APOE – Type III Hyperlipoproteinemia

Type III hyperlipoproteinemia (dysbetalipoproteinemia) is a lipid disorder characterized by impaired remnant clearance, presenting with equimolar elevations of plasma cholesterol and triglycerides and cutaneous xanthomas. The disorder is primarily linked to dysfunctional variants of the apolipoprotein E gene (APOE), which encodes a ligand for hepatic uptake of chylomicron and VLDL remnants. Individuals affected exhibit mixed hyperlipidemia, premature atherosclerosis, and respond variably to diet and lipid-lowering therapy.

1 Assess Clinical Validity

Overall validity: Definitive
Rationale: Over 100 unrelated probands with APOE rare variants, multi-family segregation, and extensive concordant functional data support a definitive gene–disease link.

2 Genetic Evidence

Inheritance is autosomal recessive, most commonly due to homozygosity for APOE*2 (Arg158→Cys) or rare loss-of-function alleles. An index case carrying APOE1 (Gly127→Asp, Arg158→Cys) with epsilon1/“null” genotype exhibited severe type III HLP and excellent therapeutic response (PMID:1392432).

Segregation analyses demonstrated affected relatives carrying a 10-bp deletion in exon 4 (bp 4037–4046) leading to truncated ApoE, with 10 heterozygotes showing remnant accumulation and elevated lipids (PMID:8571954).

Case series encompassing 86 unrelated probands have identified 24 distinct APOE variants associated with autosomal dominant familial dysbetalipoproteinemia (PMID:39684364). The variant spectrum includes missense substitutions (e.g., c.487C>T (p.Arg163Cys)), frameshifts, nonsense, and splice mutations, with both recurrent and unique alleles across populations.

3 Functional / Experimental Evidence

Mechanistically, pathogenic variants impair receptor binding to LDLR and heparan sulfate proteoglycans, reducing remnant uptake. Recombinant Cys142 ApoE variants bind receptors at 20% of normal activity (PMID:1730728). Rare Gly127Asp and Arg132Cys mutants increase macrophage cholesterol uptake and fail to rescue remnant clearance in vitro (PMID:7883834). Transgenic models confirm variant-specific lipid phenotypes and age-dependent atherosclerosis.

4 Integration & Clinical Utility

The combined genetic and functional evidence establishes APOE sequencing as critical for diagnosis of type III HLP, guiding family screening and therapeutic interventions. Genetic testing enables identification of atypical dominant variants beyond classical E2/E2 homozygosity, informing statin/fibrate use. Key take-home: APOE genotyping improves diagnostic accuracy and personalized management in dysbetalipoproteinemia.

References

• International journal of molecular sciences • 2024 • Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia. PMID:39684364
• American journal of human genetics • 1996 • A 10-bp deletion in the apolipoprotein epsilon gene causing apolipoprotein E deficiency and severe type III hyperlipoproteinemia. PMID:8571954
• The Journal of biological chemistry • 1992 • The functional characteristics of a human apolipoprotein E variant (cysteine at residue 142) may explain its association with dominant expression of type III hyperlipoproteinemia. PMID:1730728
• The Journal of clinical endocrinology and metabolism • 1995 • Identification, molecular characterization, and cellular studies of an apolipoprotein E mutant (E1) in three unrelated families with hyperlipidemia. PMID:7883834
• The Clinical investigator • 1992 • Response to therapy of a type III hyperlipoproteinemic subject with the rare apolipoprotein E1 (Gly127----Asp, Arg158----Cys) variant. PMID:1392432

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