Alternative titles; symbols
HGNC Approved Gene Symbol: VRK1
Cytogenetic location: 14q32.2 Genomic coordinates (GRCh38): 14:96,797,382-96,881,609 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q32.2 | Neuronopathy, distal hereditary motor, autosomal recessive 10 | 620542 | Autosomal recessive | 3 |
| Pontocerebellar hypoplasia type 1A | 607596 | Autosomal recessive | 3 |
The VRK1 gene encodes a serine/threonine kinase that regulates several cellular functions, including the cell cycle, gene transcription, DNA damage responses, chromatin remodeling, and the assembly of Cajal bodies through regulation of one of its substrates, coilin (COIL; 600272). VRK1 is mostly located in the nucleus, but is also present in the cytosol (summary by El-Bazzal et al., 2019; Lazo and Morejon-Garcia, 2023).
To identify novel genes involved in the regulation of cell division, Nezu et al. (1997) constructed a cDNA library enriched for human fetal liver-specific genes by suppressive subtractive hybridization. One expressed sequence tag (EST) generated from this library was found to represent a novel putative serine/threonine kinase, which the authors designated VRK1. The full-length VRK1 cDNA encodes a deduced 396-amino acid protein, which shares 40% identity over 305 amino acids with the B1R serine/threonine protein kinase of vaccinia virus. VRK1 was also found to have sequence identity (62% over 481 nucleotides) to a database EST. Conceptual translation of the EST predicted a protein of 508 amino acids that, like VRK1, had similarity to B1R kinase. The authors designated this gene VRK2 (602169). Northern blot analysis showed that expression of both VRK1 and VRK2 is widespread and elevated in highly proliferative cells, such as those in testis, thymus, and fetal liver. Renbaum et al. (2009) noted that VRK1 contains an N-terminal ATP-binding site, a serine/threonine kinase domain, an endosomal and lysosomal targeting sequence, and a C-terminal nuclear localization signal within a BAB motif.
El-Bazzal et al. (2019) found that vrk1 is expressed in mouse brain, cerebellum, spinal cord, and peripheral sciatic nerve.
The VRK1 gene contains 13 exons (Renbaum et al., 2009).
Nezu et al. (1997) designed PCR primers to amplify selectively human, but not murine, DNA and screened the Genebridge 4 radiation hybrid panel. They assigned VRK1 to chromosome 14q32 and VRK2 to chromosome 2p16-p15.
Pontocerebellar Hypoplasia Type 1A
By linkage analysis followed by candidate gene sequencing in an Ashkenazi Jewish family segregating pontocerebellar hypoplasia type 1A (PCH1A; 607596), Renbaum et al. (2009) identified a homozygous mutation in the VRK1 gene (R358X; 602168.0001). The phenotype was characterized by early-onset spinal muscular atrophy with death in late childhood.
Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In 4 sibs (family M017N) with moderate to severe intellectual disability and a phenotype compatible with pontocerebellar hypoplasia, they identified a homozygous missense mutation in the VRK1 gene (602168.0002). The parents, who were first cousins once removed, had 3 healthy children.
Autosomal Recessive Distal Hereditary Motor Neuronopathy 10
In 2 sisters (BAB3022 and BAB3280) with autosomal recessive distal hereditary motor neuronopathy-10 (HMNR10; 620542), Gonzaga-Jauregui et al. (2013) identified compound heterozygous missense mutations in the VRK1 gene (V236M, 602168.0003 and R89Q, 602168.0004). The mutations, which were found by whole-genome and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed, but both localized to the kinase domain. An unrelated patient (patient BAB5311), born of unrelated Ashkenazi Jewish parents, with a similar disorder carried a homozygous R358X mutation in the VRK1 gene (602168.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Haplotype analysis confirmed a founder effect for this mutation in the Ashkenazi Jewish population. Functional studies of the variant and studies of patient cells were not performed. Gonzaga-Jauregui et al. (2013) noted that although there were some overlapping features, the phenotype in this patient was distinct from the PCH1A phenotype reported by Renbaum et al. (2009).
