1 Ocak 2019 Dergi makalesi Açık Erişim

Johnstone, Devon L.; Al-Shekaili, Hilal H.; Tarailo-Graovac, Maja; Wolf, Nicole I.; Ivy, Autumn S.; Demarest, Scott; Roussel, Yann; Ciapaite, Jolita; van Roermund, Carlo W. T.; Kernohan, Kristin D.; Kosuta, Ceres; Ban, Kevin; Ito, Yoko; McBride, Skye; Al-Thihli, Khalid; Abdelrahim, Rana A.; Koul, Roshan; Al Futaisi, Amna; Haaxma, Charlotte A.; Olson, Heather; Olson, Heather

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  <identifier identifierType="URL">https://aperta.ulakbim.gov.tr/record/69699</identifier>
  <creators>
    <creator>
      <creatorName>Johnstone, Devon L.</creatorName>
      <givenName>Devon L.</givenName>
      <familyName>Johnstone</familyName>
    </creator>
    <creator>
      <creatorName>Al-Shekaili, Hilal H.</creatorName>
      <givenName>Hilal H.</givenName>
      <familyName>Al-Shekaili</familyName>
    </creator>
    <creator>
      <creatorName>Tarailo-Graovac, Maja</creatorName>
      <givenName>Maja</givenName>
      <familyName>Tarailo-Graovac</familyName>
    </creator>
    <creator>
      <creatorName>Wolf, Nicole I.</creatorName>
      <givenName>Nicole I.</givenName>
      <familyName>Wolf</familyName>
      <affiliation>Univ Amsterdam, Med Ctr, Amsterdam Neurosci, Dept Child Neurol, Amsterdam, Netherlands</affiliation>
    </creator>
    <creator>
      <creatorName>Ivy, Autumn S.</creatorName>
      <givenName>Autumn S.</givenName>
      <familyName>Ivy</familyName>
      <affiliation>Stanford Univ, Sch Med, Dept Neurol &amp; Neurol Sci, Div Child Neurol, Stanford, CA 94305 USA</affiliation>
    </creator>
    <creator>
      <creatorName>Demarest, Scott</creatorName>
      <givenName>Scott</givenName>
      <familyName>Demarest</familyName>
    </creator>
    <creator>
      <creatorName>Roussel, Yann</creatorName>
      <givenName>Yann</givenName>
      <familyName>Roussel</familyName>
      <affiliation>Univ Ottawa, Dept Biol, Ottawa, ON, Canada</affiliation>
    </creator>
    <creator>
      <creatorName>Ciapaite, Jolita</creatorName>
      <givenName>Jolita</givenName>
      <familyName>Ciapaite</familyName>
      <affiliation>Univ Med Ctr, Ctr Mol Med, Dept Genet, Utrecht, Netherlands</affiliation>
    </creator>
    <creator>
      <creatorName>van Roermund, Carlo W. T.</creatorName>
      <givenName>Carlo W. T.</givenName>
      <familyName>van Roermund</familyName>
      <affiliation>Univ Amsterdam, Med Ctr, Lab Genet Metab Dis, Dept Pediat &amp; Clin Chem,Lab Div, Amsterdam, Netherlands</affiliation>
    </creator>
    <creator>
      <creatorName>Kernohan, Kristin D.</creatorName>
      <givenName>Kristin D.</givenName>
      <familyName>Kernohan</familyName>
      <affiliation>Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON, Canada</affiliation>
    </creator>
    <creator>
      <creatorName>Kosuta, Ceres</creatorName>
      <givenName>Ceres</givenName>
      <familyName>Kosuta</familyName>
    </creator>
    <creator>
      <creatorName>Ban, Kevin</creatorName>
      <givenName>Kevin</givenName>
      <familyName>Ban</familyName>
    </creator>
    <creator>
      <creatorName>Ito, Yoko</creatorName>
      <givenName>Yoko</givenName>
      <familyName>Ito</familyName>
      <affiliation>Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON, Canada</affiliation>
    </creator>
    <creator>
      <creatorName>McBride, Skye</creatorName>
      <givenName>Skye</givenName>
      <familyName>McBride</familyName>
      <affiliation>Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON, Canada</affiliation>
    </creator>
    <creator>
      <creatorName>Al-Thihli, Khalid</creatorName>
      <givenName>Khalid</givenName>
      <familyName>Al-Thihli</familyName>
      <affiliation>Sultan Qaboos Univ Hosp, Genet &amp; Dev Med Clin, Muscat, Oman</affiliation>
    </creator>
    <creator>
      <creatorName>Abdelrahim, Rana A.</creatorName>
      <givenName>Rana A.</givenName>
      <familyName>Abdelrahim</familyName>
      <affiliation>Sultan Qaboos Univ Hosp, Dept Child Hlth, Muscat, Oman</affiliation>
    </creator>
    <creator>
      <creatorName>Koul, Roshan</creatorName>
      <givenName>Roshan</givenName>
