title: Identification of a novel C5L2 variant (S323I) in a French Canadian family with familial combined hyperlipemia.
abstract: 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.
  
  
  RESULTS
  DNA sequencing of C5L2 coding region in 61 unrelated probands identified a heterozygous variant (G968-->T) in 1 subject, resulting in Ser323-->Ile 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).
  
  
  CONCLUSIONS
  The S323I variant may alter C5L2 function and might be one molecular basis contributing to familial combined hyperlipidemia.
authors.affiliation: Centre de Recherche Hôpital Laval, Université Laval, Y2186, 2725 Chemin Ste Foy, Ste Foy, Québec, G1V 4G5.
authors.forename: Michel
authors.initials: M
authors.lastname: Marcil
authors.forename: Hai
authors.initials: H
authors.lastname: Vu
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Zari
authors.initials: Z
authors.lastname: Dastani
authors.forename: James C
authors.initials: JC
authors.lastname: Engert
authors.forename: Daniel
authors.initials: D
authors.lastname: Gaudet
authors.forename: Manuel
authors.initials: M
authors.lastname: Castro-Cabezas
authors.forename: Allan D
authors.initials: AD
authors.lastname: Sniderman
authors.forename: Jacques
authors.initials: J
authors.lastname: Genest
authors.forename: Katherine
authors.initials: K
authors.lastname: Cianflone
mesh_terms: D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D001692:Biological Transport; D002170:Canada / Q000208:ethnology; D003176:Complement C3 / Q000378:metabolism; D005260:Female; D005602:France / Q000208:ethnology; D014644:Genetic Variation; D005947:Glucose / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000097:blood / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D011792:Quebec; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine / Q000235:genetics*; D014280:Triglycerides / Q000096:biosynthesis
chemical_list: C417003:C5aR2 protein, human; D003176:Complement C3; D008055:Lipids; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine; D014280:Triglycerides; D005947:Glucose