Autosomal recessive hypercholesterolemia: genetics and clinical aspects

Abstract

In the last 10 years, new types of genetic hypercholesterolemia, different from familial hypercholesterolemia (FH) or familial defective apo B (FDB), have been reported; these forms have both autosomal dominant or recessive inheritance. Starting in 1995, we have described a new recessive type of hypercholesterolemia, named ARH. This disease, initially reported in one Sardinian family, is characterized by a severe increase of low-density lipoproteins (LDL) in plasma, xanthomas, xanthelasmas, and premature coronary heart disease. The family showed presence of consanguinity, bimodal distribution of cholesterol levels, and absence of vertical transmission. We have demonstrated that this hypercholesterolemia is due to a marked reduction of LDL catabolism that is caused by a selective reduction of LDLs uptake by the liver. The gene responsible for ARH maps to chromosome 1p35. It codes for an adaptor protein that interacts with the NPXY sequence in the cytoplasmic tail of LDL-R, and is necessary for the functioning of LDL-R in liver, but not in fibroblasts. Only two mutations were identified in Sardinia; a single base pair insertion in exon 4 (ARH1), and a nonsense mutation at codon 22 (ARH2). The high frequency of ARH in the island is probably due to a combination of genetic drift, consanguinity, and geographic isolation.