Novel mutations in the gene encoding ATP-binding cassette 1 in four Tangier disease kindreds

Brousseau, Margaret E.; Schaefer, Ernst J.; Dupuis, Josée; Eustace, Brenda K.; Eerdewegh, Paul Van; Goldkamp, Allison L.; Thurston, L.M.; FitzGerald, Michael G.; Yasek-McKenna, Diane; O’Neill, Gilmore; Eberhart, Gretchen P.; Weiffenbach, Barbara; Ordovás, José M.; Freeman, Mason W.; Brown, Robert H.; Gu, Jessie Z.

doi:10.1016/s0022-2275(20)34482-5

Cited by 124 publications

(5 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Proband 420 developed neuropathy at age 25 years, CHD at age 46 years, and died of this disease at age 58 years. This patient was found to be homozygous for an A ¨ C missense mutation at nucleotide 5338 of the ABC-1 transcript, resulting in the substitution of an uncharged amino acid, asparagine, with a positively charged one, histidine (22). This point mutation is located in a highly conserved region of the second transmembrane domain of the ABC-1 protein, suggesting that it has functional importance.…”

Section: Subjectsmentioning

confidence: 96%

Cellular cholesterol efflux in heterozygotes for Tangier disease is markedly reduced and correlates with high density lipoprotein cholesterol concentration and particle size

Brousseau

Eberhart

Dupuis

et al. 2000

Journal of Lipid Research

Self Cite

View full text Add to dashboard Cite

Tangier disease (TD), caused by mutations in the ATP-binding cassette 1 (ABC-1) gene, is a rare genetic disorder characterized by severe deficiency of high density lipoproteins (HDL) in the plasma, hypercatabolism of HDL, and defective apolipoprotein (apo)-mediated cellular cholesterol efflux. In the present study, we assessed plasma lipid concentrations, HDL particle size and subspecies, and cellular cholesterol efflux in 9 TD heterozygotes from a kindred in which the proband was homozygous for an A ¨ C missense mutation at nucleotide 5338 of the ABC-1 transcript. Relative to age-and gender-matched controls from the Framingham Offspring Study (FOS), TD heterozygotes had significant reductions ( P Ͻ 0.000) in HDL-C ( ؊ 54% female; ؊ 40% male) and apoA-I ( ؊ 33% female; ؊ 37% male) concentrations, as well as significantly less cholesterol ( ؊ 68% female; ؊ 58% male) distributed in the largest HDL subclasses, H5 and H4. Consequently, HDL particle size (nm) was significantly smaller ( P Ͻ 0.000) in TD heterozygotes (8.6 ؎ 0.6 female; 8.7 ؎ 0.1 male) relative to FOS controls (9.4 ؎ 0.4 female; 9.0 ؎ 0.3 male). Further studies demonstrated that apoA-I-mediated cellular cholesterol efflux in TD heterozygotes was essentially half that of controls (11 ؎ 2 vs. 20 ؎ 3% of total [ 3 H]cholesterol, P Ͻ 0.001), with strong correlations observed between cholesterol efflux and both HDL-C level (r ‫؍‬ 0.600) and particle size (r ‫؍‬ 0.680). In summary, our data demonstrate that apolipoprotein-mediated cholesterol efflux is aberrant in TD heterozygotes, as it is in homozygotes. This finding, along with the associations observed between HDL-C concentration, HDL particle size, and cholesterol efflux, supports the concept that plasma HDL-C levels are regulated, in part, by cholesterol efflux, which in turn influences HDL particle size and, ultimately, HDL apoA-I catabolism.

show abstract

Section: Subjectsmentioning

confidence: 96%

Cellular cholesterol efflux in heterozygotes for Tangier disease is markedly reduced and correlates with high density lipoprotein cholesterol concentration and particle size

Brousseau

Eberhart

Dupuis

et al. 2000

Journal of Lipid Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…The ABCA1 gene is contained within a 149-kb chromosomal locus on human chromosome 9 and comprises 50 exons encoding a 250-kDa protein. − ABCA1 is ubiquitously expressed in tissues and is transciptionally regulated by nuclear receptors and cAMP, − which has become a primary target mechanism to increase ABCA1-mediated cholesterol efflux to apoA-I. Interestingly, the cAMP-dependent induction of ABCA1 expression was primarily found in mouse macrophage cell lines. − Mutations in ABCA1 gene have been identified in familial hypoalphalipoproteinemia characterized by low plasma levels of HDL cholesterol. − In more severe cases, ABCA1 defects have been identified in patients with Tangier Disease (TD), an autosomal recessive disorder characterized by extremely low plasma HDL levels. ,− There is a good correlation between the ABCA1-mediated cholesterol efflux fibroblasts to apoA-I and the HDL levels in patients with ABCA1 mutations. , Patients with heterozygous nonfunctional ABCA1 alleles have about 50% reduction in HDL cholesterol whereas TD patients, with two nonfunctional ABCA1 alleles, have extremely low HDL. , In addition to low levels of HDL, TD patients have high plasma levels of TG and may have increased risk of cardiovascular disease, but further evidence is needed to support this notion .…”

