Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The murine pallid mutation is a platelet storage pool disease associated with the protein 4.2 (pallidin) gene

Abstract

Pallid is one of 12 independent murine mutations with a prolonged bleeding time that are models for human platelet storage pool deficiencies in which several intracellular organelles are abnormal. We have mapped the murine gene for protein 4.2 (Epb4.2) to chromosome 2 where it co–localizes with pallid. Southern blot analyses suggest that pallid is a mutation in the Epb4.2 gene. Northern blot analyses demonstrate a smaller than normal Epb4.2 transcript in affected pallid tissues, such as kidney and skin. This is the first gene defect to be associated with a platelet storage pool deficiency, and may allow the identification of a novel structure or biological pathway that influences granulogenesis.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Novak, E.K., Hui, S. & Swank, R.T. Platelet storage pool deficiency in mouse pigment mutations associated with seven distinct genetic loci. Blood 63, 536–544 (1984).

    CAS  PubMed  Google Scholar 

  2. 2

    Reddington, M. et al. Immature dense granules in platelets from mice with platelet storage pool disease. Blood 69, 1300–1306 (1987).

    CAS  PubMed  Google Scholar 

  3. 3

    Theriault, L.L. & Hurley, L.S. Ultrastructure of developing melanosomes in C57 black and pallid mice. Develop. Biol. 23, 261–275 (1970).

    CAS  Article  Google Scholar 

  4. 4

    Swank, R.T., Reddington, M., Howlett, O. & Novak, E.K. Platelet storage pool deficiency associated with inherited abnormalities of the inner ear in the mouse pigment mutants muted and mocha. Blood 78, 2036–2044 (1991).

    CAS  PubMed  Google Scholar 

  5. 5

    Bennett, V. Spectrin-based membrane skeleton: a multipotential adaptor between plasma membrane and cytoplasm. Physiol. Rev. 70, 1029–1065 (1990).

    CAS  Article  Google Scholar 

  6. 6

    Bennett, V. & Stenbuck, P.J. Association between ankyrin and the cytoplasmic domain of band 3 isolated from the human erythrocyte membrane. J. biol. Chem. 255, 6424–6432 (1980).

    CAS  PubMed  Google Scholar 

  7. 7

    Korsgren, C. & Cohen, C.M. Purification and properties of human erythrocyte band 4.2. Association with the cytoplasmic domain of band 3. J. biol. Chem. 261, 5536–5543 (1986).

    CAS  PubMed  Google Scholar 

  8. 8

    Korsgren, C. & Cohen, C.M. Associations of human erythrocyte band 4.2. Binding to ankyrin and to the cytoplasmic domain of band 3. J. biol. Chem. 263, 10212–10218 (1988).

    CAS  PubMed  Google Scholar 

  9. 9

    Friedrichs, B., Koob, R., Kraemer, D. & Drenckhahn, D. Demonstration of immunoreactive forms of erythrocyte protein 4.2 in nonerythroid Cells and tissues. Eur. J. Cell Biol. 48, 121–127 (1989).

    CAS  PubMed  Google Scholar 

  10. 10

    Risinger, M., Dotimas, E. & Cohen, C.M. Human erythrocyte protein 4.2, a high copy number membrane protein, is N-myristylated. J. biol. Chem. 267, 5680–5685 (1992).

    CAS  PubMed  Google Scholar 

  11. 11

    Korsgren, C., Lawler, J., Lambert, S., Speicher, D. & Cohen, C.M. Complete amino acid sequence and homologies of human erythrocyte membrane protein band 4.2. Proc. natn. Acad. Sci. U.S.A. 87, 613–617 (1990).

    CAS  Article  Google Scholar 

  12. 12

    Sung, L.A. et al. Molecular cloning of human protein 4.2: a major component of the erythrocyte membrane. Proc. natn. Acad. Sci. U.S.A. 87, 955–959 (1990).

    CAS  Article  Google Scholar 

  13. 13

    Phillips, M.A. et al. Primary structure of keratinocyte transglutaminase. Proc. natn. Acad. Sci. U.S.A. 87, 9333–9337 (1990).

    CAS  Article  Google Scholar 

  14. 14

    Korsgren, C. & Cohen, C.M. Organization of the gene for human erythrocyte membrane protein 4.2: structural similarities with the gene for the subunit of factor XIII. Proc. natn. Acad. Sci. U.S.A. 88, 4840–4844 (1991).

    CAS  Article  Google Scholar 

  15. 15

    Phillips, M.A., Stewart, B.E. & Rice, R.N. Genomic structure of keratinocyte transglutaminase. Recruitment of new exon for modified function. J. biol. Chem. 267, 2282–2286 (1992).

    CAS  PubMed  Google Scholar 

  16. 16

    Rybicki, A.C., Heath, R., Wolf, J.L., Lubin, B. & Schwartz, R.S. Deficiency of protein 4.2 in erythrocytes from a patient with a Coombs negative hemolytic anemia. J. clin. Invest. 81, 893–901 (1988).

    CAS  Article  Google Scholar 

  17. 17

    Ideguchi, H., Nishimura, J., Nawata, H. & Hamasaki, N. A genetic defect of erythrocyte band 4.2 protein associated with hereditary spherocytosis. Brit. J. Haematol. 74, 347–353 (1990).

    CAS  Article  Google Scholar 

  18. 18

    Ghanem, A. et al. A haemolytic syndrome associated with the complete absence of red Cell membrane protein 4.2 in two Tunisian siblings. Brit J. Haematol. 75, 414–420 (1990).

    CAS  Article  Google Scholar 

  19. 19

    Silver, J. Confidence limits for estimates of gene linkage based on analysis of recombinant inbred strains. J. Hered. 76, 436–440 (1985).