In a 37-year-old Chinese man, born of consanguineous parents, with juvenile-onset HMNR10, Feng et al. (2019) identified a homozygous nonsense mutation in the VRK1 gene (W375X; 602168.0005). The mutation, which was found by screening of a panel of candidate genes and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that it is possible that a partially functional truncated protein could be expressed.
In 2 unrelated men, each born of consanguineous Moroccan-Jewish parents, with adult-onset HMNR10, Greenbaum et al. (2020) identified a homozygous missense mutation in the VRK1 gene (R387H; 602168.0006). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Functional studies of the variant and studies of patient cells were not performed.
In 2 sibs from a nonconsanguineous Lebanese family with HMNR10, El-Bazzal et al. (2019) identified compound heterozygous missense mutations in the VRK1 gene (R219I, 602168.0007 and W254L, 602168.0008). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both mutations occurred at highly conserved residues in the kinase domain. Neither was present in the gnomAD database. Patient cells showed decreased VRK1 protein levels (59-68% decrease) due to posttranslational proteasomal degradation. Mutant VRK1 showed abnormally increased cytoplasmic localization in patient fibroblasts compared to controls, suggesting that the mutations lead to export of VRK1 to the cytoplasm for degradation. VRK1 depletion in patient fibroblasts resulted in reduced coilin (COIL; 600272) levels by facilitating its proteasomal degradation. Motor neurons from patient-derived induced pluripotent stem cells showed impaired assembly of Cajal bodies, which play a role in RNA metabolism and splicing, and a decrease in total neurite length and branching compared to controls. The authors suggested that the disorder results from disruption of RNA metabolism.
Pontocerebellar Hypoplasia Type 1A
In an Ashkenazi Jewish girl, born of consanguineous parents, with pontocerebellar hypoplasia type 1A (PCH1A; 607596), Renbaum et al. (2009) identified a homozygous c.1072C-T transition in exon 12 of the VRK1 gene, resulting in an arg358-to-ter (R358X) substitution within the NLS. There were 3 affected family members, all of whom died by age 12 years. Clinical features included poor sucking, developmental delay, progressive muscle weakness, ataxia, hyperreflexia, foot deformities, and cerebellar hypoplasia. Skeletal muscle biopsy showed neurogenic atrophy. The mutation was detected in heterozygosity in 2 of 449 unaffected Ashkenazi Jewish individuals.
Autosomal Recessive Distal Hereditary Motor Neuronopathy 10
In a 9-year-old boy (patient BAB5311), born of unrelated Ashkenazi Jewish parents, with autosomal recessive distal hereditary motor neuronopathy-10 (HMNR10; 620542), Gonzaga-Jauregui et al. (2013) identified a homozygous c.1072C-T transition (c.1072C-T, NM_003384) in the VRK1 gene resulting in an R358X mutation. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation has a frequency of 0.007% in the general population and 0.0116% in the population of European descent. Haplotype analysis confirmed a founder effect for this mutation in the Ashkenazi Jewish population. Functional studies of the variant and studies of patient cells were not performed. The patient showed decreased fetal movements and microcephaly in utero. He had hypotonia, scoliosis, poor feeding requiring tube-feeding, and electrophysiologic evidence of an axonal sensorimotor neuropathy. He did not have ataxia, hypertonia, impaired intellectual development, or pontocerebellar hypoplasia on brain imaging. Brain imaging showed a normal pons and cerebellar hemispheres, but an underdeveloped cerebellar vermis. It also showed simplified gyral pattern and progressive volume loss. Gonzaga-Jauregui et al. (2013) noted that although there were some overlapping features, the phenotype in this patient was distinct from the PCH1A phenotype reported by Renbaum et al. (2009).
