Defining the pathogenicity of creatine deficiency syndrome

Patricia Alcaide; Begoña Merinero; Pedro Ruiz-Sala; Eva Richard; Rosa Navarrete; Angela Arias; Antonia Ribes; Rafael Artuch; Jaume Campistol; Magdalena Ugarte; Pilar Rodríguez-Pombo

doi:10.1002/humu.21421

Defining the pathogenicity of creatine deficiency syndrome

Hum Mutat. 2011 Mar;32(3):282-91. doi: 10.1002/humu.21421. Epub 2011 Feb 8.

Authors

Patricia Alcaide¹, Begoña Merinero, Pedro Ruiz-Sala, Eva Richard, Rosa Navarrete, Angela Arias, Antonia Ribes, Rafael Artuch, Jaume Campistol, Magdalena Ugarte, Pilar Rodríguez-Pombo

Affiliation

¹ Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular "Severo Ochoa" CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, Spain.

PMID: 21140503
DOI: 10.1002/humu.21421

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.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Alleles
Apoptosis / genetics
Brain Diseases, Metabolic, Inborn / genetics*
Brain Diseases, Metabolic, Inborn / metabolism*
Cell Cycle / genetics
Cell Proliferation
Cells, Cultured
Child
Child, Preschool
Creatine / analysis
Creatine / deficiency
Creatine / genetics
Creatine / metabolism
Female
Genetic Variation
Guanidinoacetate N-Methyltransferase / genetics*
Humans
Male
Membrane Transport Proteins / deficiency
Membrane Transport Proteins / genetics
Membrane Transport Proteins / metabolism
Mental Retardation, X-Linked / genetics*
Mental Retardation, X-Linked / metabolism*
Methyltransferases / deficiency
Methyltransferases / genetics
Methyltransferases / metabolism
Middle Aged
Nerve Tissue Proteins / genetics*
Plasma Membrane Neurotransmitter Transport Proteins / deficiency
Plasma Membrane Neurotransmitter Transport Proteins / genetics*
Plasma Membrane Neurotransmitter Transport Proteins / metabolism
RNA, Messenger / genetics
Reactive Oxygen Species / metabolism
Stress, Physiological
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

Membrane Transport Proteins
Nerve Tissue Proteins
Plasma Membrane Neurotransmitter Transport Proteins
RNA, Messenger
Reactive Oxygen Species
SLC6A8 protein, human
Methyltransferases
GAMT protein, human
Guanidinoacetate N-Methyltransferase
p38 Mitogen-Activated Protein Kinases
Creatine

Supplementary concepts

Creatine deficiency, X-linked