Apolipoprotein A-I deficiency with accumulated risk for CHD but no symptoms of CHD

Yokota, Hiromitsu; Hashimoto, Yoshiaki; Okubo, Shigeo; Yumoto, Masato; Mashige, Fumiko; Kawamura, Mitsunobu; Kotani, Kazuo; Usuki, Yasuteru; Shimada, Sachiyo; Kawakami, Kiyoshi; Nakahara, Kazuhiko

doi:10.1016/s0021-9150(01)00724-9

Cited by 28 publications

(19 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Approximately 25 patients with apoAI defi ciency owing to nonsense mutations, a chromosomal aberration or deletion, have been reported thus far ( 41,(43)(44)(45)(46)(47). Structural mutations in the APOA1 gene such as missense mutations are a frequent cause of FHA (15-35 mg/dl) ( 48,49 ).…”

Section: Remodeling Of Hdlmentioning

confidence: 99%

“…Structural mutations in the APOA1 gene such as missense mutations are a frequent cause of FHA (15-35 mg/dl) ( 48,49 ). Although the impact of these mutations is variable ( 21,43 ), they appear to cause the greatest elevation in the risk of CAD when compared with other gene defects ( 44,48 ). The apoAI Milano variant is a notable exception, as it is associated with a reduced vascular risk despite a 67% decrease in HDL-C levels ( 20,21 ).…”

Section: Remodeling Of Hdlmentioning

confidence: 99%

See 1 more Smart Citation

Genetic causes of high and low serum HDL-cholesterol

Weissglas‐Volkov

Pajukanta

2010

Journal of Lipid Research

180

134

View full text Add to dashboard Cite

Section: Remodeling Of Hdlmentioning

confidence: 99%

Section: Remodeling Of Hdlmentioning

confidence: 99%

Genetic causes of high and low serum HDL-cholesterol

Weissglas‐Volkov

Pajukanta

2010

Journal of Lipid Research

180

134

View full text Add to dashboard Cite

“…These are APOA1 (MIM# 107680), encoding apolipoprotein (apo) A-I, ABCA1 (MIM# 600046), encoding ATP-binding cassette transporter, and LCAT (MIM# 606967), encoding lecithin:cholesterol acyltransferase (LCAT). Homozygosity for deleterious mutations in APOA1 causing a loss of apo A-I, the major constitutive apolipoprotein of HDL, results in complete HDL deficiency [Hovingh et al, 2004a;Miller et al, 1998;Yokota et al, 2002]. Homozygosity for functional mutations in ABCA1 also cause HDL deficiency, severely decreased cellular cholesterol efflux and cholesteryl ester accumulation in macrophages.…”

Section: Introductionmentioning

confidence: 99%

High prevalence of mutations in LCAT in patients with low HDL cholesterol levels in the Netherlands: Identification and characterization of eight novel mutations

Holleboom

Kuivenhoven

Peelman³

et al. 2011

Hum. Mutat.

View full text Add to dashboard Cite

Lecithin:cholesterol acyltransferase (LCAT) is crucial to the maturation of high-density lipoprotein (HDL). Homozygosity for LCAT mutations underlies rare disorders characterized by HDL-cholesterol (HDL-c) deficiency while heterozygotes have half normal HDL-c levels. We studied the prevalence of LCAT mutations in referred patients with low HDL-c to better understand the molecular basis of low HDL-c in our patients. LCAT was sequenced in 98 patients referred for HDL-c <5th percentile and in four patients referred for low HDL-c and corneal opacities. LCAT mutations were highly prevalent: in 28 of the 98 participants (29%), heterozygosity for nonsynonymous mutations was identified while 18 patients carried the same mutation (p.T147I). The four patients with corneal opacity were compound heterozygotes. All previously identified mutations are documented to cause loss of catalytic activity. Nine novel mutations-c.402G>T (p.E134D), c.403T>A (p.Y135N), c.964C>T (p.R322C), c.296G>C (p.W99S), c.736G>T (p.V246F), c.802C>T (p.R268C), c.945G>A (p.W315X), c.1012C>T (p.L338F), and c.1039C>T (p.R347C)--were shown to be functional through in vitro characterization. The effect of several mutations on the core protein structure was studied by a three-dimensional (3D) model. Unlike previous reports, functional mutations in LCAT were found in 29% of patients with low HDL-c, thus constituting a common cause of low HDL-c in referred patients in The Netherlands.

