Lipoproteins: Genetic Disorders

Abstract

AbstractThe primary function of plasma lipoproteins is to transport newly synthesised or dietary lipids in the circulation; these water‐insoluble substances include triacylglycerol, cholesterol and fat‐soluble vitamins. Mutations in genes for the many enzymes, receptors and structural proteins that regulate lipoprotein metabolism and transport are often detrimental to health, and may increase the amount of normal lipoproteins, result in accumulation of abnormal lipoproteins or cause lipoprotein deficiencies. Some defects increase the risk of coronary heart disease, whereas other deficiency disorders cause neurological and/or gastrointestinal symptoms. Genetic disorders of lipoprotein metabolism highlight the importance of lipid transport and metabolism in normal human physiology.Key ConceptsNormal regulation of plasma lipoprotein metabolism is critical for transport of lipids and fat‐soluble vitamins in the circulation.Once secreted from cells in the liver or intestine, lipoproteins undergo many complex metabolic changes in the blood circulation brought about by enzymes and their cofactors, exchange factors and cell‐surface receptors.Variation in the genes for these proteins can alter their function and cause changes in the composition, concentration and/or function of plasma lipoproteins that are frequently deleterious to health.Several defects in lipoprotein metabolism result in increased risk of premature coronary heart disease because of cholesterol deposition in the blood vessels, whereas others lead to neurological symptoms due to deficiency of fat‐soluble vitamins.The inheritance pattern varies: most known lipoprotein disorders are monogenic, with either autosomal dominant inheritance, where heterozygous carriers are affected or autosomal recessive inheritance, where heterozygous carriers are apparently unaffected. Some dominantly inherited disorders have a gene dosage effect, where homozygous individuals are more severely affected than heterozygous ones.Some gene variants only have a marked physiological effect in a particular genetic or environmental background, so not all carriers are affected.Families exist who have a clinical phenotype characteristic of a known monogenic disorder, but who have no detectable defect in the known causal genes; this suggests that novel genes still remain to be identified that influence lipoprotein metabolism.One of the commonest inherited disorders, familial combined hyperlipidaemia, is not monogenic and requires several gene variants to be present for symptoms to be manifest. These variants are also unlikely to be the same for all families.