Table 1: The Clinical Effects of loss-of-function in Lipoprotein-Binding Proteins Examined in this Review and their Translational Models.

A variety of lipoprotein-associated disorders arise from mutations in lipoprotein binding proteins or their chaperones. Clinical loss-of-function mutations in the genes coding for ApoB, LDLR, LPL, HL, and RAP lead to changes in plasma lipoprotein levels and lipid transport. Similarly, loss-of-function mutations in their specialized chaperones (RAP, LMF1, MTP) lead to similar lipid disorders. Transgenic loss-of-function mouse models have been generated for most of these genes and underscore the importance of these genes in lipid homeostasis.

Causative Gene	Associated Disorder	Mouse model	Clinical Manifestation	References
ApoB	Familial hypobetalipoproteinemia	Embryonic lethality in knockout animals, reduced plasma triglycerides in heterozygous mutants	Reduced plasma total cholesterol, LDL cholesterol, and ApoB levels, hepatic steatosis, fat-soluble vitamin deficiency.	Schonfeld et al. 2003; Chen et al. 2002; Farese et al. 1995
LDLR	Familial hypercholesterolemia	Elevated plasma LDL cholesterol in knockout animals	Elevated plasma LDL cholesterol, increased risk of ischemic heart disease	Hobbs et al. 1992; Usifo et al. 2012; Marks et al. 2003
LPL	Familial LPL deficiency	Severe hypertriglyceridemia, neonatal death	Severe hypertriglyceridemia (chylomicronemia) eruptive xanthomas, increased risk of pancreatitis.	Wittrup et al. 1999; Rodrigues et al. 2016; Weinstock et al. 1995
HL	Hepatic Lipase Deficiency	Mild increase in total cholesterol, increased HDL cholesterol.	Elevated plasma HDL, no change in plasma triglycerides, increased risk of ischemic heart disease.	Homanics et al., 1995. Andersen et al. 2003
RAP	Myopia	Whole-animal knockout causes elevated plasma LDL and TGs	Severe myopia and retinal degeneration.	Aldahmesh et al. 2013; Willnow et al. 1995
LMF1	Combined Lipase Deficiency	Embryonic lethality in homozygous knockout animals	Reduced post-heparin LPL activity, severe hypertriglyceridemia, increased risk of pancreatitis.	Serveaux Dancer et al. 2018; Peterfy et al. 2007; Ehrhardt et al. 2014
MTP	Abetalipoproteinemia	Whole-animal homozygous knockout is embryonic lethal, heterozygous animals display reduced plasma lipoproteins	Fat malabsorption, hepatomegaly, hypocholesterolemia, low plasma apoB, low plasma triglycerides, fat-soluble vitamin deficiency.	Wetterau et al. 1992; Ramasamy 2016