Identification of a novel ANGPTL3 mutation splicing associeted to severe hypobetalipoproteinemia

Introduction. Primary hypobetalipoproteinemia (pHBL) is a monogenic heterogeneous condition inherited as a dominant or recessive trait characterized by total cholesterol (TC) and/or LDL cholesterol (LDL-C) and/or apolipoprotein B (APOB) levels below the 5th percentile of the reference population. Heterozygous APOB gene mutations are responsible for the majority of the dominant pHBL causing the familial hypobetalipoproteinemia (FHBL). Loss-of-function mutations in the PCSK9 gene also cause FHBL. Familial combined hypolipidemia is a recently discovered dyslipidemic phenotype characterized by low levels of TC, triglycerides (TG), LDL-C, and high-density lipoprotein cholesterol (HDL-C). The genetic cause of familial combined hypolipidemia has been attributed to mutations in the ANGPTL3 gene. methods and Results. In this report we describe a case of a young men with severe hypolipidemia characterized by low levels of total cholesterol, triglycerides and HDL- (54 mg/dl, 26 mg/dl, 17 mg/dl respectively). The proband’s mother and father showed normal plasma lipid values suggesting a recessive mode of inheritance of the phenotype. In order to identify the molecular defects the analysis of MTP and SARA2 genes was carried out and no mutations were identified in both genes. We extended our analysis to the other known genes responsible for pHBL and we were able to identify in the ANGPTL3 gene a novel splicing mutation (insT+3, IVS5) in homozigosity. Both parents were carriers of the same mutation in heterozygosity. InsT+3, IVS5 is predict to alter the correct splicing as predicted by in silico analysis. Conclusion. We describe a clinical case with severe hypolipidemia with a recessive mode of inheritance carrying a novel mutation in Intron 5 of ANGPTL3. The mode of inheritance and the clinical implications of familial combined hypolipidemia need to be further characterized