APOB – Homozygous Familial Hypercholesterolemia

APOB encodes apolipoprotein B-100, the principal ligand for the LDL receptor. Biallelic pathogenic variants in APOB have been reported in a subset of patients with homozygous familial hypercholesterolemia (HoFH), a condition characterized by markedly elevated LDL-cholesterol levels and premature atherosclerotic cardiovascular disease. HoFH due to APOB follows an autosomal dominant inheritance pattern with codominant allele effects.

Genetic Evidence. In a Spanish registry of 97 molecularly confirmed HoFH patients, one individual was a true APOB homozygote and two were compound heterozygotes for APOB variants, without segregation data reported (PMID:27784735). These three probands carried missense changes in APOB, including the recurrent c.10580G>A (p.Arg3527Gln) variant, which has been observed across multiple populations and acts as a founder allele in some cohorts.

Variant Spectrum. APOB variants in HoFH are predominantly missense substitutions clustering in the LDL-receptor binding domain. The most widely studied is c.10580G>A (p.Arg3527Gln), which disrupts receptor affinity. Other functional variants include c.10672C>T (p.Arg3558Cys) and c.10579C>T (p.Arg3527Trp), illustrating allelic heterogeneity.

Functional Evidence. In vitro receptor-binding assays demonstrate that p.Arg3527Gln reduces LDL receptor binding by >60% compared with wild-type LDL (PMID:1993649, PMID:7989871). Competitive binding studies in cell lines and dynamic light-scattering confirm that p.Arg3531Cys and p.Arg3558Cys similarly impair LDL uptake (PMID:9254062). These data support a loss-of-function mechanism leading to LDL-cholesterol accumulation.

Clinical Correlation. Patients with APOB-related HoFH present with tendon and cutaneous xanthomas (HP:0000964), accelerated atherosclerosis (HP:0004943), and early cardiovascular events despite maximal lipid-lowering therapy. The phenotype overlaps with LDLR-mediated HoFH but may show variable therapy response.

Key Take-Home. APOB pathogenic variants contribute a limited but clinically important fraction of HoFH; genetic testing of APOB should be included in comprehensive HoFH panels to inform diagnosis and guide specialized management.

References

• Circulation: Cardiovascular Genetics • 2016 • Homozygous Familial Hypercholesterolemia in Spain: Prevalence and Phenotype-Genotype Relationship PMID:27784735
• 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
• Journal of Lipid Research • 1994 • Isolation of allele-specific, receptor-binding-defective low density lipoproteins from familial defective apolipoprotein B-100 subjects PMID:7989871
• Journal of Lipid Research • 1997 • Association of genetic variations in apolipoprotein B with hypercholesterolemia, coronary artery disease, and receptor binding of low density lipoproteins PMID:9254062

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