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On signal sequence polymorphisms and diseases of distribution
J S Rosenblum1, N B Gilula, R A Lerner
1Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037, USA.
Summary
Protein targeting sequences are polymorphic, with variations affecting enzyme distribution. This discovery may explain genetic diseases like progeria, where proteins are misdirected within cells.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Protein targeting sequences direct proteins to specific cellular locations.
- Polymorphisms in these sequences were previously unappreciated.
Purpose of the Study:
- To investigate the polymorphism of protein targeting sequences.
- To explore the potential link between sequence variation and genetic diseases.
Main Methods:
- Cloning and sequencing of mitochondrial manganese-containing superoxide dismutase.
- Comparison of sequences from normal individuals and patients with premature aging syndromes.
- Analysis of eight cell lines for signal sequence variations.
Main Results:
- A single nucleotide change in the DNA encoding the signal sequence was identified.
- This results in either alanine or valine at a specific position.
- All three combinations of the two observed signal sequences were found in analyzed cell lines.
Conclusions:
- Signal sequence polymorphisms can lead to "diseases of distribution" due to improper protein targeting.
- Mitochondrial manganese-containing superoxide dismutase exhibits such polymorphism.
- Progeria and related syndromes may represent diseases of distribution.