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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1619.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Identification of a Novel C5L2 Variant (S323I) in a French Canadian Family With Familial Combined Hyperlipemia

Michel Marcil; Hai Vu; Wei Cui; Zari Dastani; James C. Engert; Daniel Gaudet; Manuel Castro-Cabezas; Allan D. Sniderman; Jacques Genest, Jr; Katherine Cianflone

From Centre de Recherche Hôpital Laval (W.C., K.C.), Université Laval, Québec, Canada; Mike Rosenbloom Laboratory for Cardiovascular Research (H.V., W.C., A.D.S., K.C.) and Laboratory of Cardiovascular Genetics (Z.D., J.G.), Division of Cardiology (J.C.E.), Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada; Dyslipidemia, Diabetes, and Atherosclerosis Group and Community Genomics Research Centre (D.G.), Université de Montréal and Complexe Hospitalier de la Sagamie, Chicoutimi, Québec, Canada; Department of Internal Medicine (M.C.-C.), Endocrinology and Vascular Medicine, St Franciscus Gasthuis, Rotterdam, the Netherlands.

Correspondence to Katherine Cianflone, PhD, Centre de Recherche Hôpital Laval, Y2186, 2725 Chemin Ste Foy, Ste Foy, Québec, G1V 4G5. E-mail katherine.cianflone{at}crhl.ulaval.ca

Objective— A functional acylation stimulating protein (ASP) receptor, C5L2, has been recently identified in ASP-responsive cells. Impaired ASP-mediated triglyceride synthesis has previously been described in a subset of hyperapolipoprotein B/familial combined hyperlipidemia subjects.

Methods and Results— DNA sequencing of C5L2 coding region in 61 unrelated probands identified a heterozygous variant (G968T) in 1 subject, resulting in Ser323Ile substitution in the carboxyl terminal region. This variant was not detected in 2176 additional chromosomes by restriction fragment length polymorphism or fluorescence polarization genotyping. Eight family members of the proband were identified with one altered (+/–)C5L2 allele. Nine other family members had the wild-type (+/+)C5L2 sequence. The abnormal allele was associated with increased plasma triglyceride, plasma cholesterol, low-density lipoprotein (LDL) cholesterol, apolipoprotein B and ASP. Of 23 subjects tested in cell-based ASP bioactivity assays, those with C5L2(+/–) variant (n=2) had a 50% reduction in ASP-stimulated triglyceride synthesis, glucose transport and marked reduction in maximal binding (B_max). By contrast, a C5L2(+/+) family member responded normally, as did hyperapolipoprotein B normal ASP subjects compared with C5L2(+/+) controls (n=6).

Conclusion— The S323I variant may alter C5L2 function and might be one molecular basis contributing to familial combined hyperlipidemia.

DNA sequencing of C5L2-ASP receptor identified a heterozygous Ser323Ile substitution in the carboxyl-terminal region. Eight heterozygous family members demonstrated increased plasma triglyceride, cholesterol, LDL, apolipoprotein B and ASP. C5L2(+/–) cells had reduced ASP response and B_max. S323I may alter C5L2 function and contribute to familial combined hyperlipidemia.

Key Words: acylation stimulating protein • adipose • C3adesArg • gene defect • G protein–coupled receptor • hyperapolipoprotein B • triglyceride synthesis

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