      <familyName>Koul</familyName>
      <affiliation>Sultan Qaboos Univ Hosp, Dept Child Hlth, Paediat Neurol Unit, Muscat, Oman</affiliation>
    </creator>
    <creator>
      <creatorName>Al Futaisi, Amna</creatorName>
      <givenName>Amna</givenName>
      <familyName>Al Futaisi</familyName>
      <affiliation>Sultan Qaboos Univ Hosp, Dept Child Hlth, Paediat Neurol Unit, Muscat, Oman</affiliation>
    </creator>
    <creator>
      <creatorName>Haaxma, Charlotte A.</creatorName>
      <givenName>Charlotte A.</givenName>
      <familyName>Haaxma</familyName>
    </creator>
    <creator>
      <creatorName>Olson, Heather</creatorName>
      <givenName>Heather</givenName>
      <familyName>Olson</familyName>
      <affiliation>Boston Childrens Hosp, Dept Neurol, Div Epilepsy &amp; Clin Neurophysiol, Boston, MA USA</affiliation>
    </creator>
    <creator>
      <creatorName>Olson, Heather</creatorName>
      <givenName>Heather</givenName>
      <familyName>Olson</familyName>
      <affiliation>Boston Childrens Hosp, Dept Neurol, Div Epilepsy &amp; Clin Neurophysiol, Boston, MA USA</affiliation>
    </creator>
  </creators>
  <titles>
    <title>Plphp Deficiency: Clinical, Genetic, Biochemical, And Mechanistic Insights</title>
  </titles>
  <publisher>Aperta</publisher>
  <publicationYear>2019</publicationYear>
  <dates>
    <date dateType="Issued">2019-01-01</date>
  </dates>
  <resourceType resourceTypeGeneral="Text">Journal article</resourceType>
  <alternateIdentifiers>
    <alternateIdentifier alternateIdentifierType="url">https://aperta.ulakbim.gov.tr/record/69699</alternateIdentifier>
  </alternateIdentifiers>
  <relatedIdentifiers>
    <relatedIdentifier relatedIdentifierType="DOI" relationType="IsIdenticalTo">10.1093/brain/awy346</relatedIdentifier>
  </relatedIdentifiers>
  <rightsList>
    <rights rightsURI="http://www.opendefinition.org/licenses/cc-by">Creative Commons Attribution</rights>
    <rights rightsURI="info:eu-repo/semantics/openAccess">Open Access</rights>
  </rightsList>
  <descriptions>
    <description descriptionType="Abstract">Biallelic pathogenic variants in PLPBP (formerly called PROSC) have recently been shown to cause a novel form of vitamin B6-dependent epilepsy, the pathophysiological basis of which is poorly understood. When left untreated, the disease can progress to status epilepticus and death in infancy. Here we present 12 previously undescribed patients and six novel pathogenic variants in PLPBP. Suspected clinical diagnoses prior to identification of PLPBP variants included mitochondrial encephalopathy (two patients), folinic acid-responsive epilepsy (one patient) and a movement disorder compatible with AADC deficiency (one patient). The encoded protein, PLPHP is believed to be crucial for B6 homeostasis. We modelled the pathogenicity of the variants and developed a clinical severity scoring system. The most severe phenotypes were associated with variants leading to loss of function of PLPBP or significantly affecting protein stability/PLP-binding. To explore the pathophysiology of this disease further, we developed the first zebrafish model of PLPHP deficiency using CRISPR/Cas9. Our model recapitulates the disease, with plpbp(-/-) larvae showing behavioural, biochemical, and electrophysiological signs of seizure activity by 10 days post-fertilization and early death by 16 days post-fertilization. Treatment with pyridoxine significantly improved the epileptic phenotype and extended lifespan in plpbp(-/-) animals. Larvae had disruptions in amino acid metabolism as well as GABA and catecholamine biosynthesis, indicating impairment of PLP-dependent enzymatic activities. Using mass spectrometry, we observed significant B6 vitamer level changes in plpbp(-/-) zebrafish, patient fibroblasts and PLPHP-deficient HEK293 cells. Additional studies in human cells and yeast provide the first empirical evidence that PLPHP is localized in mitochondria and may play a role in mitochondrial metabolism. These models provide new insights into disease mechanisms and can serve as a platform for drug discovery.</description>
  </descriptions>
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