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
. 1994 Jun 21;91(13):6059–6063. doi: 10.1073/pnas.91.13.6059

Frameshift mutations at two hotspots in vasopressin transcripts in post-mitotic neurons.

D A Evans 1, A A van der Kleij 1, M A Sonnemans 1, J P Burbach 1, F W van Leeuwen 1
PMCID: PMC44137  PMID: 8016115

Abstract

Mutations in DNA underlie carcinogenesis, inherited pathology, and aging and are generally thought to be introduced during meiosis and mitosis. Here we report that in post-mitotic neurons specific frameshift mutations occur at high frequency. These mutations were identified in vasopressin transcripts in magnocellular neurons of the homozygous Brattleboro rat and predominantly consist of a GA deletion in GAGAG motifs. Immunocytochemistry provides evidence for similar events in wild-type rats. However, the diseased state of the Brattleboro rat, resulting in a permanent activation of vasopressin neurons, enhanced the mutational rate. These data reveal hitherto unrecognized somatic mutations in nondividing neurons.

Full text

PDF

Images in this article

6062Image
on p.6062
6062Image
on p.6062

Selected References

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

  1. Altman J., Bayer S. A. Development of the diencephalon in the rat. I. Autoradiographic study of the time of origin and settling patterns of neurons of the hypothalamus. J Comp Neurol. 1978 Dec 15;182(4 Pt 2):945–971. doi: 10.1002/cne.901820511. [DOI] [PubMed] [Google Scholar]
  2. Kuenzle C. C. Enzymology of DNA replication and repair in the brain. Brain Res. 1985 Dec;357(3):231–245. doi: 10.1016/0165-0173(85)90026-8. [DOI] [PubMed] [Google Scholar]
  3. Kunkel T. A. The mutational specificity of DNA polymerase-beta during in vitro DNA synthesis. Production of frameshift, base substitution, and deletion mutations. J Biol Chem. 1985 May 10;260(9):5787–5796. [PubMed] [Google Scholar]
  4. Kunkel T. A. The mutational specificity of DNA polymerases-alpha and -gamma during in vitro DNA synthesis. J Biol Chem. 1985 Oct 15;260(23):12866–12874. [PubMed] [Google Scholar]
  5. Matsuoka M., Nagawa F., Okazaki K., Kingsbury L., Yoshida K., Müller U., Larue D. T., Winer J. A., Sakano H. Detection of somatic DNA recombination in the transgenic mouse brain. Science. 1991 Oct 4;254(5028):81–86. doi: 10.1126/science.1925563. [DOI] [PubMed] [Google Scholar]
  6. Mezey E., Seidah N. G., Chretien M., Brownstein M. J. Demonstration of the vasopressin associated glycopeptide in the brain and peripheral tissues of the Brattleboro rat. Neuropeptides. 1986 Jan;7(1):79–85. doi: 10.1016/0143-4179(86)90082-x. [DOI] [PubMed] [Google Scholar]
  7. Rao K. S., Loeb L. A. DNA damage and repair in brain: relationship to aging. Mutat Res. 1992 Sep;275(3-6):317–329. doi: 10.1016/0921-8734(92)90035-n. [DOI] [PubMed] [Google Scholar]
  8. Richards S. J., Morris R. J., Raisman G. Solitary magnocellular neurons in the homozygous Brattleboro rat have vasopressin and glycopeptide immunoreactivity. Neuroscience. 1985 Nov;16(3):617–623. doi: 10.1016/0306-4522(85)90196-4. [DOI] [PubMed] [Google Scholar]
  9. Ripley L. S. Frameshift mutation: determinants of specificity. Annu Rev Genet. 1990;24:189–213. doi: 10.1146/annurev.ge.24.120190.001201. [DOI] [PubMed] [Google Scholar]
  10. Robbins J. H., Brumback R. A., Mendiones M., Barrett S. F., Carl J. R., Cho S., Denckla M. B., Ganges M. B., Gerber L. H., Guthrie R. A. Neurological disease in xeroderma pigmentosum. Documentation of a late onset type of the juvenile onset form. Brain. 1991 Jun;114(Pt 3):1335–1361. doi: 10.1093/brain/114.3.1335. [DOI] [PubMed] [Google Scholar]
  11. Schmale H., Borowiak B., Holtgreve-Grez H., Richter D. Impact of altered protein structures on the intracellular traffic of a mutated vasopressin precursor from Brattleboro rats. Eur J Biochem. 1989 Jul 1;182(3):621–627. doi: 10.1111/j.1432-1033.1989.tb14871.x. [DOI] [PubMed] [Google Scholar]
  12. Schmale H., Richter D. Single base deletion in the vasopressin gene is the cause of diabetes insipidus in Brattleboro rats. Nature. 1984 Apr 19;308(5961):705–709. doi: 10.1038/308705a0. [DOI] [PubMed] [Google Scholar]
  13. Seger M. A., Burbach J. P. The presence and in vivo biosynthesis of fragments of CPP (the C-terminal glycopeptide of the rat vasopressin precursor) in the hypothalamo-neurohypophyseal system. Peptides. 1987 Sep-Oct;8(5):757–762. doi: 10.1016/0196-9781(87)90054-4. [DOI] [PubMed] [Google Scholar]
  14. Sherman T. G., Watson S. J. Differential expression of vasopressin alleles in the Brattleboro heterozygote. J Neurosci. 1988 Oct;8(10):3797–3811. doi: 10.1523/JNEUROSCI.08-10-03797.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Smith K. C. Spontaneous mutagenesis: experimental, genetic and other factors. Mutat Res. 1992 Aug;277(2):139–162. doi: 10.1016/0165-1110(92)90002-q. [DOI] [PubMed] [Google Scholar]
  16. Studier F. W., Rosenberg A. H., Dunn J. J., Dubendorff J. W. Use of T7 RNA polymerase to direct expression of cloned genes. Methods Enzymol. 1990;185:60–89. doi: 10.1016/0076-6879(90)85008-c. [DOI] [PubMed] [Google Scholar]
  17. Valtin H., Sawyer W. H., Sokol H. W. Neurohypophysial principles in rats homozygous and heterozygous for hypothalamic diabetes insipidus (Brattleboro strain). Endocrinology. 1965 Oct;77(4):701–706. doi: 10.1210/endo-77-4-701. [DOI] [PubMed] [Google Scholar]
  18. Vijg J. DNA sequence changes in aging: how frequent, how important? Aging (Milano) 1990 Jun;2(2):105–123. doi: 10.1007/BF03323904. [DOI] [PubMed] [Google Scholar]
  19. van Leeuwen F. W., Caffé R., van der Sluis P. J., Sluiter A. A., van der Woude T. P., Seidah N. G., Chrétien M. Propressophysin is present in neurones at multiple sites in Wistar and homozygous Brattleboro rat brain. Brain Res. 1986 Jul 30;379(1):171–175. doi: 10.1016/0006-8993(86)90272-6. [DOI] [PubMed] [Google Scholar]
  20. van Leeuwen F., van der Beek E., Seger M., Burbach P., Ivell R. Age-related development of a heterozygous phenotype in solitary neurons of the homozygous Brattleboro rat. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6417–6420. doi: 10.1073/pnas.86.16.6417. [DOI] [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