Alternative titles; symbols
HGNC Approved Gene Symbol: NEK1
Cytogenetic location: 4q33 Genomic coordinates (GRCh38): 4:169,392,809-169,612,583 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q33 | ?Orofaciodigital syndrome II | 252100 | Autosomal recessive | 3 |
| {Amyotrophic lateral sclerosis, susceptibility to, 24} | 617892 | Autosomal dominant | 3 | |
| Short-rib thoracic dysplasia 6 with or without polydactyly | 263520 | Autosomal recessive; Digenic recessive | 3 |
NIMA-related kinases (NEKs), such as NEK1, form an evolutionarily conserved family of serine/threonine kinases thought to function in cell cycle control and cilia regulation. NEK1 has proposed functions in DNA double-strand repair, neuronal development, and coordination of cell cycle-associated ciliogenesis (summary by Thiel et al., 2011).
Using antibodies directed toward phosphotyrosine, Letwin et al. (1992) cloned and characterized the Nek1 gene from a mouse erythroleukemia cDNA expression library. The Nek1 gene encodes a 774-amino acid dual-specific protein kinase that contains an N-terminal domain (amino acids 1 to 258) with homology to the catalytic domain of NIMA, a protein kinase that controls the initiation of mitosis in Aspergillus nidulans. In situ RNA analysis of Nek1 expression in mouse gonads demonstrated a high level of expression in both male and female germ cells, with a distribution consistent with a role in meiosis. Based on these results, Letwin et al. (1992) suggested that NEK1 is a mammalian relative of the fungal NIMA cell cycle regulator.
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Nagase et al. (2001) cloned NEK1, which they designated KIAA1901. The deduced 1,265-amino acid protein shares 81% identity with the 774-amino acid mouse Nek1 serine/threonine protein kinase. RT-PCR ELISA detected highest KIAA1901 expression in adult spinal cord, followed by ovary and kidney. Moderate expression was detected in all other adult and fetal tissues and specific adult brain regions examined.
Surpili et al. (2003) stated that the deduced 1,258-amino acid human NEK1 protein has a calculated molecular mass of 128.6 kD. It has an N-terminal kinase domain of about 250 amino acids, followed by a regulatory domain that includes 5 coiled-coil regions, 2 putative nuclear localization signals (NLSs), a putative nuclear export signal (NES), serine and threonine phosphorylation sites, and a 14-3-3 protein (see 113508)-binding site.
Hilton et al. (2009) reported that the full-length mouse Nek1 protein contains 1,203 amino acids. It has an N-terminal kinase domain, followed by a basic region, a coiled-coil domain containing a bipartite NLS, and 2 NESs in the C-terminal half.
Thiel et al. (2011) reported that the NEK1 gene contains 34 exons.
Gross (2011) mapped the NEK1 gene to chromosome 4q33 based on an alignment of the NEK1 sequence (GenBank BC114491) with the genomic sequence (GRCh37).
Surpili et al. (2003) used the catalytic and regulatory domains of NEK1 as baits in yeast 2-hybrid screens of a human fetal brain cDNA library. They found that the kinase domain interacted with the N-terminal half of the corepressor protein ZBRK1 (ZNF350; 605422) only. In contrast, the regulatory domain interacted with 10 different proteins that could be divided into 3 groups: proteins associated with polycystic kidney disease (PKD; 173900) (e.g., KIF3A; 604683), proteins involved in double-strand DNA repair during the G2/M transition phase of the cell cycle (e.g., ATRX; 300032), and proteins that regulate neural cell development and function (e.g., FEZ1; 604825).
Polci et al. (2004) found that exposure of HeLa cells and HK2 human proximal renal tubular epithelial cells to sublethal doses of ionizing radiation increased the kinase activity of NEK1 and caused NEK1 to redistribute from the cytoplasm to nuclear foci. Within nuclei, NEK1 colocalized with gamma-H2AX (601772) and NFBD1 (MDC1; 607593), both of which are involved in the early response to DNA damage. Nek1-deficient primary fibroblasts from kat2J mice (see ANIMAL MODEL) were hypersensitive to DNA damage and the lethal effects of ionizing radiation. Polci et al. (2004) concluded that NEK1 is involved early in the DNA damage response pathway.
