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Tangier disease. The complete mRNA sequence encoding for preproapo-A-I
Abstract:
A cDNA library of Tangier liver mRNA has been established, and two apo-A-I-containing clones were identified. The complete derived amino acid sequence of preproapo-A-I has been established by nucleic acid sequence analysis of cloned apo-A-I cDNA and specific primer extensions on Tangier liver RNA. Sequence analysis of the longest cDNA clone, pMDB136T, established the derived amino acid sequence of residues 116-243 of plasma apo-A-I. The remaining portion of the sequence of Tangier preproapo-A-I mRNA was established by sequence analysis of specific primer extensions of synthetic oligonucleotides on Tangier liver mRNA. This latter technique provided the derived amino acid sequence of residues -24 to 116, thus completing the entire preproapo-A-I structure. The structure of Tangier preproapo-A-I was identical to normal preproapo-A-I except for a single base substitution (G----T) which resulted in the isosteric replacement of a glutamic acid residue at position 120 to aspartic acid. These results are interpreted as indicating that there is no major structural defect in Tangier apo-A-I, and the rapid rate of catabolism of apo-A-I in Tangier disease is due to a post-translational defect in apo-A-I metabolism.
Insights
Tangier disease involves rapid catabolism of apolipoprotein A-I (apo-A-I). Researchers found Tangier apo-A-I has a minor structural change, suggesting a post-translational defect causes its accelerated breakdown.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Tangier disease is characterized by severe deficiency of high-density lipoprotein (HDL) and accumulation of cholesteryl esters.
- Apolipoprotein A-I (apo-A-I) is the major protein component of HDL and plays a crucial role in reverse cholesterol transport.
- The rapid catabolism of apo-A-I is a hallmark of Tangier disease, but its underlying cause remains unclear.
Purpose of the Study:
- To elucidate the molecular basis of apo-A-I abnormalities in Tangier disease.
- To determine the complete amino acid sequence of preproapo-A-I in Tangier disease patients.
- To investigate whether structural defects in apo-A-I contribute to its rapid catabolism.
Main Methods:
- Construction of a Tangier liver cDNA library.
- Nucleic acid sequence analysis of cloned apo-A-I cDNA.
- Specific primer extension analysis on Tangier liver mRNA.
- Comparison of Tangier preproapo-A-I sequence with normal preproapo-A-I.
Main Results:
- Two apo-A-I-containing cDNA clones were identified from the Tangier liver library.
- The complete derived amino acid sequence of Tangier preproapo-A-I was established.
- Tangier preproapo-A-I differed from normal preproapo-A-I by a single base substitution (G to T) at position 120, resulting in an isosteric replacement of glutamic acid with aspartic acid.
- No major structural defect was found in Tangier apo-A-I.
Conclusions:
- The structural defect in apo-A-I in Tangier disease is minimal and unlikely to be the primary cause of its rapid catabolism.
- The accelerated breakdown of apo-A-I in Tangier disease is likely due to a post-translational defect in its metabolism.
- These findings provide insights into the pathogenesis of Tangier disease and apo-A-I metabolism.