A loss-of-function variant in OSBPL1A predisposes to low plasma HDL cholesterol levels and impaired cholesterol efflux capacity.
Among subjects with high-density-lipoprotein cholesterol (HDL-C) below the 1st percentile in the general population, we identified a heterozygous variant OSBPL1A p.C39X encoding a short truncated protein fragment that co-segregated with low plasma HDL-C.



We investigated the composition and function of HDL from the carriers and non-carriers and studied the properties of the mutant protein in cultured hepatocytes.



Plasma HDL-C and apolipoprotein (apo) A-I were lower in carriers versus non-carriers, whereas the other analyzed plasma components or HDL parameters did not differ. Sera of the carriers displayed a reduced capacity to act as cholesterol efflux acceptors (p < 0.01), whereas the cholesterol acceptor capacity of their isolated HDL was normal. Fibroblasts from a p.C39X carrier showed reduced cholesterol efflux to lipid-free apoA-I but not to mature HDL particles, suggesting a specific defect in ABCA1-mediated efflux pathway. In hepatic cells, GFP-OSBPL1A partially co-localized in endosomes containing fluorescent apoA-I, suggesting that OSBPL1A may regulate the intracellular handling of apoA-I. The GFP-OSBPL1A-39X mutant protein remained in the cytosol and failed to interact with Rab7, which normally recruits OSBPL1A to late endosomes/lysosomes, suggesting that this mutation represents a loss-of-function.



The present work represents the first characterization of a human OSBPL1A mutation. Our observations provide evidence that a familial loss-of-function mutation in OSBPL1A affects the first step of the reverse cholesterol transport process and associates with a low HDL-C phenotype. This suggests that rare mutations in OSBPL genes may contribute to dyslipidemias.
Department of Vascular Medicine, Academic Medical Center (AMC), Amsterdam, The Netherlands.
Mahdi M
MM
Motazacker
Department of Anatomy, Faculty of Medicine, University of Helsinki, Finland.
Juho
J
Pirhonen
Department of Vascular Medicine, Academic Medical Center (AMC), Amsterdam, The Netherlands.
Julian C
JC
van Capelleveen
Minerva Foundation Institute for Medical Research, Helsinki, Finland.
Marion
M
Weber-Boyvat
Department of Pediatrics, Section Molecular Genetics, University Medical Center Groningen, Groningen, The Netherlands.
Jan Albert
JA
Kuivenhoven
Minerva Foundation Institute for Medical Research, Helsinki, Finland.
Saundarya
S
Shah
Department of Vascular Medicine, Academic Medical Center (AMC), Amsterdam, The Netherlands.
G Kees
GK
Hovingh
National Institute for Health and Welfare, Genomics and Biomarkers Unit, Helsinki, Finland.
Jari
J
Metso
Department of Anatomy, Faculty of Medicine, University of Helsinki, Finland.
Shiqian
S
Li
Department of Anatomy, Faculty of Medicine, University of Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland.
Elina
E
Ikonen
National Institute for Health and Welfare, Genomics and Biomarkers Unit, Helsinki, Finland.
Matti
M
Jauhiainen
Department of Vascular Medicine, Academic Medical Center (AMC), Amsterdam, The Netherlands; Department of Experimental Vascular Medicine, AMC, Amsterdam, The Netherlands. Electronic address: g.m.dallinga@amc.nl.
Geesje M
GM
Dallinga-Thie
Department of Anatomy, Faculty of Medicine, University of Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland. Electronic address: vesa.olkkonen@helsinki.fi.
Vesa M
VM
Olkkonen
D000328:Adult; D000368:Aged; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002460:Cell Line; D008076:Cholesterol, HDL / Q000097:blood*; D003600:Cytosol / Q000378:metabolism; D050171:Dyslipidemias / Q000235:genetics; D011992:Endosomes / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D000067996:RAW 264.7 Cells; D011987:Receptors, Steroid / Q000235:genetics*; D015203:Reproducibility of Results; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins; D000098825:Oxysterol Binding Proteins
D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D011987:Receptors, Steroid; D000098825:Oxysterol Binding Proteins; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716465:rab7 GTP-binding proteins, mouse; D049452:Green Fluorescent Proteins; D020691:rab GTP-Binding Proteins
Cholesterol efflux; High-density lipoprotein; OSBPL1A; Oxysterol-binding protein; Rare variant