Splice-site mutation c.313+1, G>A in intron 3 of the LDL receptor gene results in transcripts with skipping of exon 3 and inclusion of intron 3.
BACKGROUND
Familial hypercholesterolemia (FH) patients with the splice site mutation c.313+1, G>A in intron 3 of the low density lipoprotein receptor (LDLR) gene, present with a phenotype similar to that of FH patients in general. However, a mild phenotype would have been expected from the published data showing that the mutation only causes skipping of exon 3.


METHODS
Epstein Barr virus-transformed lymphocytes from eight c.313+1, G>A heterozygotes and two c.313+1, G>A homozygotes were subjected to studies of the LDLR at the mRNA and protein levels.


RESULTS
Mutation c.313+1, G>A not only causes skipping of exon 3, but also causes inclusion of intron 3. No functional LDLR was produced from the transcript with inclusion of intron 3. The transcript with skipping of exon 3 produced a receptor which had markedly reduced ability to internalize low density lipoprotein.


CONCLUSIONS
The findings that the mutation c.313+1, G>A in the LDLR gene also generates a mutant transcript with inclusion of intron 3, explains why the mutation c.313+1, G>A may result in a severe phenotype.
Cameron
Jamie
J
Medical Genetics Laboratory, Department of Medical Genetics, Rikshospitalet University Hospital, Norway.
Holla
Øystein L
ØL
Kulseth
Mari Ann
MA
Leren
Trond P
TP
Berge
Knut Erik
KE
D015152:Blotting, Northern; D015153:Blotting, Western; D002675:Child, Preschool; D005091:Exons / Q000235:genetics*; D004854:Herpesvirus 4, Human / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics / Q000378:metabolism; D007223:Infant; D007438:Introns / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D022821:RNA Splice Sites / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014170:Transformation, Genetic
D022821:RNA Splice Sites; D011973:Receptors, LDL