title: The history of Autosomal Recessive Hypercholesterolemia (ARH). From clinical observations to gene identification.
abstract: The most frequent form of monogenic hypercholesterolemia, also known as Familial Hypercholesterolemia (FH), is characterized by plasma accumulation of cholesterol transported in Low Density Lipoproteins (LDLs). FH has a co-dominant transmission with a gene-dosage effect. FH heterozygotes have levels of plasma LDL-cholesterol (LDL-C) twice normal and present xanthomas and coronary heart disease (CHD) in adulthood. In rare FH homozygotes plasma LDL-C level is four times normal, while xanthomas and CHD are present from infancy. Most FH patients are carriers of mutations of the LDL receptor (LDLR); a minority of them carry either mutations in the Apolipoprotein B (ApoB), the protein constituent of LDLs which is the ligand for LDLR, or gain of function mutations of PCSK9, the protein responsible for the intracellular degradation of the LDLR. From 1970 to the mid 90s some publications described children with the clinical features of homozygous FH, who were born from normocholesterolemic parents, strongly suggesting a recessive transmission of FH. In these patients the involvement of LDLR and APOB genes was excluded. Interestingly, several patients were identified in the island of Sardinia (Italy), whose population has a peculiar genetic background due to geographical isolation. In this review, starting from the early descriptions of patients with putative recessive hypercholesterolemia, we highlight the milestones that led to the identification of a novel gene involved in LDL metabolism and the characterization of its encoded protein. The latter turned out to be an adaptor protein required for the LDLR-mediated endocytosis of LDLs in hepatocytes. The loss of function of this protein is the cause of Autosomal Recessive Hypercholesterolemia (ARH).
authors.affiliation: Department of Clinical & Experimental Medicine, Section of Internal Medicine, Gerontology & Nutrition, University of Ferrara, Via A. Moro, 8, I-44124 Ferrara, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Fellin
authors.affiliation: Department of Internal Medicine and Allied Sciences, Atherosclerosis Center, Sapienza University of Rome, Policlinico Umberto I, Viale del Policlinico, 00161 Rome, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Arca
authors.affiliation: Department of Clinical & Experimental Medicine, Section of Internal Medicine, Gerontology & Nutrition, University of Ferrara, Via A. Moro, 8, I-44124 Ferrara, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Zuliani
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, University of Modena & Reggio Emilia, Via Campi 287, I-41125 Modena, Italy. Electronic address: sebcal@unimore.it.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Calandra
authors.affiliation: Department of Internal Medicine, University of Genova, Viale Bendetto XV, I-16132 Genova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bertolini
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000097:blood / Q000235:genetics*; D000818:Animals; D004252:DNA Mutational Analysis; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D049673:History, 20th Century; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics* / Q000266:history / Q000473:pathology; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics / Q000473:pathology; D008297:Male; D010375:Pedigree; D006952:Hyperlipoproteinemia Type III
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C469745:LDLRAP1 protein, human
keywords: Autosomal Recessive Hypercholesterolemia; Familial Hypercholesterolemia; Low Density Lipoprotein Receptor; Low Density Lipoproteins