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      Novel motor phenotypes in patients with VRK1 mutations without pontocerebellar hypoplasia

      research-article
      Author(s): , PhD, , MBBS, , MBBS, , FRACP, , PhD, , MBChB, FRCPA, PhD, , MBBCh, MPhil, FRACP, , MBBS, FRACP, PhD, , MBBS, FRACP, PhD, , MBBS, PhD
      Publication date PMC-release:
      Journal: Neurology
      Publisher: Lippincott Williams & Wilkins

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Objective:

          To describe the phenotypes in 2 families with vaccinia-related kinase 1 ( VRK1) mutations including one novel VRK1 mutation.

          Methods:

          VRK1 mutations were found by whole exome sequencing in patients presenting with motor neuron disorders.

          Results:

          We identified pathogenic mutations in the VRK1 gene in the affected members of 2 families. In family 1, compound heterozygous mutations were identified in VRK1, c.356A>G; p.H119R, and c.1072C>T; p.R358*, in 2 siblings with adult onset distal spinal muscular atrophy (SMA). In family 2, a novel VRK1 mutation, c.403G>A; p.G135R and c.583T>G; p.L195V, were identified in a child with motor neuron disease.

          Conclusions:

          VRK1 mutations can produce adult-onset SMA and motor neuron disease in children without pontocerebellar hypoplasia.

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          Spinal muscular atrophy with pontocerebellar hypoplasia is caused by a mutation in the VRK1 gene.

          Paul Renbaum, Efrat Kellerman, Ranit Jaron … (2009)
          The spinal muscular atrophies (SMAs) are a genetically and clinically heterogeneous group of disorders characterized by degeneration and loss of anterior horn cells in the spinal cord, leading to muscle weakness and atrophy. Spinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH, also known as pontocerebellar hypoplasia type 1 [PCH1]) is one of the rare infantile SMA variants that include additional clinical manifestations, and its genetic basis is unknown. We used a homozygosity mapping and positional cloning approach in a consanguineous family of Ashkenazi Jewish origin and identified a nonsense mutation in the vaccinia-related kinase 1 gene (VRK1) as a cause of SMA-PCH. VRK1, one of three members of the mammalian VRK family, is a serine/threonine kinase that phosphorylates p53 and CREB and is essential for nuclear envelope formation. Its identification as a gene involved in SMA-PCH implies new roles for the VRK proteins in neuronal development and maintenance and suggests the VRK genes as candidates for related phenotypes.
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            p53 Stabilization and accumulation induced by human vaccinia-related kinase 1.

            Pedro Lazo, Ana Sevilla, José Vega (2004)
            Variations in intracellular levels of p53 regulate many cellular functions and determine tumor susceptibility. Major mechanisms modulating p53 levels include phosphorylation and interaction of p53 with specific ubiquitin ligases that promote its degradation. N-terminal phosphorylation regulates the interaction of p53 with several regulatory molecules. Vaccinia-related kinase 1 (VRK1) is the prototype of a new Ser-Thr kinase family in the human kinome. VRK1 is located in the nucleus outside the nucleolus. Overexpression of VRK1 increases the stability of p53 by a posttranslational mechanism leading to its accumulation by a mechanism independent of the Chk2 kinase. Catalytically inactive VRK1 protein (a K179E mutant) does not induce p53 accumulation. VRK1 phosphorylates human p53 in Thr18 and disrupts p53-Mdm2 interaction in vitro, although a significant decrease in p53 ubiquitination by Mdm2 in vivo was not detected. VRK1 kinase does not phosphorylate Mdm2. VRK1-mediated p53 stabilization was also detected in Mdm2(-/-) cells. VRK1 also has an additive effect with MdmX or p300 to stabilize p53, and p300 coactivation and acetylation of p53 is enhanced by VRK1. The p53 stabilized by VRK1 is transcriptionally active. Suppression of VRK1 expression by specific small interfering RNA provokes several defects in proliferation, situating the protein in the regulation of this process. VRK1 might function as a switch controlling the proteins that interact with p53 and thus modifying its stability and activity. We propose VRK1 as the first step in a new pathway regulating p53 activity during cell proliferation.
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              Human VRK1 Is an Early Response Gene and Its Loss Causes a Block in Cell Cycle Progression

