A nonsense mutation in the exon 2 of the 3-hydroxy-3-methylglutaryl coenzyme A lyase (HL) gene producing three mature mRNAs is the main cause of 3-hydroxy-3-methylglutaric aciduria in European Mediterranean patients

Archives of Biochemistry and Biophysics
Cesar CasaleFausto G Hegardt

Abstract

3-Hydroxy-3-methylglutaric aciduria is a rare recessive monogenic disorder that affects ketogenesis and the catabolism of L-leucine. We report the biochemical and molecular characterization of a mutation in the 3-hydroxy-3-methylglutaryl coenzyme A lyase gene in four new probands, three Spanish and one Turkish, affected by 3-hydroxy-3-methylglutaric aciduria, all homozygous for the nonsense mutation Glu37Ter, which was reported by our group in two probands of Portuguese and Moroccan origin (15). In addition to the aberrant mRNAs found in the two previous probands, a novel species of mature HL mRNA was observed in the patients studied here, since a new cDNA, skipped in exons 2 and 3, was obtained from the mRNAs by reverse-transcription PCR (RT-PCR). Thus, three mRNA species were produced in aberrant splicings as a result of this nonsense mutation: (i) one of the expected size that contains the premature stop codon UAA, (ii) another with a deletion of 84 bp corresponding to the whole of exon 2, and (iii) a new species found now, with a deletion of 192 bp corresponding to skipping of the whole of exons 2 and 3, whose translation product led to the loss of seven amino acids in the leader peptide and 57 amino acids in the terminal d...Continue Reading

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Citations

Jun 10, 2010·Journal of Inherited Metabolic Disease·Beatriz PuisacJuan Pié
May 29, 2004·Journal of Physiology and Biochemistry·J PieF G Hegardt
Nov 28, 2008·Clinica Chimica Acta; International Journal of Clinical Chemistry·Wei-De LinFuu-Jen Tsai
Apr 27, 2007·Molecular Genetics and Metabolism·Patricia CarrascoNúria Casals
Dec 18, 2007·Journal of Inherited Metabolic Disease·C R VargasM Wajner
Aug 19, 2007·Molecular Genetics and Metabolism·Juan PiéNúria Casals
May 15, 2003·The Journal of Biological Chemistry·Núria CasalsFausto G Hegardt
Dec 11, 2019·International Journal of Molecular Sciences·María ArnedoJuan Pié
Feb 16, 2020·Orphanet Journal of Rare Diseases·Sarah C Grünert, Jörn Oliver Sass
Oct 2, 2003·Journal of Inherited Metabolic Disease·E PospísilováJ Zeman
Nov 7, 1998·Mutation Research·C R Valentine

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