Chen et al. (2008) showed that NEK1 relocalized to sites of DNA damage in HK2 cells following exposure to a variety of DNA-damaging agents. Knockdown of NEK1 in HK2 cells abrogated the ability of ionizing radiation to induce activating phosphorylation of the checkpoint kinases CHK1 (603078) and CHK2 (604373).
Hilton et al. (2009) found that Nek1 accumulated in nuclei of mouse IMCD3 renal epithelial cells following inhibition of nuclear export. Mutation analysis revealed a functional NLS in the basic region of mouse Nek1 in addition to the classic bipartite NLS in its coiled-coil domain. Each of the NLSs could independently direct nuclear accumulation of Nek1. Hilton et al. (2009) concluded that NEK1 cycles through the nucleus via its nuclear localization and export signals.
Using coimmunoprecipitation analysis, Fang et al. (2015) showed that C21ORF2 (603191) interacted with NEK1 in HeLa cells. Depletion of C21ORF2 via short hairpin RNA did not alter cell proliferation, but it increased cell sensitivity to ionizing radiation. Knockdown of C21ORF2 caused defective DNA repair via homologous recombination, but not nonhomologous end joining, and C21ORF2-knockdown cells did not show defective activation of G2-phase DNA damage checkpoint. NEK1, but not C21ORF2, translocated to nucleus following exposure of cells to ionizing radiation. Overexpression of NEK1 rescued the DNA repair defect due to C21ORF2 depletion. Fang et al. (2015) concluded that C21ORF2 and NEK1 function in the same DNA damage repair pathway.
By affinity proteomics and coimmunoprecipitation assays, Wheway et al. (2015) demonstrated that C21ORF2, NEK1, and SPATA7 (609868) are part of the same protein complex. Further analysis showed that NEK1 pulled down C21ORF2 from bovine retinal lysates. Immunofluorescence studies showed that C21ORF2 colocalizes with NEK1 and SPATA7 at the basal body in human TERT-RPEI cells, and GST pull-down of SPATA7 from bovine retinal lysates efficiently recovered endogenous C21ORF2 and NEK1. Partial rescue of ciliopathy features in nek1-null zebrafish by human wildtype C21ORF2 further demonstrated the functional interaction between C21ORF2 and NEK1. Wheway et al. (2015) suggested that the retinal phenotype observed in C21ORF2-mutated individuals might result from a dysfunctional SPATA7/C21ORF2-containing module in patient photoreceptors, whereas the skeletal phenotype observed in both C21ORF2- and NEK1-mutated individuals probably had a common origin in the disruption of C21ORF2/NEK1 interaction.
Short-Rib Thoracic Dysplasia 6 with or without Polydactyly
Thiel et al. (2011) considered the NEK1 gene, located within the short rib-polydactyly syndrome type II (Majewski type) (SRTD6; 263520) locus region on chromosome 4q32.1-q34.3, as a likely candidate for the disorder because mutant mice homozygous for the orthologous gene show polycystic kidney disease, craniofacial anomalies, and growth reduction. By sequencing of the NEK1 gene in the affected probands from 2 consanguineous families, they identified homozygosity for different mutations in each (604588.0001-604588.0002). In the proband from a nonconsanguineous family, they identified heterozygosity for an insertion mutation in the NEK1 gene (604588.0003) and heterozygosity for a missense mutation in the DYNC2H1 gene (603297.0016); no second mutation was found in either gene, and each parent was heterozygous for one of the mutations. Thiel et al. (2011) found that absence of functional full-length NEK1 severely reduces cilia number and alters cilia morphology in vivo.
El Hokayem et al. (2012) analyzed the NEK1 gene in 11 unrelated cases with a diagnosis of short rib-polydactyly syndrome type II, all of which were either terminated pregnancies or cases of neonatal death, and identified 4 homozygous mutations in 4 cases (see, e.g., 604588.0001 and 604588.0004).
