title: The SR protein SC35 is responsible for aberrant splicing of the E1alpha pyruvate dehydrogenase mRNA in a case of mental retardation with lactic acidosis.
abstract: 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.
authors.affiliation: UMR 5535, IFR122, CNRS-UMII, Institut de Génétique Moléculaire de Montpellier, 1919 route de Mende, 34293 Montpellier, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Gabut
authors.forename: Manuèle
authors.initials: M
authors.lastname: Miné
authors.forename: Cécile
authors.initials: C
authors.lastname: Marsac
authors.forename: Michèle
authors.initials: M
authors.lastname: Brivet
authors.forename: Jamal
authors.initials: J
authors.lastname: Tazi
authors.forename: Johann
authors.initials: J
authors.lastname: Soret
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics* / Q000378:metabolism; D017398:Alternative Splicing / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D005091:Exons / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000378:metabolism; D007438:Introns / Q000235:genetics; D007888:Leigh Disease / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000235:genetics*; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D022821:RNA Splice Sites / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012261:Ribonucleoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000068103:Serine-Arginine Splicing Factors; D013577:Syndrome
chemical_list: D009687:Nuclear Proteins; D011768:Pyruvate Dehydrogenase Complex; D022821:RNA Splice Sites; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D030481:Pyruvate Dehydrogenase (Lipoamide)