In 4 sibs (family M017N) with moderate to severe intellectual disability and a phenotype compatible with pontocerebellar hypoplasia (PCH1A; 607596), Najmabadi et al. (2011) identified a homozygous C-to-T transition in the VRK1 gene at genomic coordinate chr14:96,388,943, resulting in an arg133-to-cys (R133C) substitution. The parents, who were first cousins once removed, were heterozygous for the mutation and had 3 healthy children.
In 2 sisters (BAB3022 and BAB3280) with autosomal recessive distal hereditary motor neuronopathy-10 (HMNR10; 620542), Gonzaga-Jauregui et al. (2013) identified compound heterozygous missense mutations in the VRK1 gene: a c.706G-A transition (c.706G-A, NM_003384), resulting in a val236-to-met (V236M) substitution, and a c.266G-A transition, resulting in an arg89-to-gln (R89Q; 602168.0004) substitution. The mutations, which were found by whole-genome and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed, but both localized to the kinase domain. These patients had a severe disorder with onset in infancy, delayed motor development, hypotonia, and microcephaly. Cognitive development was normal. Brain imaging showed a simplified gyral pattern. Neither was able to walk at 10 and 2 years of age; the older sister required a feeding tube and tracheostomy.
For discussion of the c.266G-A transition (c.266G-A, NM_003384) in the VRK1 gene, resulting in an arg89-to-gln (R89Q; 602168.0004) substitution, that was found in compound heterozygous state in 2 sisters with autosomal recessive distal hereditary motor neuronopathy-10 (HMNR10; 620542) by Gonzaga-Jauregui et al. (2013), see 602168.0003.
In a 37-year-old Chinese man, born of consanguineous parents, with juvenile-onset autosomal recessive distal hereditary motor neuronopathy-10 (HMNR10; 620542), Feng et al. (2019) identified a homozygous c.1124G-A transition in the VRK1 gene, resulting in a trp375-to-ter (W375X) substitution near the C terminus. The mutation, which was found by screening of a panel of candidate genes and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that it is possible that a partially functional truncated protein could be expressed. The patient had onset of slowly progressive distal muscle weakness and atrophy of the lower limbs at 15 years of age, followed by upper limb involvement. Nerve conduction studies showed a pure motor axonal neuropathy without sensory involvement. Brain imaging was normal.
In 2 unrelated men, each born of consanguineous Moroccan-Jewish parents, with adult-onset autosomal recessive distal hereditary motor neuronopathy-10 (HMNR10; 620542), Greenbaum et al. (2020) identified a homozygous c.1160G-A transition (c.1160G-A, NM_003384.3) in exon 13 of the VRK1 gene, resulting in an arg387-to-his (R387H) substitution at the C terminus. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. The R387H mutation is not present in the European, African, Asian, or Ashkenazi Jewish populations in gnomAD, but is present in the Latino population (0.00064, 22 of 34,514 alleles) and has an overall frequency of 0.000084, all in the heterozygous state. Functional studies of the variant and studies of patient cells were not performed. The patients had onset of symptoms in their forties; 1 had mild distal sensory involvement with nocturnal respiratory difficulties. Brain imaging and cognition were normal in both.
In 2 sibs from a nonconsanguineous Lebanese family with autosomal recessive distal hereditary motor neuronopathy-10 (HMNR10; 620542), El-Bazzal et al. (2019) identified compound heterozygous missense mutations in the VRK1 gene: a c.656G-T transversion (c.656G-T, NM_003384) in exon 8, resulting in an arg219-to-ile (R219I) substitution, and a c.761G-T transversion in exon 9, resulting in a trp254-to-leu (W254L; 602168.0008) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both mutations occurred at highly conserved residues in the kinase domain. Neither was present in the gnomAD database. Patient cells showed decreased VRK1 protein levels (59-68% decrease) due to posttranslational proteasomal degradation. Mutant VRK1 showed abnormally increased cytoplasmic localization in patient fibroblasts compared to controls, suggesting that the mutations lead to export of VRK1 to the cytoplasm for degradation. VRK1 depletion in patient fibroblasts resulted in reduced coilin (COIL; 600272) levels by facilitating its proteasomal degradation. Motor neurons from patient-derived induced pluripotent stem cells showed impaired assembly of Cajal bodies, which play a role in RNA metabolism and splicing, and a decrease in total neurite length and branching compared to controls. The authors suggested that the disorder results from disruption of RNA metabolism. The patients, who were adults at the time of the report, had onset of slowly progressive distal muscle weakness and atrophy affecting all 4 limbs around 10 years of age. They also had mild upper motor neuron signs, including hyperreflexia and extensor plantar responses.