In a 3-year-old British girl with SRTD, McInerney-Leo et al. (2015) identified compound heterozygosity for mutations in the NEK1 gene: a splice site mutation (604588.0009) and a missense mutation (P172S; 604588.0010).
In a 12.5-year-old boy with severe retinal dystrophy, narrow thorax, short ribs, mild platyspondyly, and mild metaphyseal changes in the long bones, who had been clinically diagnosed with axial spondylometaphyseal dysplasia (see 602271) but was negative for mutation in the C21ORF2 gene, Wang et al. (2017) performed whole-exome sequencing and identified compound heterozygosity for a nonsense mutation (S1036X; 604588.0011) and a missense mutation (D1277A; 604588.0012) in the NEK1 gene. The authors suggested that the phenotypic variability exhibited in this patient might be explained by the location of mutations on the NEK1 protein, since most of the previously reported mutations were located in the N terminus whereas this patient's mutations were in the C terminus.
Susceptibility to Amyotrophic Lateral Sclerosis 24
Brenner et al. (2016) analyzed the association between NEK1 variants and familial amyotrophic lateral sclerosis (ALS) in 265 familial ALS index patients and 827 in-house control individuals. They identified an increased frequency of NEK1 loss-of-function variants in the familial ALS patient group (allele frequency 0.57%) compared with the control group (allele frequency 0.06%) (p = 0.0474, Fisher exact test). Brenner et al. (2016) also identified 3 loss-of-function mutations in the 3 individuals in the familial ALS patient group (e.g., ser1036 to ter, 604588.0005 and arg812 to ter, 604588.0006). One loss-of-function variant was identified in the control cohort. The likelihood of incomplete penetrance was supported by the presence of the S1036X mutation in a brother of the proband, who had no signs or symptoms 4 years after the death of the index patient and 9 years after onset of his disease.
Kenna et al. (2016) applied exomewide rare variant burden (RVB) analysis, trained with established ALS genes, to 1,022 index familial ALS cases and 7,315 controls and identified a significant association between loss-of-function variants in NEK1 and familial ALS risk. They then performed whole-genome sequencing of 4 ALS patients from an isolated community in the Netherlands with a restricted genetic lineage. Autozygosity mapping identified 4 candidate disease variants occurring in detectable runs of homozygosity. The NEK1 variant arg261 to his (R261H; 604588.0007) was the only variant identifiable in all patients and the only variant which occurred in homozygosity in more than 1 individual; it was present in homozygosity in 2 patients and was heterozygous in the other 2. Metaanalysis of disease association of the R261H variant in in independent group of 6,172 sporadic ALS cases and 4,417 matched controls from 8 countries identified a clear minor allele excess in cases, with a combined significance of p = 4.8 x 10(-5), OR = 2.4; disease association was also observed in the familial ALS case-control data and a metaanalysis of all patients (7,194) and controls (11,732) combined. DNA availability facilitated segregation analysis of only 1 NEK1 loss-of-function variant, arg550 to ter (R550X; 604588.0008), which Kenna et al. (2016) also detected in the affected mother of the identified proband. To validate the effect of loss-of-function variants observed in familial ALS and assess any potential contribution to sporadic disease, Kenna et al. (2016) analyzed the full sequencing data of the NWK1 coding region for 2,303 SALS cases and 1,059 controls. Rare variant burden (RVB) analysis confirmed a significant excess of loss-of-function variants in cases (23/2,303 sporadic ALS samples vs 0/1,059 controls, OR = 22.2, p = 1.5 x 10(-4)). Metaanalysis of discovery and replication loss-of-function analyses yielded a combined significance of p = 3.4 x 10(-8), OR = 8.8. In total, Kenna et al. (2016) identified 120 predicted nonsynonymous NEK1 variants in familial and sporadic ALS samples and controls.
Orofaciodigital Syndrome II
In 2 brothers with OFD2 (252100), Monroe et al. (2016) identified compound heterozygosity for mutations in the NEK1 gene, c.464G-C (604588.0013) and c.1226G-A (604588.0014). Sanger sequencing confirmed the mutations, and their unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in public variant databases. Analysis of patient fibroblasts showed a significant reduction in cilia number compared to control fibroblasts.
