title: Defining the pathogenicity of creatine deficiency syndrome.
abstract: This work examined nine patients with creatine deficiency syndrome (CDS): six with a creatine transport (CRTR) defect and three with a GAMT defect. Eleven nucleotide variations were detected: six in SLC6A8 and five in GAMT. These changes were analyzed at the mRNA level and specific alleles (most of which bore premature stop codons) were selected as nulls because they provoked nonsense-mediated decay activation. The impact of these CDS mutations on metabolic stress (ROS production, p38MAPK activation, aberrant proliferation and apoptosis) was analyzed in patient fibroblast cultures. Oxidative stress contributed toward the severe form of CDS, with increases seen in the intracellular ROS content and the percentage of apoptotic cells. An altered cell cycle was also seen in a number of CRTR and GAMT fibroblast cell lines (mostly those carrying null alleles). p38MAPK activation only correlated with oxidative stress in the CRTR cells. Based on intracellular creatine levels, the contribution of energy depletion toward metabolic stress was demonstrable only in selected CRTR cells. Together, these findings suggest that the apoptotic response to genotoxic damage in the present CDS cells may have been triggered by different cell signaling pathways. They also suggest that reducing oxidative stress could be helpful in treating CDS. Hum Mutat 32:1-10, 2011. © 2011 Wiley-Liss, Inc.
authors.affiliation: Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular "Severo Ochoa" CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Alcaide
authors.forename: Begoña
authors.initials: B
authors.lastname: Merinero
authors.forename: Pedro
authors.initials: P
authors.lastname: Ruiz-Sala
authors.forename: Eva
authors.initials: E
authors.lastname: Richard
authors.forename: Rosa
authors.initials: R
authors.lastname: Navarrete
authors.forename: Angela
authors.initials: A
authors.lastname: Arias
authors.forename: Antonia
authors.initials: A
authors.lastname: Ribes
authors.forename: Rafael
authors.initials: R
authors.lastname: Artuch
authors.forename: Jaume
authors.initials: J
authors.lastname: Campistol
authors.forename: Magdalena
authors.initials: M
authors.lastname: Ugarte
authors.forename: Pilar
authors.initials: P
authors.lastname: Rodríguez-Pombo
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D017209:Apoptosis / Q000235:genetics; D020739:Brain Diseases, Metabolic, Inborn / Q000235:genetics* / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003401:Creatine / Q000032:analysis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D050937:Guanidinoacetate N-Methyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000378:metabolism*; D008780:Methyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050480:Plasma Membrane Neurotransmitter Transport Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C094770:SLC6A8 protein, human; D008780:Methyltransferases; C494506:GAMT protein, human; D050937:Guanidinoacetate N-Methyltransferase; D048051:p38 Mitogen-Activated Protein Kinases; D003401:Creatine