title: 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.
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 domain of the mature enzyme. The association of a nonsense mutation with the skipping of the exon that contains it, plus the following exon, is an unusual finding not seen previously in HL deficiencies. The mutation described here shows the highest incidence (> 37%) of total HL deficiencies reported.
authors.affiliation: Unit of Biochemistry, School of Pharmacy, University of Barcelona, Spain.
authors.forename: C H
authors.initials: CH
authors.lastname: Casale
authors.forename: N
authors.initials: N
authors.lastname: Casals
authors.forename: J
authors.initials: J
authors.lastname: Pié
authors.forename: N
authors.initials: N
authors.lastname: Zapater
authors.forename: C
authors.initials: C
authors.lastname: Pérez-Cerdá
authors.forename: B
authors.initials: B
authors.lastname: Merinero
authors.forename: M
authors.initials: M
authors.lastname: Martínez-Pardo
authors.forename: J J
authors.initials: JJ
authors.lastname: García-Peñas
authors.forename: J M
authors.initials: JM
authors.lastname: García-Gonzalez
authors.forename: R
authors.initials: R
authors.lastname: Lama
authors.forename: B T
authors.initials: BT
authors.lastname: Poll-The
authors.forename: J A
authors.initials: JA
authors.lastname: Smeitink
authors.forename: R J
authors.initials: RJ
authors.lastname: Wanders
authors.forename: M
authors.initials: M
authors.lastname: Ugarte
authors.forename: F G
authors.initials: FG
authors.lastname: Hegardt
mesh_terms: D002675:Child, Preschool; D005091:Exons / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D019083:Mediterranean Region; D015093:Meglutol / Q000652:urine*; D009154:Mutation; D007652:Oxo-Acid-Lyases / Q000235:genetics*
chemical_list: D015093:Meglutol; D007652:Oxo-Acid-Lyases; C021410:3-hydroxy-3-methylglutaryl-coenzyme A lyase