APOB (apolipoprotein B; HGNC:603, NCBI Gene ID 338) is a human locus mapped to chromosome band 2p24.1 that encodes hepatic ApoB-100 (4,536 aa; ~512 kDa) & intestinal RNA-edited ApoB-48 (2,152 aa; ~240 kDa). APOB acts in VLDL, IDL, LDL & Lp(a) assembly, LDLR ligand binding, and intestinal chylomicron transport, together with Apolipoprotein B-100 Protein, Apolipoprotein B-48 Protein, and LDLR (Low-Density Lipoprotein Receptor Gene). Encodes both hepatic ApoB-100 and intestinal ApoB-48 via site-specific C-to-U mRNA editing, serving as the structural scaffold of atherogenic lipoproteins.
VLDL, IDL, LDL & Lp(a) assembly, LDLR ligand binding, and intestinal chylomicron transport
Clinical / Therapeutic Role
Ligand-defective APOB (p.Arg3527Gln) causes familial hypercholesterolemia type 2; truncations cause familial hypobetalipoproteinemia
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 29-exon gene spanning 43 kb at chromosome 2p24.1, featuring an extraordinary 7,572-bp exon 26—the longest internal coding exon in the human genome—which contains codon 2153 (CAA encoding glutamine) targeted by the APOBEC1 cytidine deaminase editosome.
Cellular & Tissue Expression Profile: Transcribed exclusively in hepatic hepatocytes (which lack APOBEC1 and translate full-length 4,536-residue ApoB-100) and small intestinal enterocytes (where APOBEC1 edits cytidine-6666 to uridine, converting codon 2153 CAA to a premature UAA stop codon to produce N-terminal 2,152-residue ApoB-48).
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Each VLDL, IDL, LDL,Lp(a), and chylomicron particle contains exactly one non-exchangeable molecule of ApoB; hepatic ApoB-100 is lipidated in the endoplasmic reticulum by microsomal triglyceride transfer protein (MTTP) and contains the C-terminal basic LDLR-binding domain (residues 3359–3369) missing from ApoB-48.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Heterozygous missense mutations in the receptor-binding domain (classically p.Arg3527Gln, formerly R3500Q) impair LDLR affinity and cause autosomal dominant familial ligand-defective ApoB-100 (FDB / FH2), whereas truncating nonsense or frameshift mutations cause familial hypobetalipoproteinemia (FHBL1) with ultra-low LDL-cholesterol and predisposition to hepatic steatosis.
Therapeutic & Clinical Pharmacology: Clinical plasma ApoB concentration is the definitive measure of total atherogenic particle number; APOB mRNA was directly targeted by the FDA-approved antisense oligonucleotide mipomersen for homozygous familial hypercholesterolemia.