Lipoprotein Glomerulopathy: Molecular Characterization of Three Italian Patients and Literature Survey

Abstract Background: Lipoprotein glomerulopathy (LPG) is a rare kidney disease, mainly reported in Asian subjects, linked with rare APOE gene mutations resulting in a structurally abnormal Apolipoprotein E (ApoE), the plasma accumulation of lipoprotein remnants and the formation of lipid thrombi in glomerular capillaries. This study reports the molecular characterization of three unrelated Italian patients with long standing LPG. Methods: We sequenced the APOE gene in the LPG patients and their family members and determined the haplotype cosegregating with the APOE mutation. We also sequenced other genes and looked at the distribution of common SNPs, known to be involved in lipoprotein metabolism. Finally we reviewed the LPG cases reported in the literature. Results: The three patients showed the clinical, biochemical and histological features of LPG. They were found to be heterozygous for the APOE c.527 G>C, p.(Arg176Pro) mutation, previously reported in two Japanese subjects. Five patients’ relatives, carrying the mutation, were free of LPG. The mutation co-segregated with the same haplotype in all carriers, suggesting a common ancestor. The search for additional genetic variants promoting plasma accumulation of lipoprotein remnants failed to show differences between APOE mutation carriers with or without LPG. The literature survey showed that 145 LPG cases had been clinically described and rare APOE mutations had been documented in102. The analysis of 95 fully characterized LPG cases suggests that the phenotypic expression of the disease in APOE mutation carriers mainly depend on the plasma accumulation of lipoprotein remnants above a threshold value. Indeed, APOE mutation carriers without LPG had lower plasma lipids than carriers with LPG. Conclusions: The p.(Arg176Pro) substitution in ApoE is associated with LPG in Caucasians. However, as in the case of other rare APOE mutations found in other populations, this mutation is necessary but not sufficient for the development of LPG