show abstract

“…These patients had very low HDL concentrations in plasma and suffered from premature atherosclerosis. Also, an association of a high risk for premature atherosclero-sis and lower plasma levels of apoA-I has been observed; however, few mutations in the APOA1/C3/A4 gene cluster that result in reduced levels or absence of apoA-I lead to atherosclerosis (13). In contrast, single deficiencies in apoA-I, apoC-III, and likely apoA-IV are not sufficient to predispose mice to atherosclerosis (14)(15)(16), whereas overexpression of human apoA-I (17) and apoA-IV (18) but not apoC-III (19) had been reported to protect mice from genetic or diet-induced atherosclerosis.…”

mentioning

confidence: 99%

Characterization of a new mouse model for human apolipoprotein A-I/C-III/A-IV deficiency

Mezdour

Larigauderie

Castro

et al. 2006

Journal of Lipid Research

View full text Add to dashboard Cite

Human data raised the possibility that coronary heart disease is associated with mutations in the apolipoprotein gene cluster APOA1/C3/A4 that result in multideficiency of cluster-encoded apolipoproteins and hypoalphalipoproteinemia. To test this hypothesis, we generated a mouse model for human apolipoprotein A-I (apoA-I)/C-III/A-IV deficiency. Homozygous mutants (Apoa1/c3/a4 2/2 ) lacking the three cluster-encoded apolipoproteins were viable and fertile. In addition, feeding behavior and growth were apparently normal. Total cholesterol (TC), high density lipoprotein cholesterol (HDLc), and triglyceride levels in the plasma of fasted mutants fed a regular chow were 32% (P , 0.001), 17% (P , 0.001), and 70% (P , 0.01), respectively, those of wild-type mice. When fed a high-fat Western-type (HFW) diet, Apoa1/ c3/a4 2/2 mice showed a further decrease in HDLc concentration and a moderate increase in TC, essentially in non-HDL fraction. The capacity of Apoa1/c3/a4 2/2 plasma to promote cholesterol efflux in vitro was decreased to 75% (P , 0.001), and LCAT activity was decreased by 38% (P , 0.01). Despite the very low total plasma cholesterol, the imbalance in lipoprotein distribution caused small but detectable aortic lesions in one-third of Apoa1/c3/a4 2/2 mice fed a HFW diet. In contrast, none of the wild-type mice had lesions. These results demonstrate that Apoa1/c3/a4 2/2 mice display clinical features similar to human apoA-I/C-III/A-IV deficiency (i.e., marked hypoalphalipoproteinemia) and provide further support for the apoa1/c3/a4 gene cluster as a minor susceptibility locus for atherosclerosis in mice. Supplementary key words apoa1/c3/a4 gene cluster (mouse) . APOA1/ C3/A4 gene cluster (human) . knockout mouse . hypoalphalipoproteinemia . high-fat Western-type diet . atherosclerosis A strong inverse association exists between plasma high density lipoprotein cholesterol (HDLc) levels and the incidence of coronary artery disease in humans (1). The major locus controlling HDLc levels is APOA1 (for apolipoprotein A-I), a member of the apolipoprotein gene cluster APOA1/C3/A4 (2). The cluster genes, APOA1, APOC3, and APOA4, are evolutionarily related and tandemly organized in a region of 17 kb DNA on human chromosome 11, proximal to APOA5, a new member of the apolipoprotein gene family (3). These APOA1/C3/A4 genes code for three apolipoproteins, apoA-I, apoC-III, and apoA-IV, respectively. ApoA-I is a 28 kDa protein synthesized in the liver and small intestine (4). It is the major protein component of HDL. Through its ability to promote cholesterol efflux from cultured cells (5) and to activate LCAT (6), apoA-I plays a key role in reverse cholesterol transport, a mechanism postulated to prevent extrahepatic tissues from accumulating excess cholesterol (7). Apolipoprotein C-III is a 9 kDa protein produced predominantly in the liver. It is a major component of plasma chylomicrons and VLDL. ApoC-III inhibits the hydrolysis of triglyceride by lipoprotein lipase. Apolipoprotein A-IV is a 46 kDa protein associat...

show abstract

Apolipoprotein A-I deficiency with accumulated risk for CHD but no symptoms of CHD

Cited by 28 publications

References 33 publications

Genetic causes of high and low serum HDL-cholesterol

Genetic causes of high and low serum HDL-cholesterol

High prevalence of mutations in LCAT in patients with low HDL cholesterol levels in the Netherlands: Identification and characterization of eight novel mutations

Characterization of a new mouse model for human apolipoprotein A-I/C-III/A-IV deficiency

Contact Info

Product

Resources

About