on April 20, 2006
Published online before print April 20, 2006, doi: 10.1161/01.ATV.0000222907.72985.0b
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Submitted on December 8, 2005
Accepted on April 6, 2006
Identification of a Novel C5L2 Variant (S323I) in a French Canadian Family With Familial Combined Hyperlipemia
Michel Marcil ;
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.
* To whom correspondence should be addressed. 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 (G968
T) 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 (Bmax). 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.
Key words: acylation-stimulating protein • adipose • C3adesArg • gene defect • G protein-coupled receptor • hyperapolipoprotein B • triglyceride synthesis
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