              Alberto Valbuena, Inmaculada Lopez-Sanchez, Pedro Lazo (2008)
              Background In mammalian cells regulatory proteins controlling the cell cycle are necessary due to the requirements of living in a heterogeneous environment of cell-interactions and growth factors. VRK1 is a novel serine-threonine kinase that phosphorylates several transcription factors and is associated with proliferation phenotypes. Methodology/Principal Findings In this report VRK1 has been identified as regulated in the cell cycle. VRK1 gene expression is activated by the addition of serum to starved cells, indicating it is required for the exit of G0 phase and entry in G1; a response that parallels the re-expression of MYC, FOS and CCND1 (cyclin D1) genes, suggesting that VRK1 is an early-response gene. VRK1 gene expression is also shutdown by serum withdrawal. The human VRK1 gene promoter cloned in a luciferase reporter responds similarly to serum. In response to serum, the level of VRK1 protein expression has a positive correlation with cell proliferation markers such as phosphorylated-Rb or PCNA, and is inversely correlated with cell cycle inhibitors such as p27. The elimination of VRK1 by siRNA results in a G1 block in cell division, and in loss of phosphorylated-Rb, cyclin D1, and other proliferation markers. Elimination of VRK1 by siRNA induces a reduction of cell proliferation. VRK1 colocalizes with p63 in proliferating areas of squamous epithelium, and identifies a subpopulation in the basal layer. Conclusions/Significance VRK1 is an immediate early response gene required for entry in G1, and due to its implication in normal cell proliferation and division, might be a new target for development of inhibitors of cellular proliferation.
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                Contributors
                Marion Stoll:
                Comment :

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                1. NONE

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                1. NONE

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                Hooiling Teoh:
                Comment :

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                1. NONE

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                1. I received scholarship support from the Thyne Reid Foundation

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                James Lee:
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                Stephen Reddel:
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                1. 1. CSL 2. Baxter 3. Genzyme 4. Biogen 5. National Immunoglobulin Governmental Advisory Council, Australia

                Gifts:

                1. NONE

                Funding for travel or speaker honoraria:

                1. 1. CSL 2. Genzyme 3. Biogen

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                1. 1. National IVIG Governance Council of Australia

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                1. Beeren Foundation

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                1. 1. Sydney Neurology 2. Medical Safety Systems

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                1. NSW government Treasury Managed Fund, expert witness affidavit, 2014.

                Ying Zhu:
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                Hugo Sampaio:
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                Michelle Farrar:
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                1. Biogen Spinal Muscular Atrophy Therapeutics Scientific Advisory Committee Australia

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                1. Scientific consultancy Biogen Idec.

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                1. 1. Motor Neuron Diseases Research Institute of Australia Beryl Bayley Postdoctoral Fellowship 2. Motor Neuron Diseases Research Institute of Australia Grant in Aid 3. Thyne Reid Foundation

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                Garth Nicholson:
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                Journal
                Journal ID (nlm-ta): Neurology
                Journal ID (iso-abbrev): Neurology
                Journal ID (hwp): neurology
                Journal ID (publisher-id): neur
                Journal ID (pmc): neurology
                Journal ID (publisher-id): NEUROLOGY
                Title: Neurology
                Publisher: Lippincott Williams & Wilkins (Hagerstown, MD )
                ISSN (Print): 0028-3878
                ISSN (Electronic): 1526-632X
                Publication date (Print): 05 July 2016
                Publication date PMC-release: 05 July 2016
                Volume: 87
                Issue: 1
                Pages: 65-70
                Affiliations
                From the Molecular Medicine Laboratory (M.S., G.N.), Neurology Department (J.L.), ANZAC Research Institute (G.N.), and NSW Health Pathology (G.N.), Concord Hospital (S.R.); Departments of Neurology (H.T., H.S., M.F.) and Genetics (T.R.), Sydney Children's Hospital; Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine (H.T., H.S., M.F.), and St Vincent's Clinical School (T.R.), The University of New South Wales, Sydney; Kolling Institute (Y.Z.), Royal North Shore Hospital, Newcastle GOLD Service, Hunter Genetics, Waratah; SEALS Haematology and Genetics Laboratory (M.B.), Prince of Wales Hospital, Sydney; Kinghorn Centre for Clinical Genomics (T.R.); and Sydney Medical School (G.N.), University of Sydney, Australia.
                Author notes
                Correspondence to Dr. Garth Nicholson: garth.nicholson@ 123456sydney.edu.au

                Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing charge was paid by the authors.

                [*]

                These authors contributed equally to this work.

                [‡]

                These authors are co–senior authors.

                Article
                Publisher ID: NEUROLOGY2015714451
                DOI: 10.1212/WNL.0000000000002813
                PMC ID: 4932233
                PubMed ID: 27281532
                SO-VID: cb46c677-452a-479c-b4e8-14b22af3a1ef
                Copyright © © 2016 American Academy of Neurology
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

                History
                Date received : 03 January 2016
                Date accepted : 17 March 2016
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                Subject: 178
                Subject: Article
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