ANGPTL3 – Familial Combined Hypolipidemia (FHBL2)

Familial combined hypolipidemia, also known as familial hypobetalipoproteinemia 2 (FHBL2), is a rare autosomal recessive disorder caused by biallelic loss-of-function variants in ANGPTL3. Seven unrelated homozygous individuals have been reported, including the first Japanese case (1 proband ([PMID:38699738])) and six S17X homozygotes in a metabolomic study ([PMID:30816800]). The phenotype is characterized by extreme reductions in LDL-cholesterol and triglycerides without overt complications.

Genetic evidence supports a Moderate clinical validity: 7 homozygous probands with biallelic ANGPTL3 LOF variants ([PMID:38699738], [PMID:30816800]), consistent lipid phenotype, but limited familial segregation data. The inheritance is autosomal recessive, and no additional affected relatives have been described.

The variant spectrum in FHBL2 includes homozygous truncating or frameshift alleles. Notably, c.439_442del (p.Asn147_Asp177del) abolishes the coiled-coil domain, leading to undetectable serum ANGPTL3 and LDL-C of 34 mg/dL without steatorrhea or atherosclerosis ([PMID:38699738]). Heterozygous carriers of LOF variants exhibit mild lipid changes without clinical disease.

Mechanistically, ANGPTL3 is a liver-secreted inhibitor of lipoprotein lipase (LPL). Proteolytic cleavage at Arg221↓Ala222 and Arg224↓Thr225 is required for activation of its N-terminal domain, which inhibits LPL and raises plasma triglycerides in mice ([PMID:12909640]). A cleavage-resistant mutant shows reduced hypertriglyceridemic activity, confirming activation by processing.

Functional studies in human knockouts and animal models demonstrate that complete absence of ANGPTL3 increases postheparin LPL activity, lowers free fatty acids, enhances fatty acid β-oxidation, and abolishes postprandial TRL elevation without adverse compensatory effects ([PMID:23661675], [PMID:30816800]). Threshold analyses in 19 families revealed that hypolipidemic effects require plasma ANGPTL3 <25% of normal, with secondary increases in PCSK9 furin-cleavage promoting LDL clearance ([PMID:28633452]).

No conflicting evidence disputes the ANGPTL3–FHBL2 association. In sum, genetic and experimental data coherently link ANGPTL3 deficiency to FHBL2. Additional segregation studies could further solidify the association. Key take-home: ANGPTL3 LOF variants cause autosomal recessive FHBL2, providing a validated target for LDL-lowering therapies.

References

• Heliyon • 2024 • The first Japanese case with familial combined hypolipidemia without any complications caused by loss-of function variants in ANGPTL3: Case report. PMID:38699738
• Journal of Biological Chemistry • 2003 • Protein region important for regulation of lipid metabolism in angiopoietin-like 3 (ANGPTL3): ANGPTL3 is cleaved and activated in vivo. PMID:12909640
• Journal of Clinical Investigation • 2009 • Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. PMID:19075393
• Journal of Clinical Endocrinology and Metabolism • 2017 • Threshold Effects of Circulating Angiopoietin-Like 3 Levels on Plasma Lipoproteins. PMID:28633452
• Arteriosclerosis, Thrombosis, and Vascular Biology • 2019 • Metabolomic Signature of Angiopoietin-Like Protein 3 Deficiency in Fasting and Postprandial State. PMID:30816800

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