title: Characterization of splice variants of the genes encoding human mitochondrial HMG-CoA lyase and HMG-CoA synthase, the main enzymes of the ketogenesis pathway.
abstract: The genes HMGCS2 and HMGCL encode the two main enzymes for ketone-body synthesis, mitochondrial HMG-CoA synthase and HMG-CoA lyase. Here, we identify and describe possible splice variants of these genes in human tissues. We detected an alternative transcript of HMGCS2 carrying a deletion of exon 4, and two alternative transcripts of HMGCL with deletions of exons 5 and 6, and exons 5, 6 and 7, respectively. All splice variants maintained the reading frame. However, Western blot studies and overexpression measurements in eukaryotic or prokaryotic cell models did not reveal HL or mHS protein variants. Both genes showed a similar distribution of the inactive variants in different tissues. Surprisingly, the highest percentages were found in tissues where almost no ketone bodies are synthesized: heart, skeletal muscle and brain. Our results suggest that alternative splicing might coordinately block the two main enzymes of ketogenesis in specific human tissues.
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology and Pediatrics, School of Medicine, University of Zaragoza, C/Domingo Miral s/n, 50009, Zaragoza, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Puisac
authors.forename: Mónica
authors.initials: M
authors.lastname: Ramos
authors.forename: María
authors.initials: M
authors.lastname: Arnedo
authors.forename: Sebastián
authors.initials: S
authors.lastname: Menao
authors.forename: María Concepción
authors.initials: MC
authors.lastname: Gil-Rodríguez
authors.forename: María Esperanza
authors.initials: ME
authors.lastname: Teresa-Rodrigo
authors.forename: Angeles
authors.initials: A
authors.lastname: Pié
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: de Karam
authors.forename: Jan-Jaap
authors.initials: JJ
authors.lastname: Wesselink
authors.forename: Ignacio
authors.initials: I
authors.lastname: Giménez
authors.forename: Feliciano J
authors.initials: FJ
authors.lastname: Ramos
authors.forename: Nuria
authors.initials: N
authors.lastname: Casals
authors.forename: Paulino
authors.initials: P
authors.lastname: Gómez-Puertas
authors.forename: Fausto G
authors.initials: FG
authors.lastname: Hegardt
authors.forename: Juan
authors.initials: J
authors.lastname: Pié
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D053898:Biosynthetic Pathways / Q000235:genetics*; D015153:Blotting, Western; D019295:Computational Biology; D057809:HEK293 Cells; D006801:Humans; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007657:Ketone Bodies / Q000096:biosynthesis*; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics*; D007652:Oxo-Acid-Lyases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017433:Protein Structure, Secondary; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D007527:Isoenzymes; D007657:Ketone Bodies; D006904:Hydroxymethylglutaryl-CoA Synthase; D007652:Oxo-Acid-Lyases; C021410:3-hydroxy-3-methylglutaryl-coenzyme A lyase