Silent exonic mutations in the low-density lipoprotein receptor gene that cause familial hypercholesterolemia by affecting mRNA splicing

Clinical Genetics
Joep C DefescheA F H Stalenhoef

Abstract

In a large group of patients with the clinical phenotype of familial hypercholesterolemia, such as elevated low-density lipoprotein (LDL) cholesterol and premature atherosclerosis, but without functional mutations in the genes coding for the LDL receptor and apolipoprotein B, we examined the effect of 128 seemingly neutral exonic and intronic DNA variants, discovered by routine sequencing of these genes. Two variants, G186G and R385R, were found to be associated with altered splicing. The nucleotide change leading to G186G resulted in the generation of new 3'-splice donor site in exon 4 and R385R was associated with a new 5'-splice acceptor site in exon 9 of the LDL receptor gene. Splicing of these alternate splice sites leads to an in-frame 75-base pair deletion in a stable mRNA of exon 4 in case of G186G and R385R resulted in a 31-base pair frame-shift deletion in exon 9 and non-sense-mediated mRNA decay.

References

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Citations

Nov 17, 2009·Cellular and Molecular Life Sciences : CMLS·Maria J MarcaidaGuillermo Montoya
Jun 28, 2011·The Journal of Molecular Diagnostics : JMD·Neng ChenIris Schrijver
Nov 22, 2014·Journal of Medical Genetics·Sigrid W FouchierJoep C Defesche
Feb 9, 2017·Current Opinion in Lipidology·Mafalda BourbonEric J Sijbrands
Feb 6, 2017·Current Opinion in Lipidology·Paul N Hopkins, Stacey R Lane
Jan 21, 2017·Atherosclerosis·Ronen DurstEran Leitersdorf
Apr 18, 2009·Genetic Testing and Molecular Biomarkers·Kristian TvetenMari Ann Kulseth
Dec 16, 2010·Current Opinion in Lipidology·Sebastiano CalandraStefano Bertolini
Nov 9, 2016·Journal of Medical Genetics·Sarah LeighSteve E Humphries

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