Human Molecular Genetics, Vol 5, 1325-1331, Copyright © 1996 by Oxford University Press
JC Webb, DD Patel, CC Shoulders, BL Knight and AK Soutar
Mutations in the coding sequence, splice junctions or promoter of the gene
for the low density lipoprotein (LDL) receptor are known to be the
underlying cause of familial hypercholesterolaemia (FH), but mutations of
this type cannot be identified in all patients with a clinical diagnosis of
FH. We show here that minor sequence changes elsewhere in introns can be
deleterious. A minor rearrangement 30 bp upstream from the junction of
intron 9 with exon 10 was detected as a heteroduplex in amplified genomic
DNA from one out of 300 heterozygous FH patients. The mutation destroys the
only consensus sequence for a splicing branch point in intron 9 and
analysis of mRNA from cells from the patient showed that it causes
retention of intron 9 or, more rarely, in the use of cryptic splice sites
in exon 10. The effect of the mutation on mRNA splicing was confirmed by
analysis of mRNA in cells transfected with LDL-receptor mini-gene
constructs expressing exons 9 and 10, together with the normal or mutant
intron 9. A common C/T polymorphism within this branch point in intron 9 of
the LDL-receptor gene does not affect mRNA splicing in vitro and is not
associated with significant differences in mean plasma cholesterol
concentration in a healthy population.
ARTICLES
Genetic variation at a splicing branch point in intron 9 of the low density lipoprotein (LDL)-receptor gene: a rare mutation that disrupts mRNA splicing in a patient with familial hypercholesterolaemia and a common polymorphism
MRC Lipoprotein Team, Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK.
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