Last Updated: June 29, 2024
Clinical Features of APOB Truncation Mutations
Familial hypobetalipoproteinemia (FHBL) is an autosomal dominant disorder that is most commonly due to truncating loss-of-function mutations in the APOB gene. The characteristic features of FHBL, caused by these APOB truncating mutations, are low plasma concentrations of total cholesterol, LDL cholesterol (LDL-C), and apoB-100. Typical findings in these patients are plasma apoB-100 levels that are <25% of normal and LDL-C of 20mg/dL–50mg/dL (normal optimal levels should be <100mg/dL with the normal range considered to be 100mg/dL–129mg/dL).
The lack of apoB-100 synthesis in the liver results in a nearly 75% reduction in VLDL production and secretion. Due to the role of hepatic VLDL secretion in overall triglyceride metabolism in the liver, patients with FBHL are at risk for hepatic steatosis. Unlike in the case of metabolic dysfunction-associated fatty liver disease (MAFLD), the fatty infiltration observed in the livers of FHBL patients does not appear to be associated with hepatic or peripheral insulin resistance. However, several FHBL patients have developed steatohepatitis, cirrhosis, and hepatocellular carcinoma as a result of the triglyceride accumulation in the liver. MAFLD is the preferred designation for the hepatic disease that was originally defined as non-alcoholic fatty liver disease, NAFLD.
Molecular Biology of APOB
The APOB gene is located on chromosome 2p24.1 and is composed of 29 exons that encode an apoB-100 precursor protein of 4563 amino acids. In the liver the full-length apoB protein is generated and the nomenclature used for this protein is apoB-100, signifying 100% of the coding region of the apoB mRNA. Within the small intestines the apoB mRNA is edited at amino acid 2180 resulting in the conversion of a CAA codon (glutamine) to a stop codon (UAA). This editing results in the generation of a smaller apoB protein in the small intestines, designated apoB-48, signifying 48% of the coding capacity of the apoB mRNA.
Over 60 mutations producing truncations in the APOB gene have been identified as causes of FHBL. The largest percentage of truncating APOB mutations in FHBL are found in exon 29. The nomenclature of the truncated apoB-100 proteins refers to the percentage of the protein remaining relative to full-length apoB-100. The various truncations found in FHBL, using the percentile nomenclature, are apoB-2 to apoB-89.
Pharmacology of APOB
Because truncating mutations in the APOB gene, in FHBL patients, result in low serum LDL-C, the pharmacologic targeting of apoB for treatment of hypercholesterolemia has been under intense development. The drug called mipomersen is a synthetic single strand anti-sense oligonucleotide (ASO) to the apoB mRNA and represents the first ASO approved as a drug by the US FDA. Mipomersen is solely used in the treatment of patients with homozygous familial hypercholesterolemia. Injection of mipomersen in these patients is associated with a reduction of LDL-C by up to 25%.