Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1990 May;87(10):3909–3913. doi: 10.1073/pnas.87.10.3909

Hypermutability of CpG dinucleotides in the propeptide-encoding sequence of the human albumin gene.

S O Brennan 1, K Arai 1, J Madison 1, C B Laurell 1, M Galliano 1, S Watkins 1, R Peach 1, T Myles 1, P George 1, F W Putnam 1
PMCID: PMC54013  PMID: 2339130

Abstract

An electrophoretically slow albumin variant was detected with a phenotype frequency of about 1:1000 in Sweden and was also found in a family of Scottish descent from Kaikoura, New Zealand, and in five families in Tradate, Italy. Structural study established that the major variant component was arginyl-albumin, in which arginine at the -1 position of the propeptide is still attached to the processed albumin. A minor component with the amino-terminal sequence of proalbumin was also present as 3-6% of the total albumin. After amplification of the gene segment encoding the prepro sequence of albumin, specific hybridization of DNA to an oligonucleotide probe encoding cysteine at position -2 indicated the mutation of arginine at the -2 position to cysteine (-2 Arg----Cys). This produced the propeptide sequence Arg-Gly-Val-Phe-Cys-Arg. This was confirmed by sequence analysis after pyridylethylation of the cysteine. This mutation produces an alternate signal peptidase cleavage site in the variant proalbumin precursor of arginyl-albumin giving rise to two possible products, arginyl-albumin and the variant proalbumin. Another plasma from Bremen had an alloalbumin with a previously described substitution (1 Asp----Val), which also affects propeptide cleavage. Hypermutability of two CpG dinucleotides in the codons for the diarginyl sequence may account for the frequency of mutations in the propeptide. Mutation at these two sites results in a series of recurrent proalbumin variants that have arisen independently in diverse populations.

