title: RNA sequencing of creatine transporter (SLC6A8) deficient fibroblasts reveals impairment of the extracellular matrix.
abstract: Creatine transporter (SLC6A8) deficiency is the most common cause of cerebral creatine syndromes, and is characterized by depletion of creatine in the brain. Manifestations of this X-linked disorder include intellectual disability, speech/language impairment, behavior abnormalities, and seizures. At the moment, no effective treatment is available. In order to investigate the molecular pathophysiology of this disorder, we performed RNA sequencing on fibroblasts derived from patients. The transcriptomes of fibroblast cells from eight unrelated individuals with SLC6A8 deficiency and three wild-type controls were sequenced. SLC6A8 mutations with different effects on the protein product resulted in different gene expression profiles. Differential gene expression analysis followed by gene ontology term enrichment analysis revealed that especially the expression of genes encoding components of the extracellular matrix and cytoskeleton are altered in SLC6A8 deficiency, such as collagens, keratins, integrins, and cadherins. This suggests an important novel role for creatine in the structural development and maintenance of cells. It is likely that the (extracellular) structure of brain cells is also impaired in SLC6A8-deficient patients, and future studies are necessary to confirm this and to reveal the true functions of creatine in the brain.
authors: Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands; Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Benjamin
authors: B
authors: Nota
authors: Joseph D T
authors: JD
authors: Ndika
authors: Jiddeke M
authors: JM
authors: van de Kamp
authors: Warsha A
authors: WA
authors: Kanhai
authors: Silvy J M
authors: SJ
authors: van Dooren
authors: Mark A
authors: MA
authors: van de Wiel
authors: Gerard
authors: G
authors: Pals
authors: Gajja S
authors: GS
authors: Salomons
mesh_terms: D020739:Brain Diseases, Metabolic, Inborn / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D003401:Creatine / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D013569:Synapses / Q000235:genetics / Q000378:metabolism
chemical_list: D026901:Membrane Transport Proteins; D050480:Plasma Membrane Neurotransmitter Transport Proteins; C080679:creatine transporter; D003401:Creatine
keywords: RNA-seq; SLC6A8; creatine; epilepsy; extracellular matrix