A NONSENSE MUTATION IN THE 3-HYDROXY-3-METHYLGLUTARYL-COA LYASE GENE PRODUCES EXON SKIPPING IN 2 PATIENTS OF DIFFERENT ORIGIN WITH 3-HYDROXY-3-METHYLGLUTARYL-COA LYASE DEFICIENCY
J. Pie et al., A NONSENSE MUTATION IN THE 3-HYDROXY-3-METHYLGLUTARYL-COA LYASE GENE PRODUCES EXON SKIPPING IN 2 PATIENTS OF DIFFERENT ORIGIN WITH 3-HYDROXY-3-METHYLGLUTARYL-COA LYASE DEFICIENCY, Biochemical journal, 323, 1997, pp. 329-335
A novel nonsense mutation associated with the skipping of constitutive
exon 2 of the 3-hydroxy-3-methylglutaryl-CoA lyase gene was found in
two patients, from Portugal and Morocco, with 3-hydroxy-3-methylglutar
ic acidemia. By reverse transcriptase PCR and single-strand conformati
onal polymorphism a G-T transversion was located, at nucleotide 109, o
f the 3-hydroxy-3-methylglutaryl-CoA lyase cDNA, within exon 2. Two mR
NAs were produced as a result of this nonsense mutation: one of the ex
pected size that contains the premature stop codon UAA, and the other
with a deletion of 84 bp corresponding to the whole of exon 2. This de
letion produced the loss of the last seven amino acids of the leader p
eptide and the first 21 amino acids of the mature protein. The nonsens
e mutation was found in a purine-rich GGAAG sequence, which is equal t
o, or similar to, others reported to be exonic splicing enhancers (ESE
). We suggest that the nonsense mutation may affect a possible ESE on
exon 2, which would hinder the splice site selection and facilitate an
aberrant splice with the skipping of this exon. Determination by quan
titative PCR shows that the ratio of mRNA with the nonsense mutation t
o the mRNA with the deletion is approx. 3:1.