminus of NEK2A, but not that of NEK2B, has a nucleolar targeting/retention activity.


Gene Structure

Hames and Fry (2002) determined that the NEK2 gene contains 8 coding exons. Alternate polyadenylation signals are located in intron 7 and exon 8.


Mapping

By fluorescence in situ hybridization, Schultz et al. (1994) detected NEK2 signals on both 1q32.2-q41 and 14q12. They suggested that the human genome harbors either a NEK2 pseudogene or a second, closely related functional gene.

By somatic cell hybrid analysis and sequence analysis, Hames and Fry (2002) mapped the functional NEK2 gene to chromosome 1. They identified intronless NEK2-like pseudogenes on chromosomes 2, 14, and 22.


Gene Function

By both immunofluorescence microscopy and subcellular fractionation, Fry et al. (1998) found that human NEK2 localizes to the centrosome throughout the cell cycle. Overexpression of active NEK2 induces a splitting of centrosomes, whereas prolonged expression of either active or inactive NEK2 leads to dispersal of centrosomal material and loss of a focused microtubule-nucleating activity. The authors stated that centrosome dispersal may result from titration or competitive displacement of a NEK2-interacting protein and is unlikely to directly reflect a physiologic event, while centrosome splitting probably results from the phosphorylation of centrosomal proteins by NEK2. They concluded that NEK2 is important for centrosome integrity and may play a role in the regulation of centrosome separation.

Hames and Fry (2002) found that NEK2A and NEK2B could form homo- and heterodimers. Both isoforms localized to the centrosome, but only NEK2A induced centrosome splitting upon overexpression.

Noguchi et al. (2004) found that the C terminus of NEK2A, but not that of NEK2B, associated with NEK11 (609779) at the nucleolus in human osteosarcoma cells. Noncatalytic regions of each kinase were involved in complex formation. The longer NEK11 isoform, NEK11L, interacted with phosphorylated NEK2A and showed weaker interaction with a kinase-inactive NEK2A mutant. Both NEK2A autophosphorylation activity and NEK11L-NEK2A complex formation increased in G1/S-arrested cells. NEK2 phosphorylated NEK11 in its C-terminal autoinhibitory domain and elevated NEK11 kinase activity by dissociating the autoinhibitory domain from the N-terminal catalytic domain.

Bahmanyar et al. (2008) found that stabilization of beta-catenin (CTNNB1; 116806), mimicking mutations found in cancer, induced centrosome splitting, similar to ectopic NEK2 activation. They identified beta-catenin as a substrate and binding partner for NEK2 in vitro and in vivo and found that beta-catenin colocalized with the NEK2 substrates rootletin (CROCC; 615776) and CNAP1 (CEP2; 609689) between centrosomes. CNAP1 and rootletin were required for localization of beta-catenin between centrosomes in interphase, whereas beta-catenin had rootletin-independent binding sites on chromosomes at mitotic spindle poles. In response to ectopic expression of active NEK2 in interphase cells, rootletin was reduced at interphase centrosomes and beta-catenin localized to rootletin-independent sites on centrosomes, an event required for centrosome separation in mitosis.

Fang et al. (2014) found that NEK2A phosphorylated the centrosomal proteins centlein (CNTLN; 611870) and CEP68 (616889) in vitro and caused their dissociation from centrosomes in U2OS cells, resulting in centrosome splitting.

Man et al. (2015) found that NEK2-dependent phosphorylation reduced CEP68 stability during mitosis in HeLa cells, leading to CEP68 dissociation from centrosomes. Degradation of phosphorylated CEP68 was dependent upon the F-box protein beta-TRCP (BTRC; 603482) and was reduced by proteasome inhibition, suggesting that NEK2-mediated phosphorylation targets CEP68 for ubiquitination and proteasome-mediated degradation.

Chen et al. (2015) found that CEP85 (618898) interacted and colocalized with NEK2A at the proximal ends of centrioles in transfected human cells. The interaction required the C-terminal region of NEK2A and a region of CEP85 that the authors termed the NEK2A-binding domain (NBD). NEK2A and CEP85 formed a granule meshwork encasing the proximal ends of both mother and daughter centrioles. CEP85 functioned as an antagonist of NEK2A and inhibited NEK2A kinase activity in centrosome disjunction. The NBD and centrosome localization domain of CEP85 were both required for efficient suppression of centrosome disjunction in human cells.

Hellmuth and Stemmann (2020) showed that human cells that enter mitosis with already active separase (ESPL1; 604143) rapidly undergo death in mitosis owing to direct cleavage of antiapoptotic MCL1 (159552) and BCLXL (600039) by separase. Cleavage not only prevents MCL1 and BCLXL from sequestering proapoptotic BAK (600516), but also converts them into active promoters of death in mitosis. The data strongly suggested that the deadliest cleavage fragment, the C-terminal half of MCL1, forms BAK/BAX (600040)-like pores in the mitochondrial outer membrane. MCL1 and BCLXL are turned into separase substrates only upon phosphorylation by NEK2A. Early mitotic degradation of this kinase is therefore crucial for preventing apoptosis upon scheduled activation of separase in metaphase. Speeding up mitosis by abrogation of the spindle assembly checkpoint (SAC) results in a temporal overlap of the enzymatic activities of NEK2A and separase and consequently in cell death. Hellmuth and Stemmann (2020) proposed that NEK2A and separase jointly check on SAC integrity and eliminate cells that are prone to chromosome missegregation owing to accelerated progression through early mitosis.


