The SR Protein SC35 Is Responsible for Aberrant Splicing of the E1α Pyruvate Dehydrogenase mRNA in a Case of Mental Retardation with Lactic Acidosis
Copyright policy )The SR Protein SC35 Is Responsible for Aberrant Splicing of the E1α Pyruvate Dehydrogenase mRNA in a Case of Mental Retardation with Lactic Acidosis
Pyruvate dehydrogenase (PDH) complex deficiency is a major cause of lactic acidosis and Leigh's encephalomyelopathies in infancy and childhood, resulting in early death in the majority of patients. Most of the molecular defects have been localized in the coding regions of the E1alpha PDH gene. Recently, we identified a novel mutation of the E1alpha PDH gene in a patient with an encephalopathy and lactic acidosis. This mutation, located downstream of exon 7, activates a cryptic splice donor and leads to the retention of intronic sequences. Here, we demonstrate that the mutation results in an increased binding of the SR protein SC35. Consistently, ectopic overexpression of this splicing factor enhanced the use of the cryptic splice site, whereas small interfering RNA-mediated reduction of the SC35 protein levels in primary fibroblasts from the patient resulted in the almost complete disappearance of the aberrantly spliced E1alpha PDH mRNA. Our findings open the exciting prospect for a novel therapy of an inherited disease by altering the level of a specific splicing factor.
Cultured Exons/genetics Fibroblasts/metabolism Humans Introns/genetics Leigh Disease/*genetics/metabolism Mental Retardation/genetics/metabolism Mutation/genetics Nuclear Proteins/antagonists & inhibitors/genetics/*metabolism Pyruvate Dehydrogenase (Lipoamide)/*genetics Pyruvate Dehydrogenase Complex/genetics Pyruvate Dehydrogenase Complex Deficiency Disease/genetics/metabolism RNA Interference RNA Splice Sites/genetics/*physiology RNA, Pyruvate Dehydrogenase Complex, Intellectual Disability, Messenger/metabolism RNA, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, Pyruvate Dehydrogenase (Lipoamide), RNA, Messenger, RNA, Small Interfering, Pyruvate Dehydrogenase Complex Deficiency Disease, Cells, Cultured, Nuclear Proteins, RNA-Binding Proteins, Exons, Fibroblasts, Introns, Alternative Splicing, Lactic/*genetics/metabolism Alternative Splicing/genetics/*physiology Cells, Ribonucleoproteins, Mutation, Acidosis, Lactic, RNA Interference, RNA Splice Sites, Small Interfering/genetics/pharmacology RNA-Binding Proteins/antagonists & inhibitors/genetics/metabolism Ribonucleoproteins/antagonists & inhibitors/genetics/*metabolism Syndrome, Leigh Disease, Acidosis
Cultured Exons/genetics Fibroblasts/metabolism Humans Introns/genetics Leigh Disease/*genetics/metabolism Mental Retardation/genetics/metabolism Mutation/genetics Nuclear Proteins/antagonists & inhibitors/genetics/*metabolism Pyruvate Dehydrogenase (Lipoamide)/*genetics Pyruvate Dehydrogenase Complex/genetics Pyruvate Dehydrogenase Complex Deficiency Disease/genetics/metabolism RNA Interference RNA Splice Sites/genetics/*physiology RNA, Pyruvate Dehydrogenase Complex, Intellectual Disability, Messenger/metabolism RNA, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, Pyruvate Dehydrogenase (Lipoamide), RNA, Messenger, RNA, Small Interfering, Pyruvate Dehydrogenase Complex Deficiency Disease, Cells, Cultured, Nuclear Proteins, RNA-Binding Proteins, Exons, Fibroblasts, Introns, Alternative Splicing, Lactic/*genetics/metabolism Alternative Splicing/genetics/*physiology Cells, Ribonucleoproteins, Mutation, Acidosis, Lactic, RNA Interference, RNA Splice Sites, Small Interfering/genetics/pharmacology RNA-Binding Proteins/antagonists & inhibitors/genetics/metabolism Ribonucleoproteins/antagonists & inhibitors/genetics/*metabolism Syndrome, Leigh Disease, Acidosis
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