Associations Pending Confirmation
Hikoya et al. (2023) reported a Japanese sister and brother with juvenile retinitis pigmentosa (see 604393) and mutation in the NEK1 gene. Corrected visual acuity at first visit was binocular 20/63 in the girl, and 20/100 OD and 20/63 OS in the boy. The sibs had narrowing of the retinal blood vessels, tilted optic discs, and extensive retinal pigment epithelium atrophy in the fundus with an extinguished pattern on electroretinography. Optical coherence tomography showed a mottled ellipsoid band with progressive loss in the outer macular layer, the edges of which corresponded to the ring of hyperautofluorescence on fundus autofluorescence imaging. Over 9 years of follow-up, the sibs experienced progressive visual field constriction, and visual acuity worsened to 20/200. Their heights were within the normal range for the Japanese population, and radiologic examination did not reveal any skeletal abnormalities. Whole-exome sequencing revealed that both sibs were compound heterozygous for mutations in the NEK1 gene: a missense mutation (c.240G-A; M80I) and an in-frame 6-bp duplication (c.634_639dup; V212_L213dup), both located within the well-conserved serine-threonine kinase catalytic domain. The variants were validated by Sanger sequencing, and the unaffected parents were each heterozygous for 1 of the variants, neither of which was found in 218 in-house exomes or in the gnomAD or 4.7KJPN databases. The authors noted that the sibs were also compound heterozygous for missense variants (V371M and E2496D) in the PIEZO1 gene (611184), but their phenotype was different from the 2 PIEZO1-associated disorders, dehydrated hereditary stomatocytosis (DHS; 194380) and lymphatic malformation-6 (LMPHM6; 616843). The authors also stated that it was unclear why the sibs exhibited only retinal dystrophy, given that their variants were located in the catalytic domain.
Vogler et al. (1999) and Janaswami et al. (1997) described 2 independent mutant alleles, designated kat and kat(2J), that cause pleiotropic effects that include facial dysmorphism, dwarfing, male sterility, anemia, cystic choroid plexus, and progressive polycystic kidney disease. The latent onset of cystogenesis and similarity of the renal pathology to human autosomal dominant polycystic kidney disease (e.g., PKD1; 601313) made this an attractive animal model for the study of renal cystogenesis. The mutations mapped to mouse chromosome 8. By positional cloning, Upadhya et al. (2000) identified Nek1 as the gene that is altered by the kat and kat(2J) spontaneous mutations. The complex pleiotropic phenotypes seen in the homozygous mutant animals suggested that the NEK1 protein participates in different signaling pathways to regulate diverse cellular processes. The findings identified a previously unsuspected role for NEK1 in the kidney and opened a new avenue for studying cystogenesis and identifying possible modes of therapy.
Using low dose ionizing or ultraviolet radiation, Chen et al. (2008) found that Nek1 -/- kat2J cells had defective G1/S- and M-phase checkpoints and failed to activate Chk1 and Chk2 in response to DNA damage. In addition, DNA was not properly repaired, double-stranded DNA breaks persisted, and excessive numbers of chromosome breaks were observed in the absence of Nek1.
In a male infant who died 1 hour postpartum with a clinical diagnosis of short rib-polydactyly syndrome type II (SRTD6; 263520), from a consanguineous family of Turkish origin (family 1), Thiel et al. (2011) identified a homozygous 379C-T transition in exon 5 of the NEK1 gene, resulting in an arg127-to-ter (R127X) substitution within the N-terminal kinase domain. Quantitative real-time PCR analysis of NEK1 demonstrated a 64% reduction of cDNA levels in lymphoblastoid cell lines in the affected individual and 30 to 40% reduction in the heterozygous parents, indicating only a partial nonsense-mediated mRNA decay of the mutant allele. The parents and unaffected sibs were heterozygous for the mutation, which was not found in 378 control chromosomes of the same ethnic origin.
In a male fetus with a clinical diagnosis of SRPS type II, from a pregnancy terminated at 20 weeks' gestation, El Hokayem et al. (2012) identified homozygosity for the R127X mutation in the NEK1 gene. The consanguineous French parents were both heterozygous for the mutation, which was not found in 200 control chromosomes.
