Familial hypobetalipoproteinemia.

Abetalipoproteinemia (ABL) is an inherited disease characterized by the virtual absence of apolipoprotein B (apoB)-containing lipoproteins from plasma. Only limited numbers of families have been screened for mutations in the microsomal triglyceride transfer protein (MTP) gene. To clarify the genetic basis of clinical diversity of ABL, mutations of the MTP gene have been screened in 4 unrelated patients with ABL. Three novel mutations have been identified: a frameshift mutation caused by a single adenine deletion at position 1389 of the cDNA, and a missense mutation, Asn780Tyr, each in homozygous forms; and a splice site mutation, 2218-2A ¨ G, in a compound heterozygous form. The frameshift and splice site mutations are predicted to encode truncated forms of MTP. When transiently expressed in Cos-1 cells, the Asn780Tyr mutant MTP bound protein disulfide isomerase (PDI) but displayed negligible MTP activity. It is of interest that the patient having the Asn780Tyr mutation, a 27-year-old male, has none of the manifestations characteristic of classic ABL even though his plasma apoB and vitamin E were virtually undetectable. These results indicated that defects of the MTP gene are the proximal cause of ABL.

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confidence: 99%

Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia

Ohashi

Ishibashi

Osuga

et al. 2000

“…A unique mRNA editing in the small intestine generates a truncated form of apoB corresponding to its N-terminal 48% (apoB-48) (9), which directs the formation of chylomicrons (10). A number of other truncated forms of apoB corresponding to the N-terminal 28% to 90%, are found in plasma of human subjects with hypobetalipoproteinemia, a condition that is characterized by low levels of plasma apoB-containing lipoproteins (11,12). These truncations result from mutations in the apoB gene.…”

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confidence: 99%

“…Analysis of truncated apoB-containing lipoproteins isolated from patients' plasma showed that forms of apoB containing as little as 37% of the N-terminal region (apoB-37) appear to have the necessary structural information to direct the formation of triacylglycerol (TAG)-rich lipoproteins such as VLDL (11). However, forms corresponding to 31% of the N-terminal region of apoB (apoB-31), or shorter, lose their ability to recruit enough TAG to form VLDL, and unlike the longer forms, are secreted in both lipid-associated (on high density lipoprotein-like particles) and lipid-poor states (11). These findings therefore suggest that amino acid sequences beyond apoB-31 may be more lipophilic, and thereby capable of recruiting TAG.…”

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confidence: 99%

The N-terminal 17% of apoB binds tightly and irreversibly to emulsions modeling nascent very low density lipoproteins

Herscovitz

Derksen

Walsh

et al. 2001

The N-terminal 17% of apolipoprotein B (apoB-17) readily associates with dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles (MLV) to form large (240-Å diameter) discoidal particles. Because apoB is normally secreted with triacylglycerol (TAG)-rich lipoproteins, we studied the binding of apoB-17 to triolein-rich emulsions modeling nascent TAG-rich very low density-like lipoproteins. Emulsions with the following composition (by weight) were prepared: 85-89% triolein, 1.1-1.4% cholesterol, and 10-14% phosphatidylcholines (PC) including either egg yolk (EY)-, dimyristoyl (DM)-, or dipalmitoyl (DP)-PC representing (at 25 Њ C), respectively, a fluid surface, a surface at transition, and a mainly solid surface. The respective sizes were 1,260 ؎ 500, 1,070 ؎ 450, and 830 ؎ 300 Å mean diameter. The emulsions were incubated with conditioned medium containing apoB-17, and then reisolated by ultracentrifugation. Analysis of the emulsion-bound proteins by gel electrophoresis showed that all three emulsions bound primarily apoB-17. The DPPC emulsions bound more apoB-17 than EYPC or DMPC emulsions. Immunoaffinitypurified apoB-17 exhibited saturable, high affinity binding to EYPC and DPPC emulsions. The respective K d values were 32 Ϯ 23 and 85 Ϯ 27 nM and capacities (N) were 10 and 58 molecules of apoB-17 per particle. When apoB-17 bound to emulsions was incubated with DMPC MLV at 26 Њ C for 18 h, it remained bound to the emulsions, indicating that once bound to these emulsions it is unable to exchange off and solubilize DMPC into discs. In contrast, apoE-3 bound to emulsions dissociated from the emulsions when incubated with DMPC MLV and formed discs. Thus, apoB-17 binds strongly and irreversibly to emulsions modeling nascent lipoproteins. It therefore may play an important role in the stabilization of nascent VLDL and chylomicrons. -Herscovitz, H.

“…It is still a matter of debate whether the low cholesterol or the increased concentration of precursors or both is the most harmful component in growth and development of these patients. On the basis of experience with familial hypobetalipoproteinemia (10), in which plasma cholesterol in heterozygotes is as low as in some SLOS cases, without any clinical effect, we hypothesized that the cholesterol precursors 7DHC and 8DHC may be toxic. Both precursors are structurally similar to cholesterol (differing only in having an extra double bond in the cholesterol Bring) and therefore may interfere with the important role of cholesterol.…”

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confidence: 99%

Simvastatin: a new therapeutic approach for Smith-Lemli-Opitz syndrome

Jira

Wevers

Jong

et al. 2000

100

The Smith-Lemli-Opitz syndrome (SLOS) is caused by deficient ⌬ 7 -dehydrocholesterol reductase, which catalyzes the final step of the cholesterol biosynthetic pathway, resulting in low cholesterol and high concentrations of its direct precursors 7-dehydrocholesterol (7DHC) and 8DHC. We hypothesized that i ) 7DHC and 8DHC accumulation contributes to the poor outcome of SLOS patients and ii ) blood exchange transfusions with hydroxymethylglutaryl (HMG)-CoA reductase inhibition would improve the precursor-to-cholesterol ratio and may improve the clinical outcome of SLO patients. First, an in vitro study was performed to study sterol exchange between plasma and erythrocyte membranes. Second, several exchange transfusions were carried out in vivo in two SLOS patients. Third, simvastatin was given for 23 and 14 months to two patients. The in vitro results illustrated rapid sterol exchange between plasma and erythrocyte membranes. The effect of exchange transfusion was impressive and prompt but the effect on plasma sterol levels lasted only for 3 days. In contrast, simvastatin treatment for several months demonstrated a lasting improvement of the precursor-to-cholesterol ratio in plasma, erythrocyte membranes, and cerebrospinal fluid (CSF). Plasma precursor concentrations decreased to 28 and 33% of the initial level, respectively, whereas the cholesterol concentration normalized by a more than twofold increase. During the follow-up period all morphometric parameters improved. The therapy was well tolerated and no unwanted clinical side effects occurred. This is the first study in which the blood cholesterol level in SLOS patients is normalized with a simultaneous significant decrease in precursor levels. There was a lasting biochemical improvement with encouraging clinical improvement. Statin therapy is a promising novel approach in SLOS that deserves further studies in larger series of patients.