ABCA1 – Tangier Disease

ABCA1 encodes the ATP-binding cassette transporter A1, also known as cholesterol-efflux regulatory protein, which mediates efflux of cholesterol and phospholipids to apolipoprotein A-I (apoA-I). Loss-of-function variants in ABCA1 lead to near-absent plasma HDL-cholesterol and accumulation of cholesteryl esters in macrophages, defining Tangier disease (TD).

TD follows an autosomal recessive inheritance pattern. Four unrelated families with defective cellular cholesterol efflux were shown to carry biallelic ABCA1 mutations ([PMID:10533863]). Over 30 unrelated TD probands have since been reported with truncating, splice-site, missense, and deep-intronic variants, fulfilling the genetic case series criteria for a strong association.

The spectrum of pathogenic variants includes nonsense, frameshift, splice-site, and missense changes. A recurrent example is c.5038C>T (p.Arg1680Trp) observed in a Japanese TD patient with corneal lipidosis and premature coronary atherosclerosis ([PMID:12111371]). Other variants cluster in nucleotide-binding domains and extracellular loops, underscoring key functional regions of ABCA1.

Clinically, TD patients present with orange-colored tonsils, hepatosplenomegaly, peripheral neuropathy, corneal opacity, and premature coronary artery atherosclerosis (HP:0005181, HP:0009830, HP:0001433, HP:0007957). HDL-C is typically <5 mg/dL, and ApoA-I is markedly reduced, while triglycerides may be normal or elevated.

Functional studies demonstrate that ABCA1 mutations abolish apoA-I-mediated cholesterol efflux in patient fibroblasts and transfected cell lines. The ABCA1 promoter is sterol-responsive via LXR/RXR binding ([PMID:10858438]), and macrophage-specific ABCA1 knockout in apoE-deficient mice accelerates atherosclerosis ([PMID:11950702]). Rescue experiments with wild-type ABCA1 restore cholesterol efflux, confirming a loss-of-function mechanism.

No robust conflicting evidence has emerged; rare isolated low HDL cases without ABCA1 mutations likely reflect other HDL-metabolism genes. Phenotypic variability is modulated by promoter haplotypes and modifier loci, but the core TD phenotype remains specific to biallelic ABCA1 loss.

ABCA1 has a definitive gene-disease relationship with autosomal recessive Tangier disease. Genetic testing for ABCA1 variants is central to diagnosis and family screening. Functional assays of cholesterol efflux can confirm pathogenicity. Therapeutic strategies to enhance ABCA1 expression or activity may ameliorate TD manifestations.

Key Take-home: Biallelic ABCA1 variants cause Tangier disease via defective cholesterol efflux, warranting early genetic diagnosis and targeted management to mitigate atherosclerotic and neurologic complications.

References

• Lancet • 1999 • Mutations in the ABC1 gene in familial HDL deficiency with defective cholesterol efflux PMID:10533863
• The Journal of Biological Chemistry • 2000 • Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor PMID:10858438
• Arteriosclerosis, Thrombosis, and Vascular Biology • 2002 • Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in macrophages PMID:11950702

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