PubMed Health⌕ Search

Biomedical subjects

Sally P A McCormick

Publications and source records attributed to Sally P A McCormick.

6 recordsLinked to original sources
PubMed2005

Promoter haplotype of a new ABCA1 mutant influences expression of familial hypoalphalipoproteinemia.

Mutations in the ATP-binding cassette A1 (ABCA1) transporter cause the high-density lipoprotein (HDL) deficiency syndromes of Tangier disease and familial hypoalphalipoproteinemia (FHA). Between individuals carrying ABCA1 mutations, the expression of FHA can be highly variable. Using denaturing HPLC (dHPLC) and direct promoter sequencing we screened the ABCA1 gene of a family with Tangier disease and variable expression of FHA. A new mutation (R1068H) within the first ATP-binding domain was identified in homozygous form in the Tangier disease individual and was present in several family members. Haplotyping of both 1068H alleles in the proband showed homozygosity in the coding region, however, the maternal 1068H allele had three single nucleotide polymorphisms (SNPs) in the promoter previously reported to be associated with reduced ABCA1 expression and HDL levels. An analysis of HDL levels based on 1068H allele haplotype showed the paternal 1068H heterozygotes to have the expected low HDL levels (0.67+/-0.16mmol/L), while maternal 1068H heterozygotes showed normal HDL levels (1.18+/-0.14mmol/L). Haplotype analysis of the wildtype allele amongst heterozygotes showed no haplotype that was common to the paternal or maternal side. We propose that the paternal 1068H ABCA1 allele causes a negative effect on the function of the wildtype allele and is associated with low HDL levels. In contrast, the maternal 1068H allele has less effect and is associated with a relatively normal HDL level. We conclude that haplotypes of mutant ABCA1 alleles may contribute to the phenotypic variance shown between FHA individuals.

ATP Binding Cassette Transporter 1↗
PubMed2005

Elastic lamina defects are an early feature of aortic lesions in the apolipoprotein E knockout mouse.

The aortae from male apolipoprotein E knockout (apoE-/-) mice were examined by serial section immunohistochemistry and electron microscopy to determine the continuity of the internal elastic lamina (IEL) and its association with developing intimal lesions. While in this model, defects in the elastic laminae have previously been described beneath advanced xanthomatous lesions, this study demonstrates that disruption of the IEL may be a primary factor in the localization and pathogenesis of intimal lesions in the apoE-/- mouse. IEL defects were found beneath early lesions in animals as young as 8 weeks of age. Small defects without associated intimal alteration were also observed. The elastic tissue defects beneath early intimal lesions were usually transversely orientated with abrupt "break" edges. Regions consistent with direct enzymatic digestion of the IEL were relatively rare and only observed beneath advanced plaques, particularly in the brachiocephalic artery. The presence of IEL defects around branch sites of old C57BL/6J control mice along with their matching localization and morphology in apoE-/- appears consistent with biomechanical fatigue rather than direct enzymatic degradation. In conclusion, disruption of the IEL appears to be a prominent early, if not initial, feature of the apoE-/- model of atherosclerosis and may act as the nidus upon which intimal lesions develop.

Animals↗
PubMed2004

Structural features of apolipoprotein B synthetic peptides that inhibit lipoprotein(a) assembly.

Lipoprotein(a) [Lp(a)] is assembled via an initial noncovalent interaction between apolipoprotein B100 (apoB) and apolipoprotein(a) [apo(a)] that facilitates the formation of a disulfide bond between the two proteins. We previously reported that a lysine-rich, alpha-helical peptide spanning human apoB amino acids 4372-4392 was an effective inhibitor of Lp(a) assembly in vitro. To identify the important structural features required for inhibitory action, new variants of the apoB4372-4392 peptide were investigated. Introduction of a central leucine to proline substitution abolished the alpha-helical structure of the peptide and disrupted apo(a) binding and inhibition of Lp(a) formation. Substitution of hydrophobic residues in the apoB4372-4392 peptide disrupted apo(a) binding and inhibition of Lp(a) assembly without disrupting the alpha-helical structure. Substitution of all four lysine residues in the peptide with arginine decreased the IC50 from 40 microM to 5 microM . Complexing of the arginine-substituted peptide to dimyristoylphosphatidylcholine improved its activity further, yielding an IC50 of 1 microM. We conclude that the alpha-helical structure of apoB4372-4392, in combination with hydrophobic residues at the lipid/water interface, is crucial for its interaction with apo(a). Furthermore, the interaction of apoB4372-4392 with apo(a) is not lysine specific, because substitutions with arginine result in a more effective inhibitor.

