Quagliarini Fabiana, Vallvé Joan-Carles, Campagna Filomena, Alvaro Adriana, Fuentes-Jimenez Francisco José, Sirinian Maria Isabella, Meloni Francesca, Masana Luis, Arca Marcello
Department of Clinical and Medical Therapy, Unit of Medical Therapy, Sapienza University of Rome, Policlinico Umberto, I Viale del Policlinico 155, 00161 Rome, Italy.
Mol Genet Metab. 2007 Nov;92(3):243-8. doi: 10.1016/j.ymgme.2007.06.012. Epub 2007 Aug 7.
Autosomal recessive hypercholesterolemia (ARH) is a rare genetic defect that causes marked elevation of plasma low-density lipoprotein cholesterol (LDL-C) and premature atherosclerosis. It is due to mutations in the ARH gene that plays a critical role in the internalization of LDL receptor (LDLR) in liver cells. We describe a Spanish family where a 24-year-old proband and his 13-year-old sister showed the typical characteristics of ARH. The proband's LDLR activity in peripheral lymphocytes was 14% of normal and his in vivo LDL catabolism was reduced by 64% compared to normal. Notably, the sister showed normal lipid levels when her umbilical cord blood was tested. In this family, ARH was due to homozygosity for a large approximately 1.6kb deletion that eliminates exon 4 of ARH gene. Analysis of ARH mRNA demonstrated that the fusion of exon 3 to exon 5 during the splicing of the primary transcript changes the reading frame leading to stop codon 7 amino acids downstream in exon 5. No protein product was detected in affected individuals by immunoblot analysis. This novel mutation adds new support to the molecular heterogeneity of ARH in the Mediterranean basin.