Full text

PDF
3909

Images in this article

3910Image
on p.3910
3912Image
on p.3912

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abdo Y., Rousseaux J., Dautrevaux M. Proalbumin Lille, a new variant of human serum albumin. FEBS Lett. 1981 Aug 31;131(2):286–288. doi: 10.1016/0014-5793(81)80386-9. [DOI] [PubMed] [Google Scholar]
  2. Andrews P. C., Dixon J. E. A procedure for in situ alkylation of cystine residues on glass fiber prior to protein microsequence analysis. Anal Biochem. 1987 Mar;161(2):524–528. doi: 10.1016/0003-2697(87)90484-2. [DOI] [PubMed] [Google Scholar]
  3. Arai K., Ishioka N., Huss K., Madison J., Putnam F. W. Identical structural changes in inherited albumin variants from different populations. Proc Natl Acad Sci U S A. 1989 Jan;86(2):434–438. doi: 10.1073/pnas.86.2.434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Arai K., Madison J., Huss K., Ishioka N., Satoh C., Fujita M., Neel J. V., Sakurabayashi I., Putnam F. W. Point substitutions in Japanese alloalbumins. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6092–6096. doi: 10.1073/pnas.86.16.6092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Arai K., Madison J., Shimizu A., Putnam F. W. Point substitutions in albumin genetic variants from Asia. Proc Natl Acad Sci U S A. 1990 Jan;87(1):497–501. doi: 10.1073/pnas.87.1.497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brennan S. O., Carrell R. W. A circulating variant of human proalbumin. Nature. 1978 Aug 31;274(5674):908–909. doi: 10.1038/274908a0. [DOI] [PubMed] [Google Scholar]
  7. Brennan S. O., George P. M., Peach R. J. Characterisation of a slow component of normal human serum albumin. Clin Chim Acta. 1988 Aug 31;176(2):179–184. doi: 10.1016/0009-8981(88)90205-7. [DOI] [PubMed] [Google Scholar]
  8. Brennan S. O., Herbert P. Albumin Canterbury (313 Lys----Asn). A point mutation in the second domain of serum albumin. Biochim Biophys Acta. 1987 Apr 8;912(2):191–197. doi: 10.1016/0167-4838(87)90088-4. [DOI] [PubMed] [Google Scholar]
  9. Brennan S. O., Myles T., Peach R. J., Donaldson D., George P. M. Albumin Redhill (-1 Arg, 320 Ala----Thr): a glycoprotein variant of human serum albumin whose precursor has an aberrant signal peptidase cleavage site. Proc Natl Acad Sci U S A. 1990 Jan;87(1):26–30. doi: 10.1073/pnas.87.1.26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Brennan S. O. Propeptide cleavage: evidence from human proalbumins. Mol Biol Med. 1989 Feb;6(1):87–92. [PubMed] [Google Scholar]
  11. Brennan S. O. The molecular abnormality of albumin Parklands: 365 Asp----His. Biochim Biophys Acta. 1985 Aug 23;830(3):320–324. doi: 10.1016/0167-4838(85)90289-4. [DOI] [PubMed] [Google Scholar]
  12. Cooper D. N., Krawczak M. Cytosine methylation and the fate of CpG dinucleotides in vertebrate genomes. Hum Genet. 1989 Sep;83(2):181–188. doi: 10.1007/BF00286715. [DOI] [PubMed] [Google Scholar]
  13. Galliano M., Minchiotti L., Iadarola P., Zapponi M. C., Ferri G., Castellani A. A. Structural characterization of a chain termination mutant of human serum albumin. J Biol Chem. 1986 Mar 25;261(9):4283–4287. [PubMed] [Google Scholar]
  14. Galliano M., Minchiotti L., Stoppini M., Tàrnoky A. L. A new proalbumin variant: albumin Jaffna (-1 Arg----Leu). FEBS Lett. 1989 Sep 25;255(2):295–299. doi: 10.1016/0014-5793(89)81109-3. [DOI] [PubMed] [Google Scholar]
  15. Huss K., Madison J., Ishioka N., Takahashi N., Arai K., Putnam F. W. The same substitution, glutamic acid----lysine at position 501, occurs in three alloalbumins of Asiatic origin: albumins Vancouver, Birmingham, and Adana. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6692–6696. doi: 10.1073/pnas.85.18.6692. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jeppsson J. O., Laurell C. B., Franzén B. Agarose gel electrophoresis. Clin Chem. 1979 Apr;25(4):629–638. [PubMed] [Google Scholar]
  17. Laurell C. B. Electroimmuno assay. Scand J Clin Lab Invest Suppl. 1972;124:21–37. doi: 10.3109/00365517209102748. [DOI] [PubMed] [Google Scholar]
  18. Laurell C. B., Niléhn J. E. A new type of inherited serum albumin anomaly. J Clin Invest. 1966 Dec;45(12):1935–1945. doi: 10.1172/JCI105498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Minchiotti L., Galliano M., Iadarola P., Meloni M. L., Ferri G., Porta F., Castellani A. A. The molecular defect in a COOH-terminal-modified and shortened mutant of human serum albumin. J Biol Chem. 1989 Feb 25;264(6):3385–3389. [PubMed] [Google Scholar]
  20. Minghetti P. P., Ruffner D. E., Kuang W. J., Dennison O. E., Hawkins J. W., Beattie W. G., Dugaiczyk A. Molecular structure of the human albumin gene is revealed by nucleotide sequence within q11-22 of chromosome 4. J Biol Chem. 1986 May 25;261(15):6747–6757. [PubMed] [Google Scholar]
  21. Takahashi N., Takahashi Y., Blumberg B. S., Putnam F. W. Amino acid substitutions in genetic variants of human serum albumin and in sequences inferred from molecular cloning. Proc Natl Acad Sci U S A. 1987 Jul;84(13):4413–4417. doi: 10.1073/pnas.84.13.4413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Takahashi N., Takahashi Y., Isobe T., Putnam F. W., Fujita M., Satoh C., Neel J. V. Amino acid substitutions in inherited albumin variants from Amerindian and Japanese populations. Proc Natl Acad Sci U S A. 1987 Nov;84(22):8001–8005. doi: 10.1073/pnas.84.22.8001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Takahashi N., Takahashi Y., Putnam F. W. Structural changes and metal binding by proalbumins and other amino-terminal genetic variants of human serum albumin. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7403–7407. doi: 10.1073/pnas.84.21.7403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Youssoufian H., Antonarakis S. E., Bell W., Griffin A. M., Kazazian H. H., Jr Nonsense and missense mutations in hemophilia A: estimate of the relative mutation rate at CG dinucleotides. Am J Hum Genet. 1988 May;42(5):718–725. [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES