Spinal Muscular Atrophy with Pontocerebellar Hypoplasia Is Caused by a Mutation in the VRK1 Gene

Renbaum, Paul; Kellerman, Efrat; Jaron, Ranit; Geiger, Dan; Segel, Reeval; Liu, Ming; King, Mary Claire; Levy-Lahad, Ephrat

doi:10.1016/j.ajhg.2009.07.006

Cited by 175 publications

(174 citation statements)

References 28 publications

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“…Its D. melanogaster ortholog, NHK-1, also affects meiotic recombination (72). Recently a recessive mutation in VRK1, R385X, manifested a complex syndrome with a pontocerebellar hypoplasia, ataxia, and muscular atrophy (73). Although the pathogenic role of VRK1 in this clinical report is not clear, it is interesting to note that patients with mutations in other kinases, like ATM and ATR, also present motor coordination problems and ataxia (1).…”

Section: Discussionmentioning

confidence: 82%

Vaccinia-related Kinase 1 (VRK1) Is an Upstream Nucleosomal Kinase Required for the Assembly of 53BP1 Foci in Response to Ionizing Radiation-induced DNA Damage

Sanz-García

Monsalve

Sevilla

et al. 2012

Journal of Biological Chemistry

141

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Background:The cellular response to DNA damage requires multiple signaling pathways to guarantee genomic stability. Results: Vaccinia-related kinase 1 (VRK1) is activated by ionizing radiation and required for formation of 53BP1 foci in response to DNA damage. Conclusion: Human VRK1 is an early step in the cellular response to DNA damage induced by ionizing radiation. Significance: VRK1 forms part of a novel pathway for DNA protection.

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Section: Discussionmentioning

confidence: 82%

Vaccinia-related Kinase 1 (VRK1) Is an Upstream Nucleosomal Kinase Required for the Assembly of 53BP1 Foci in Response to Ionizing Radiation-induced DNA Damage

Sanz-García

Monsalve

Sevilla

et al. 2012

Journal of Biological Chemistry

141

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“…Defects in these genes are associated with several forms of myopathies (41), including limb-girdle muscular dystrophy 2F, which causes limb musculature wasting and locomotory troubles in juvenile individuals. Additionally, many selected genes are involved in balance and motor coordination, including VRK1 and TCTN1, with defects associated with underdevelopment of the cerebellum, motor dysfunction and muscle hypotonia (42,43), and CNTN6, loss of which causes motor coordination and equilibrium impairment in KO mice (44). This set of genes also includes a member of the collagen protein family, COL22A1, which localizes to myotendinous and articular junctions (45).…”

Section: Resultsmentioning

confidence: 99%

Prehistoric genomes reveal the genetic foundation and cost of horse domestication

Schubert

Jónsson

Chang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

278

281

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The domestication of the horse ∼5.5 kya and the emergence of mounted riding, chariotry, and cavalry dramatically transformed human civilization. However, the genetics underlying horse domestication are difficult to reconstruct, given the near extinction of wild horses. We therefore sequenced two ancient horse genomes from Taymyr, Russia (at 7.4-and 24.3-fold coverage), both predating the earliest archeological evidence of domestication. We compared these genomes with genomes of domesticated horses and the wild Przewalski's horse and found genetic structure within Eurasia in the Late Pleistocene, with the ancient population contributing significantly to the genetic variation of domesticated breeds. We furthermore identified a conservative set of 125 potential domestication targets using four complementary scans for genes that have undergone positive selection. One group of genes is involved in muscular and limb development, articular junctions, and the cardiac system, and may represent physiological adaptations to human utilization. A second group consists of genes with cognitive functions, including social behavior, learning capabilities, fear response, and agreeableness, which may have been key for taming horses. We also found that domestication is associated with inbreeding and an excess of deleterious mutations. This genetic load is in line with the "cost of domestication" hypothesis also reported for rice, tomatoes, and dogs, and it is generally attributed to the relaxation of purifying selection resulting from the strong demographic bottlenecks accompanying domestication. Our work demonstrates the power of ancient genomes to reconstruct the complex genetic changes that transformed wild animals into their domesticated forms, and the population context in which this process took place.ancient DNA | horse domestication | Przewalski's horse | positive selection | cost of domestication T he domestication of the horse had a far-reaching impact on the sociopolitical and economic trajectories of human societies (1). It not only provided meat and milk (2) but also enabled the development of continent-sized nomadic empires, by transforming warfare and allowing for the rapid spread of goods and information over long distances. However, despite the characterization of the genome of modern horses (3), an understanding of the genetic processes underlying horse domestication is still lacking. In other organisms, such an understanding is usually achieved by comparing the genomes of domesticated species and their wild relatives (4-6), but this approach is not directly applicable to horses. Recent genome-wide analyses have shown that Przewalski's horse, the last truly wild horse population remaining today, is not the direct ancestor of domesticated SignificanceThe domestication of the horse revolutionized warfare, trade, and the exchange of people and ideas. This at least 5,500-ylong process, which ultimately transformed wild horses into the hundreds of breeds living today, is difficult to reconstruct from archeological data...

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“…S2A and B) and we found that a change in the charge in this region resulted in increased binding. Noteworthy, when the mutation that causes spinal muscular atrophy, VRK1(R358X) [50], was tested we showed that VRK1 was still able to interact with p53 ( Fig. S2A and B).…”

Section: Vrk1 Stably Interacts With P53 Forming a Basal Protein Complexmentioning

confidence: 99%

VRK1 interacts with p53 forming a basal complex that is activated by UV‐induced DNA damage

et al. 2014

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a b s t r a c t DNA damage immediate cellular response requires the activation of p53 by kinases. We found that p53 forms a basal stable complex with VRK1, a Ser-Thr kinase that responds to UV-induced DNA damage by specifically phosphorylating p53. This interaction takes place through the p53 DNA binding domain, and frequent DNA-contact mutants of p53, such as R273H, R248H or R280K, do not disrupt the complex. UV-induced DNA damage activates VRK1, and is accompanied by phosphorylation of p53 at Thr-18 before it accumulates. We propose that the VRK1-p53 basal complex is an early-warning system for immediate cellular responses to DNA damage. Structured summary of protein interactions:VRK1 physically interacts with p53 by anti bait coimmunoprecipitation (1, 2, 3, 4) VRK1 physically interacts with p53 by pull down (1,2,3)

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Spinal Muscular Atrophy with Pontocerebellar Hypoplasia Is Caused by a Mutation in the VRK1 Gene

Cited by 175 publications

References 28 publications

Vaccinia-related Kinase 1 (VRK1) Is an Upstream Nucleosomal Kinase Required for the Assembly of 53BP1 Foci in Response to Ionizing Radiation-induced DNA Damage

Vaccinia-related Kinase 1 (VRK1) Is an Upstream Nucleosomal Kinase Required for the Assembly of 53BP1 Foci in Response to Ionizing Radiation-induced DNA Damage

Prehistoric genomes reveal the genetic foundation and cost of horse domestication

VRK1 interacts with p53 forming a basal complex that is activated by UV‐induced DNA damage

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