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Silent exonic mutations in the low‐density lipoprotein receptor gene that cause familial hypercholesterolemia by affecting mRNA splicing
Author(s) -
Defesche JC,
Schuurman EJM,
Klaaijsen LN,
Khoo KL,
Wiegman A,
Stalenhoef AFH
Publication year - 2008
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/j.1399-0004.2008.00999.x
Subject(s) - exon , rna splicing , splice , genetics , familial hypercholesterolemia , gene , apolipoprotein b , biology , splice site mutation , ldl receptor , coding region , alternative splicing , microbiology and biotechnology , lipoprotein , rna , cholesterol , endocrinology
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.