In a male fetus at 21 weeks of gestation with a clinical diagnosis of SRPS type II (SRTD6; 263520), from a consanguineous family of Bedouin origin (family 2), Thiel et al. (2011) identified a homozygous splice site mutation in intron 10 (869-2A-G) in the NEK1 gene. The parents and unaffected sibs were heterozygous for the mutation, which was not found in 370 control chromosomes of the same ethnic origin.
In a male fetus at 19 weeks of gestation with a clinical diagnosis of SRPS type II (SRTD6; 263520), from a nonconsanguineous family of German origin (family 3), Thiel et al. (2011) identified a heterozygous 1-bp insertion (1640_1641insA) in the NEK1 gene, resulting in a premature stop codon (Asn547LysfsTer2); this individual was also heterozygous for a missense mutation in the DYNC2H1 (11747G-A; 603297.0016), thus indicating biallelic digenic inheritance. No second mutation was found in either gene, and each parent was heterozygous for one of the mutations, neither of which was found in 382 population-matched control chromosomes.
In a male fetus with a clinical diagnosis of SRPS type II (SRTD6; 263520) from a pregnancy terminated at 20 weeks, El Hokayem et al. (2012) identified homozygosity for a 433G-A transition in exon 6 of the NEK1 gene, resulting in a gly145-to-arg (G145R) substitution in the kinase domain. The nonconsanguineous parents, who were from Madagascar, were both heterozygous for the mutation, which was not found in 200 control chromosomes.
In a male proband with amyotrophic lateral sclerosis (ALS24; 617892), Brenner et al. (2016) identified heterozygosity for a c.3107C-G transversion in the NEK1 gene resulting in a ser1036-to-ter (S1036X) substitution between the 2 C-terminal nuclear export sequences of the protein. The proband had symptom onset at age 59 and died at age 63. The proband's mother died of ALS at age 62 after a disease duration of 5 years. The proband's brother carried the mutation but was unaffected 4 years after the death of the proband and 9 years after onset of the proband's symptoms; the age of the unaffected brother was not given.
In a female proband with amyotrophic lateral sclerosis (ALS24; 617892), Brenner et al. (2016) identified heterozygosity for a c.2434A-T transversion in the NEK1 gene that resulted in an arg812-to-ter (R812X) substitution predicted to truncate the C-terminal nuclear export sequences of the protein. The proband had symptom onset at 75 years of age and was alive after 18 months' disease duration. The uncle of the proband died of ALS at age 70; her father, who may have transmitted the disease mutation, died at age 43 of cardiac complications secondary to infection. While neuropsychological testing in the proband revealed no difficulties in ALS-specific domains such as executive function, ALS-atypical hippocampal/temporal lobe functions, such as nonverbal memory, were impaired. This was consistent with severe atrophy of the hippocampus and some atrophy of caudate and thalamus seen on MRI.
Kenna et al. (2016) identified 4 patients with amyotrophic lateral sclerosis (ALS24; 617892) from an isolated community in the Netherlands with a population of less than 25,000 and a restricted genetic lineage. Whole-genome sequencing followed by autozygosity mapping identified 4 candidate disease variants occurring in detectable runs of homozygosity. The NEK1 variant arg261 to his (R261H) was the only variant identifiable in all patients and the only variant which occurred in homozygosity in more than 1 individual; it was present in homozygosity in 2 patients and was heterozygous in the other 2, raising the possibility that even a single copy of the allele may increase disease risk. Clinical evaluation of the 4 cases did not find any overt differences in disease phenotype. Kenna et al. (2016) then tested for the R261H variant among 6,172 sporadic ALS cases and 4,417 matched controls from 8 countries. Metaanalysis of all independent population strata identified a clear minor allele excess in cases with a combined significance of p = 4.8 x 10(-5) and an odds ratio of 2.4. The authors also observed disease association in the familial ALS case-control data, with an odds ratio of 2.7 and a p of 1.5 x 10(-3). Metaanalysis combining familial ALS, sporadic ALS, and all controls showed an odds ratio of 2.4 with a p value of 1.2 x 10(-7).