Molecular Genetics

Nishiguchi et al. (2013) performed whole-genome sequencing in 16 unrelated RP patients from diverse ethnic backgrounds, and in 1 Japanese female patient, who did not have any clear-cut mutations in known RP genes, they identified a homozygous frameshift mutation in the NEK2 gene (604043.0001). By sequencing the NEK2 gene in a mixed cohort of 192 American and 64 Japanese RP patients, as well as in 13 patients with retinal degeneration who had previously shown linkage to the NEK2 region, they identified a Japanese male RP patient who was heterozygous for the same NEK2 frameshift mutation. However, he also carried a frameshift mutation in the known RP-associated RPGR gene (312610) that had previously been described as a sufficient cause of X-linked RP (see 300029) by Vervoort et al. (2000); studies in zebrafish suggested that the RPGR allele interacts in trans with the NEK2 locus to exacerbate photoreceptor defects.

Role in Left-Right Patterning

By high-resolution genotyping of 262 heterotaxy (see HTX1, 306955) subjects and 991 controls, Fakhro et al. (2011) identified a 2-fold excess of subjects with rare genic copy number variations (CNVs) in heterotaxy (14.5% vs 7.4%, p = 1.5 x 10(-4)). Although 7 of 45 heterotaxy CNVs were large chromosomal abnormalities, 38 smaller CNVs altered a total of 61 genes, 22 of which had Xenopus orthologs. In situ hybridization identified 7 of these 22 genes with expression in the ciliated left-right organizer, a marked enrichment compared with 40 of 845 previously studied genes (7-fold enrichment, p less than 10(-6)). Morpholino knockdown in Xenopus of heterotaxy candidate genes demonstrated that 5 genes (NEK2; ROCK2, 604002; TGFBR2, 190182; GALNT11, 615130; and NUP188, 615587) strongly disrupted both morphologic left-right development and expression of PITX2 (601542), a molecular marker of left-right patterning. These effects were specific, because 0 of 13 control genes from rare heterotaxy or control CNVs produced significant left-right abnormalities (p = 0.001).


Animal Model

Nishiguchi et al. (2013) generated Nek2 -/- morphant zebrafish and observed gross ocular defects, including microphthalmia and enlarged eye sockets at 5 days postfertilization. Histologic analysis of the photoreceptor layer showed a persistent decrease in the number of photoreceptors with large central domains of condensed chromatin in all morphant embryos and in none of the controls, suggesting a loss of rod photoreceptors specific to the suppression of Nek2. Immunohistochemical analysis demonstrated depletion of approximately 24% of rhodopsin-positive rod photoreceptors, and mislocalization of rod opsin throughout the photoreceptor cells was evident in the central retina of morphant specimens, consistent with the hypothesis that NEK2 is required for the appropriate trafficking of rhodopsin to the outer segments.


ALLELIC VARIANTS 1 Selected Example):

.0001   RETINITIS PIGMENTOSA 67 (1 patient)

NEK2, 8-BP DEL/1-BP INS, NT617
SNP: rs398122961, ClinVar: RCV000076909

In a Japanese woman with retinitis pigmentosa (RP67; 615565) who was born of consanguineous parents, Nishiguchi et al. (2013) identified homozygosity for an 8-bp deletion/1-bp insertion (c.617_624delTGTATGAGinsA) in the NEK2 gene, causing a frameshift (Leu206fs) predicted to result in nonsense-mediated mRNA decay. The mutation was not found in 1,273 Japanese or 95 North American controls. In addition, Nishiguchi et al. (2013) identified a Japanese male patient who was heterozygous for the same NEK2 frameshift mutation, but who also carried a frameshift mutation in the known RP-associated RPGR gene (312610.0026) that had previously been described as a sufficient cause of X-linked RP (see 300029) by Vervoort et al. (2000); studies in zebrafish suggested that the RPGR allele interacts in trans with the NEK2 locus to exacerbate photoreceptor defects.


REFERENCES

  1. Arama, E., Yanai, A., Kilfin, G., Bernstein, A., Motro, B. Murine NIMA-related kinases are expressed in patterns suggesting distinct functions in gametogenesis and a role in the nervous system. Oncogene 16: 1813-1823, 1998. [PubMed: 9583679] [Full Text: https://doi.org/10.1038/sj.onc.1201710]

  2. Bahmanyar, S., Kaplan, D. D., DeLuca, J. G., Giddings, T. H., Jr., O'Toole, E. T., Winey, M., Salmon, E. D., Casey, P. J., Nelson, W. J., Barth, A. I. M. Beta-catenin is a Nek2 substrate involved in centrosome separation. Genes Dev. 22: 91-105, 2008. [PubMed: 18086858] [Full Text: https://doi.org/10.1101/gad.1596308]

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Contributors:
Ada Hamosh - updated : 09/21/2020
Bao Lige - updated : 05/29/2020
Patricia A. Hartz - updated : 03/31/2016
Ada Hamosh - updated : 1/16/2014
Marla J. F. O'Neill - updated : 12/13/2013
Patricia A. Hartz - updated : 3/12/2008
Patricia A. Hartz - updated : 12/13/2005

Creation Date:
Rebekah S. Rasooly : 7/22/1999

Edit History:
carol : 03/01/2021
alopez : 09/21/2020
carol : 08/28/2020
mgross : 06/18/2020
mgross : 05/29/2020
mgross : 03/31/2016
carol : 10/6/2014
mgross : 5/14/2014
alopez : 1/16/2014
carol : 12/18/2013
carol : 12/17/2013
mcolton : 12/13/2013
mgross : 3/18/2008
terry : 3/12/2008
mgross : 12/13/2005
jlewis : 7/23/1999
jlewis : 7/23/1999
jlewis : 7/22/1999