For discussion of the c.761G-T transversion (c.761G-T, NM_003384) in exon 9 of the VRK1 gene, resulting in a trp254-to-leu (W254L) substitution, that was found in compound heterozygous state in 2 sibs with autosomal recessive distal hereditary motor neuronopathy-10 (HMNR10; 620542) by El-Bazzal et al. (2019), see 602168.0007.
El-Bazzal, L., Rihan, K., Bernard-Marissal, N., Castro, C., Chouery-Khoury, E., Desvignes, J.-P., Atkinson, A., Bertaux, K., Koussa, S., Levy, N., Bartoli, M., Megarbane, A., Jabbour, R., Delague, V. Loss of Cajal bodies in motor neurons from patients with novel mutations in VRK1. Hum. Molec. Genet. 28: 2378-2394, 2019. [PubMed: 31090908] [Full Text: https://doi.org/10.1093/hmg/ddz060]
Feng, S.-Y., Li, L.-Y., Feng, S.-M., Zou, Z.-Y. A novel VRK1 mutation associated with recessive distal hereditary motor neuropathy. Ann. Clin. Transl. Neurol. 6: 401-405, 2019. [PubMed: 30847374] [Full Text: https://doi.org/10.1002/acn3.701]
Gonzaga-Jauregui, C., Lotze, T., Jamal, L., Penney, S., Campbell, I. M., Pehlivan, D., Hunter, J. V., Woodbury, S. L., Raymond, G., Adesina, A. M., Jhangiani, S. N., Reid, J. G., Muzny, D. M., Boerwinkle, E., Lupski, J. R., Gibbs, R. A., Wiszniewski, W. Mutations in VRK1 associated with complex motor and sensory axonal neuropathy plus microcephaly. JAMA Neurol. 70: 1491-1498, 2013. [PubMed: 24126608] [Full Text: https://doi.org/10.1001/jamaneurol.2013.4598]
Greenbaum, L., Barel, O., Nikitin, V., Hersalis-Eldar, A., Kol, N., Reznik-Wolf, H., Dominissini, D., Pras, E., Dori, A. Identification of a homozygous VRK1 mutation in two patients with adult-onset distal hereditary motor neuropathy. Muscle Nerve 61: 395-400, 2020. [PubMed: 31837156] [Full Text: https://doi.org/10.1002/mus.26779]
Lazo, P. A., Morejon-Garcia, P. VRK1 variants at the cross road of Cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseases. Neurobiol. Dis 183: 106172, 2023. [PubMed: 37257665] [Full Text: https://doi.org/10.1016/j.nbd.2023.106172]
Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478: 57-63, 2011. [PubMed: 21937992] [Full Text: https://doi.org/10.1038/nature10423]
Nezu, J., Oku, A., Jones, M. H., Shimane, M. Identification of two novel human putative serine/threonine kinases, VRK1 and VRK2, with structural similarity to vaccinia virus B1R kinase. Genomics 45: 327-331, 1997. [PubMed: 9344656] [Full Text: https://doi.org/10.1006/geno.1997.4938]
Renbaum, P., Kellerman, E., Jaron, R., Geiger, D., Segel, R., Lee, M., King, M. C., Levy-Lahad, E. Spinal muscular atrophy with pontocerebellar hypoplasia is caused by a mutation in the VRK1 gene. Am. J. Hum. Genet. 85: 281-289, 2009. [PubMed: 19646678] [Full Text: https://doi.org/10.1016/j.ajhg.2009.07.006]