In a proband with amyotrophic lateral sclerosis (ALS24; 617892) and his affected mother, Kenna et al. (2016) identified an arg550-to-ter (R550X) mutation in the NEK1 gene.
In a 3-year-old girl from the British Isles (patient SKDP-126.3) with short-rib thoracic dysplasia without polydactyly (SRTD6; 263520), McInerney-Leo et al. (2015) identified compound heterozygosity for mutations in the NEK1 gene: a splice site mutation (c.869-1G-T, NM_001199399) in intron 12, and a c.514C-T transition in exon 8, resulting in a pro172-to-ser (P172S; 604588.0010) substitution. Neither mutation was found in internal or public variant databases. A heterozygous mutation in another SRTD-associated gene was detected in this patient, an H297Q substitution in the WDR60 gene (615462), and the authors noted that this variant might modify the SRTD phenotype.
For discussion of the c.514C-T transition (c.514C-T, NM_001199399) in exon 8 of the NEK1 gene, resulting in a pro172-to-ser (P172S) substitution, that was found in compound heterozygous state in a 3-year-old British girl with short-rib thoracic dysplasia without polydactyly (SRTD6; 263520) by McInerney-Leo et al. (2015), see 604588.0009.
In a 12.5-year-old boy with severe retinal dystrophy, narrow thorax, short ribs, mild platyspondyly, and mild metaphyseal changes in the long bones (SRTD6; 263520), Wang et al. (2017) performed whole-exome sequencing and identified compound heterozygosity for mutations in the NEK1 gene: a c.3107C-G transversion (c.3107C-G, NM_001199397) in exon 31, resulting in a ser1036-to-ter (S1036X) substitution, and a c.3830A-C transversion (c.3830A-C, NM_001199397) in exon 35, resulting in an asp1277-to-ala (D1277A; 604588.0012) substitution The authors suggested that the phenotypic variability exhibited in this patient might be explained by the location of mutations on the NEK1 protein, since most of the previously reported mutations were located in the N terminus whereas this patient's mutations were in the C terminus.
For discussion of the c.3830A-C transversion (c.3830A-C, NM_001199397) in exon 35 of the NEK1 gene, resulting in an asp1277-to-ala (D1277A) substitution, that was found in compound heterozygous state in a 12.5-year-old boy with short-rib thoracic dysplasia without polydactyly (SRTD6; 263520) by Wang et al. (2017), see 604588.0011.
In 2 brothers with Mohr syndrome (OFD2; 252100), Monroe et al. (2016) identified compound heterozygosity for mutations in the NEK1 gene: a c.464G-C transversion (c.464G-C, NM_012224.2) at the last base of exon 6, and a c.1226G-A transition in exon 15 (604588.0014). Although the c.464G-C transversion appeared to code for a serine155-to-threonine substitution (S155T), PCR and Sanger sequencing revealed that the variant resulted in alternative splicing with skipping of exon 6 and introduction of a premature stop codon 18 amino acids after the frameshift. Any resulting transcript escaping nonsense-mediated decay would lack the critical DFG motif essential for the correct conformation of the ATP-binding site of the kinase domain. The correctly spliced product, including exon 6, had no visible alternative allele C at position 464, indicating that the variant has no or minimal effect on coding changes from serine to threonine at this position. Sanger sequencing showed that the c.1226G-A transition, which was predicted to introduce a stop codon at trp409 (W409X), resulted in nonsense-associated alternative splicing, removing exon 15 including the first coiled-coil domain, followed by continuation of the transcript in the same reading frame, resulting in a nearly full-length transcript. Immunocytochemical analysis of patient-derived fibroblasts showed a statistically significant reduction in cilia number, but not cilia length, compared with control fibroblasts; and there was an increase in cytoplasmic acetylated alpha-tubulin (see 602529), a marker of the ciliary axoneme.
For discussion of the c.1226G-A transition (c.1226G-A, NM_012224.2) in exon 15 of the NEK1 gene that was found in compound heterozygous state in 2 brothers with orofaciodigital syndrome II (OFD2; 252100) by Monroe et al. (2016), see 604588.0013.
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