Section: 1 Atp-binding Cassette Transporter 1 (Abca1) and Cholesterol...mentioning

confidence: 99%

“…20 The ABCA1 gene is contained within a 149-kb chromosomal locus on human chromosome 9 and comprises 50 exons encoding a 250-kDa protein. [21][22][23] ABCA1 is ubiquitously expressed in tissues and is transciptionally regulated by nuclear receptors and cAMP, [24][25][26][27] which has become a primary target mechanism to increase ABCA1-mediated cholesterol efflux to apoA-I. Interestingly, the cAMP-dependent induction of ABCA1 expression was primarily found in mouse macrophage cell lines.…”

Section: Atp-binding Cassette Transporter 1 (Abca1) and Cholesterol E...mentioning

confidence: 99%

HDL: The Metabolism, Function, and Therapeutic Importance

Wang¹,

Briggs²

2003

Chem. Rev.

123

View full text Add to dashboard Cite

show abstract

“…For ABCA1, we have shown how protein−protein interactions are important in the post-translational regulation of the transporter. By analyzing a mutation carried by a Tangier patient that deletes the 46 highly conserved C-terminal amino acids of ABCA1, we identified a VFVNFA motif between amino acids −41 and −46 that is critical for efflux function and the ability of ABCA1 to bind apoA-I , . This motif can act in trans to inhibit ABCA1 efflux activity and the binding of apoA-I, suggesting it may represent a novel protein−protein interaction domain.…”

mentioning

confidence: 99%

SPTLC1 Binds ABCA1 To Negatively Regulate Trafficking and Cholesterol Efflux Activity of the Transporter

et al. 2008

Self Cite

View full text Add to dashboard Cite

ABCA1 transport of cholesterol and phospholipids to nascent HDL particles plays a central role in lipoprotein metabolism and macrophage cholesterol homeostasis. ABCA1 activity is regulated both at the transcriptional level and at the post-translational level. To explore mechanisms involved in the post-translational regulation of the transporter, we have used affinity purification and mass spectrometry to identify proteins that bind ABCA1 and influence its activity. Previously, we demonstrated that an interaction between β 1-syntrophin stimulated ABCA1 activity, at least in part, be slowing the degradation of the transporter. This work demonstrates that one subunit of the serine palmitoyltransferase enzyme, SPTLC1, but not subunit 2 (SPTLC2), is copurified with ABCA1 and negatively regulates its function. In human THP-I macrophages and in mouse liver, the ABCA1-SPTLC1 complex was detected by co-immunoprecipitation, demonstrating that the interaction occurs in cellular settings where ABCA1 activity is critical for HDL genesis. Pharmacologic inhibition of SPTLC1 with myriocin, which resulted in the disruption of the SPTLC1-ABCA1 complex, and siRNA knockdown of SPTLC1 expression both stimulated ABCA1 efflux by nearly 60% (p < 0.05). In contrast, dominant-negative mutants of SPTLC1 inhibited ABCA1 efflux, indicating that a reduced level of sphingomyelin synthesis could not explain the effect of myriocin on ABCA1 activity. In 293 cells, the SPTLC1 inhibition of ABCA1 activity led to the blockade of the exit of ABCA1 from the endoplasmic reticulum. In contrast, myriocin treatment of macrophages increased the level of cell surface ABCA1. In composite, these results indicate that the physical interaction of ABCA1 and SPTLC1 results in reduction of ABCA1 activity and that inhibition of this interaction produces enhanced cholesterol efflux.Disruption of cellular cholesterol homeostasis leads to a variety of pathological conditions, including cardiovascular disease (1). Active efflux of cholesterol to extracellular

show abstract

Novel mutations in the gene encoding ATP-binding cassette 1 in four Tangier disease kindreds

Cited by 124 publications

References 52 publications

Cellular cholesterol efflux in heterozygotes for Tangier disease is markedly reduced and correlates with high density lipoprotein cholesterol concentration and particle size

Cellular cholesterol efflux in heterozygotes for Tangier disease is markedly reduced and correlates with high density lipoprotein cholesterol concentration and particle size

HDL: The Metabolism, Function, and Therapeutic Importance

SPTLC1 Binds ABCA1 To Negatively Regulate Trafficking and Cholesterol Efflux Activity of the Transporter

Contact Info

Product

Resources

About