A frequently occurring mutation in the lipoprotein lipase gene (Asn291Ser) contributes to the expression of familial combined hyperlipidemia.
We performed denaturing gradient gel electrophoresis (DGGE) of exons 4, 5, 6 and their exon-intron boundaries of the LPL-gene in 169 unrelated male patients suffering from familial combined hyperlipidemia (FCH). Twenty patients were found to carry a nucleotide substitution in exon 6. Sequence and PCR/digestion analysis revealed one common mutation (Asn291Ser) in all these cases. This mutation was talso present in 215 male controls, albeit at a lower frequency than in FCH patients (10/215 = 4.6% vs. 20/169 = 11.8%; p < 0.02). Analysis of lipid, lipoprotein and apolipoprotein levels demonstrated an association between the presence of this Asn291Ser substitution and decreased HDL-cholesterol (0.94 +/- 0.31 vs. 1.12 +/- 0.26 mmol/l; p < 0.04) in our controls. FCH patients carrying this mutation showed decreased HDL-cholesterol (0.75 +/- 0.16 vs. 0.95 +/- 0.36 mmol/l; p = 0.05) and increased triglyceride levels (5.96 +/- 4.12 vs. 3.48 +/- 1.78 mmol/l; p < 0.005) compared to non-carriers. The high triglyceride and low HDL-cholesterol phenotype in carriers of this substitution was most obvious when BMI exceeded 27 kg/m2. Our study of male FCH patients revealed the presence of a common mutation in the LPL-gene that is associated with lipoprotein abnormalities, indicating that defective LPL is at least one of the factors contributing to the FCH-phenotype.
Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
P W
PW
Reymer
B E
BE
Groenemeyer
E
E
Gagné
L
L
Miao
E E
EE
Appelman
J C
JC
Seidel
D
D
Kromhout
S M
SM
Bijvoet
K
K
van de Oever
T
T
Bruin
D001216:Asparagine / Q000235:genetics*; D001483:Base Sequence; D017931:DNA Primers; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000235:genetics*; D008074:Lipoproteins / Q000097:blood; D008297:Male; D008969:Molecular Sequence Data; D017354:Point Mutation; D012694:Serine / Q000235:genetics*
D017931:DNA Primers; D008055:Lipids; D008074:Lipoproteins; D012694:Serine; D001216:Asparagine; D008071:Lipoprotein Lipase