Objective-Mutations of the ANGPTL3 gene have been associated with a novel form of primary hypobetalipoproteinemia, the combined hypolipidemia (cHLP), characterized by low total cholesterol and low HDL-cholesterol levels. The aim of this work is to define the role of ANGPTL3 gene as determinant of the combined hypolipidemia phenotype in 2 large cohorts of 913 among American and Italian subjects with primary hypobetalipoproteinemia (total cholesterol Ͻ5th percentile). Methods and Results-The combined hypolipidemia cut-offs were chosen according to total cholesterol and HDL-cholesterol levels reported in the ANGPTL3 kindred described to date: total cholesterol levels, Ͻ2nd percentile and HDL-cholesterol, levels Ͻ2nd decile. Seventy-eight subjects with combined hypolipidemia were analyzed for ANGPTL3 and APOB genes. We identified nonsense and/or missense mutations in ANGPTL3 gene in 8 subjects; no mutations of the APOB gene were found. Mutated ANGPTL3 homozygous/compound heterozygous subjects showed a more severe biochemical phenotype compared to heterozygous or ANGPTL3 negative subjects, although ANGPTL3 heterozygotes did not differ from ANGPTL3 negative subjects. Conclusion-These results demonstrated that in a cohort of subjects with severe primary hypobetalipoproteinemia the prevalence of ANGPTL3 gene mutations responsible for a combined hypolipidemia phenotype is about 10%, whereas mutations of APOB gene are absent. Key Words: epidemiology Ⅲ lipoproteins Ⅲ genetics Ⅲ hypobetalipoproteinemia P rimary hypobetalipoproteinemia (pHBL) is a monogenic condition inherited as a dominant or recessive trait 1 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, 1,2 causing the familial hypobetalipoproteinemia (FHBL). The clinical phenotype of heterozygous FHBL is usually mild, being frequently characterized by fatty liver and levels of APOB and LDL-C reduced by 60%. 1,2 The homozygous or compound heterozygous APOB mutations are in some cases responsible for a more severe biochemical and clinical phenotype, similar to the abetalipoproteinemia (ABL) due to homozygous mutations in the MTP gene, characterized 3,4 by intestinal malabsorption, pigmentary retinal degeneration, ataxic neuropathy, and almost undetectable levels of LDL-C and APOB.Recently mutations in the PCSK9 gene have been identified as cause of FHBL in kindred of African American 5 and Caucasian 6 descent. These mutations are associated with a pHBL phenotype that is not complicated by fatty liver as shown in FHBL due to APOB gene mutations.Mutations in the ANGPTL3 gene have been recently identified in a kindred affected by "familial combined hypolipidemia." 7 The affected members of the kindred were found to be compound heterozygous for 2 ANGPTL3 nonsense mutations and their lipid profile was characterized by low levels of TC, triglycerides (TG), LDL-C, and high-densi...

Objective In familial hypobetalipoproteinemia (FHBL), fatty liver is a characteristic feature, and there are several reports of associated cirrhosis and hepatocarcinoma. We investigated a large kindred in which low-density lipoprotein (LDL) cholesterol, fatty liver and hepatocarcinoma displayed an autosomal dominant pattern of inheritance. Approach and Results The proband was a 25 year-old female with low plasma cholesterol and hepatic steatosis. Low plasma levels of total cholesterol and fatty liver were observed in 10 more family members; 1 member was affected by liver cirrhosis and four more subjects died of either hepatocarcinoma or carcinoma on cirrhosis. To identify the causal mutation in this family, we performed exome sequencing in two participants with hypocholesterolemia and fatty liver. Approximately 22,400 single nucleotide variants were identified in each sample. After variant filtering, 300 novel shared variants remained. A nonsense variant, p.K2240X due to an A>T mutation in exon 26 of APOB (c.6718A>T) was identified and this variant was confirmed by Sanger sequencing. The gentotypic analysis of 16 family members in total showed that this mutation segregated with the low cholesterol trait. In addition, genotyping of the PNPLA3 p.I148M did not show significant frequency differences between carriers and non-carriers of the c.6718A>T APOB gene mutation. Conclusions We used exome sequencing to discover a novel nonsense mutation in exon 26 of APOB (p.K2240X) responsible for low cholesterol and fatty liver in a large kindred. This mutation may also be responsible for cirrhosis and liver cancer in this family.