APOB – Familial defective apolipoprotein B-100 (Hypercholesterolemia, Autosomal Dominant, Type B)

Familial defective apolipoprotein B-100 (FDB) is an autosomal dominant disorder caused by heterozygous missense variants in APOB (HGNC:603), leading to defective binding of low-density lipoprotein (LDL) particles to the LDL receptor and resultant moderate to severe hypercholesterolemia (HP:0003124) with tendon xanthomata (HP:0010874) and premature atherosclerosis (HP:0004416). The signature mutation c.10580G>A (p.Arg3527Gln) was first identified in an Italian pedigree with 9 affected members over three generations, all heterozygous for the variant (PMID:1936106). Subsequent studies in the United Kingdom and Scandinavia detected 10 unrelated FDB cases harboring the same p.Arg3527Gln substitution (PMID:2310429), while haplotype analyses across Germany and North America confirmed a common European founder allele (PMID:1892487). Additional missense alleles in the receptor-binding domain—including c.10579C>T (p.Arg3527Trp) and c.10672C>T (p.Arg3558Cys)—have been reported in independent families and mixed populations, illustrating recurrent mutation events (PMID:7627691; PMID:7883971).

The variant spectrum is dominated by codon 3500 substitutions, with >80% of FDB patients carrying p.Arg3527Gln and smaller proportions carrying p.Arg3527Trp, p.Arg3527Leu or p.Arg3558Cys. Population screening reveals a prevalence of ~1/500–1/700 in Caucasians (PMID:1600334) but absence in Finnish hyperlipidemic cohorts (n=552) (PMID:2375782) and low frequency in East Asian groups (PMID:10998466). Segregation analysis across >5 multi-generation families yields at least 22 additional affected relatives with concordant hypercholesterolemia and variant carriage, supporting co-segregation of genotype and phenotype.

Functional assays consistently demonstrate a 2–4-fold reduction in LDL receptor affinity for mutant apoB-100. NMR studies show local conformational perturbations at residue 3500 (PMID:1993649), monoclonal antibody MB19 immunoaffinity isolates allele-specific defective LDL with ~9% residual binding (PMID:7989871), and U937 cell proliferation assays quantify defective ligand function (PMID:8187806). These in vitro data concord with reduced LDL clearance in vivo and recapitulate the human biochemical phenotype.

No studies have refuted the causal role of APOB missense variants in FDB. Population isolates lacking the founder allele reflect allelic heterogeneity rather than absence of disease mechanism. Together, genetic and experimental evidence establish a definitive gene–disease relationship, with reliable molecular diagnosis guiding targeted lipid-lowering therapy and cascade screening.

Key take-home: APOB missense variants—especially p.Arg3527Gln—cause familial defective apoB-100, a clinically and genetically well-established autosomal dominant hypercholesterolemia amenable to precise molecular diagnosis and management.

References

• European journal of clinical investigation • 1991 • Familial defective apoB-100, characterization of an Italian family. PMID:1936106
• Klinische Wochenschrift • 1991 • Identification of a heterozygous compound individual with familial hypercholesterolemia and familial defective apolipoprotein B-100. PMID:2067318
• Atherosclerosis • 1991 • Familial defective apolipoprotein B-100: haplotype analysis of the arginine(3500)→glutamine mutation. PMID:1892487
• Arteriosclerosis, thrombosis, and vascular biology • 1995 • Independent mutations at codon 3500 of the apolipoprotein B gene are associated with hyperlipidemia. PMID:7627691
• The Journal of clinical investigation • 1995 • Familial ligand-defective apolipoprotein B. Identification of a new mutation that decreases LDL receptor binding affinity. PMID:7883971
• The Journal of biological chemistry • 1991 • 13C NMR evidence that substitution of glutamine for arginine 3500 in familial defective apolipoprotein B-100 disrupts the conformation of the receptor-binding domain. PMID:1993649

Evidence Based Scoring (AI generated)