Animals↗
PubMed2003

Mutation of lysine residues in apolipoprotein B-100 causes defective lipoprotein[a] formation.

Lipoprotein[a] (Lp[a]) is assembled by a two-step process involving an initial lysine-dependent binding between apolipoprotein B-100 (apoB-100) and apolipoprotein[a] (apo[a]) that facilitates the formation of a disulphide bond between apoB-100Cys4,326 and apo[a]Cys4,057. Previous studies of transgenic mice expressing apoB-95 (4,330 amino acids) and apoB-97 (4,397 amino acids) have shown that apoB-100 amino acids 4,330-4,397 are important for the initial binding to apo[a]. Furthermore, a lysine-rich peptide spanning apoB-100 amino acids 4,372-4,392 has recently been shown to bind apo[a] and inhibit Lp[a] assembly in vitro. This suggests that a putative apo[a] binding site exists in the apoB-4,372-4,392 region. The aim of our study was to establish whether the apoB-4,372-4,392 sequence was important for Lp[a] assembly in the context of the full-length apoB-100. Transgenic mice were created that expressed a mutant human apoB-100, apoB-100K4-->S4, in which all four lysine residues in the 4,372-4,392 sequence were mutated to serines. The apoB-100K4-->S4 mutant showed a reduced capacity to form Lp[a] in vitro compared with wild-type human apoB-100. Double transgenic mice expressing both apoB-100K4-->S4 and apo[a] contained significant amounts of free apo[a] in the plasma, indicating a less-efficient assembly of Lp[a] in vivo. Taken together, these results clearly show that the apoB-4,372-4,392 sequence plays a role in Lp[a] assembly.

Amino Acid Sequence↗
PubMed2003

A synthetic peptide that inhibits lipoprotein(a) assembly.

OBJECTIVE: We previously reported that human apolipoprotein B100 (apoB) amino acids 4330-4397 were important for the initial noncovalent binding to apolipoprotein(a) [apo(a)] that facilitates lipoprotein(a) [Lp(a)] assembly. In this study, we aimed to further define the apoB sequences within the 4330-4397 region that were important for the noncovalent binding to apo(a). METHODS AND RESULTS: Alignment of the human apoB4330-4397 sequence with mouse apoB, which also noncovalently binds apo(a), revealed stretches of similar sequence, including a lysine-rich sequence spanning apoB amino acids 4372-4392. Structural analysis of the apoB4372-4392 sequence using the WHEEL program predicted an amphipathic alpha-helix. Circular dichroism studies of a synthetic peptide spanning human apoB amino acids 4372-4392, both in the absence and presence of dimyristoylphosphatidylcholine, confirmed the alpha-helical nature of the sequence. We tested the ability of the apoB4372-4392 peptide to bind to apo(a) and found that the peptide bound to apo(a) with high affinity but not to Lp(a). The apoB4372-4392 peptide inhibited Lp(a) assembly in Lp(a) formation assays far more effectively than the lysine analogue, epsilon-amino-n-caproic acid (IC50=40 micromol/L versus 10 mmol/L, respectively). Incorporation of the apoB4372-4392 peptide onto dimyristoylphosphatidylcholine vesicles yielded an even more effective inhibitor (IC50=4 micromol/L). CONCLUSIONS: Our study shows that the apoB4372-4392 sequence mediates the initial noncovalent binding to apo(a) and has demonstrated that the apoB4372-4392 peptide is a novel and effective inhibitor of Lp(a) assembly.

Amino Acid Sequence↗