    CAS  Article  Google Scholar 

  20. 20

    Taylor, B.A. Recombinant inbred strains: use in genetic mapping. in Genetic Variants and Strains of the Laboratory Mouse, 2nd edn (eds Lyon, M.F. & Searle, A.G. ) 773–796 (Oxford University Press, New York, 1989).

    Google Scholar 

  21. 21

    Ahmed, F., Lundin, L.G. & Shire, J.G.M. Lysosomal mutations increase susceptibility to anaesthetics. Experientia 45, 1133–1135 (1989).

    CAS  Article  Google Scholar 

  22. 22

    Novak, E.K. et al. Cocoa: a new mouse model for platelet storage pool deficiency. Brit J. Haematol. 69, 371–378 (1988).

    CAS  Article  Google Scholar 

  23. 23

    Swank, R.T., Sweet, H.O., Davisson, M.T., Reddington, M. & Novak, E.K. Sandy: a new mouse model for platelet storage pool deficiency. Genet. Res. 58, 51–62 (1991).

    CAS  Article  Google Scholar 

  24. 24

    Roberts, E. A new mutation in the house mouse (mus musculus). Science 74, 569 (1931).

    CAS  Article  Google Scholar 

  25. 25

    Lane, P.W. & Lyon, M.F. in Genetic Variants and Strains of the Laboratory Mouse, 2nd edition (eds Lyon, M. F. & Searle, A. G. ) 825–842 (Oxford University Press, New York, 1989).

    Google Scholar 

  26. 26

    Flaherty, L. in The Mouse in Biomedical Research, Vol. I, (eds Foster, H.L., Small, J.D. & Fox, J.G. ) 215–222 (Academic Press, New York, 1981).

    Google Scholar 

  27. 27

    Conboy, J. et al. Molecular analysis of insertion/deletion mutations in protein 4.1 in elliptocytosis II. Determination of molecular genetic origins of rearrangements. J. clin. Invest. 86, 524–530 (1990).

    CAS  Article  Google Scholar 

  28. 28

    Conboy, J.G., Chan, J.Y., Chasis, J.A., Kan, Y.W. & Mohandas, N. Tissue-and development-specific alternative RNA splicing regulates expression of multiple isoforms of erythroid membrane protein 4.1. J. biol. Chem. 266, 8273–8280 (1991).

    CAS  PubMed  Google Scholar 

  29. 29

    McCluer, R.H., Williams, M.A., Gross, S.K. & Meisler, M.H. Testosterone effects on the induction and urinary excretion of mouse kidney glycosphingolipids associated with lysosomes. J. biol. Chem. 256, 13112–13120 (1981).

    CAS  PubMed  Google Scholar 

  30. 30

    Novak, E. K. & Swank, R.T. Lysosomal dysfunctions associated with mutations at mouse pigment genes. Genetics 92, 189–204 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Novak, E.K., Wieland, F., Jahreis, G.P. & Swank, R.T. Altered secretion of kidney lysosomal enzymes in the mouse pigment mutants ruby-eye, ruby-eye2J, and maroon. Biochem. Genet. 18, 549–561 (1980).

    CAS  Article  Google Scholar 

  32. 32

    Meisler, M. Synthesis and secretion of kidney ß-galactosidase in mutant le/le mice. J. biol. Chem. 253, 3129–3134 (1978).

    CAS  PubMed  Google Scholar 

  33. 33

    Novak, E.K., Swank, R.T. & Meisler, M.H. Pigmentation and lysosome function in mice homozygous for both pale ear and Belge-J pigment genes. Genet. Res. 35, 195–204 (1980).

    CAS  Article  Google Scholar 

  34. 34

    Depinho, R.A. & Kaplan, K.L. The Hermarisky-Pudlak syndrome. Report of three cases and review of pathophysiology and management considerations. Medicine 64, 192–202 (1985).

    CAS  Article  Google Scholar 

  35. 35

    Boxer, G.J. et al. Abnormal platelet function in Chediak-Higashi syndrome. Brit J. Haematol 35, 521–533 (1977).

    CAS  Article  Google Scholar 

  36. 36

    Abo, T., Roder, J.C., Abo, W., Copper, M.D. & Balch, C.M. Natural killer (HNK-1+) Cells in Chediak-Higashi patients are present in normal numbers but are abnormal in function and morphology. J. clin. Invest. 70, 193–197 (1982).

    CAS  Article  Google Scholar 

  37. 37

    Orn, A. et al. Pigment mutations in the mouse which also affect lysosomal functions lead to suppressed natural killer Cell activity. Scand. J. Immunol. 15, 305–310 (1982).

    CAS  Article  Google Scholar 

  38. 38

    Clark, E.A., Schultz, L.D. & Pollack, S.B. Mutations in mice that influence natural killer (NK) Cell activity. Immunogenetics 12, 601–613 (1981).

    CAS  Article  Google Scholar 

  39. 39

    Roder, J. & Duwe, A., The beige mutation in the mouse selectively impairs natural killer Cell function. Nature 278, 451–453 (1979).

    CAS  Article  Google Scholar 

  40. 40

    Lyon, M.F. Absence of otoliths in the mouse: an effect of the pallid mutant. J. Genet. 51, 638–650 (1953).

    Article  Google Scholar 

  41. 41

    Southern, E.M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J. molec. Biol. 98, 503–517 (1975).

    CAS  Article  Google Scholar 

  42. 42

    Peters, L.L. et al. Purkinje Cell degeneration associated with erythroid ankyrin deficiency in nb/nb mice. J. Cell Biol. 114, 114–121, (1991).

    Article  Google Scholar 

  43. 43

    White, R.A., Birkenmeier, C.S., Peters, L.L., Barker, J.E. & Lux, S.E. Murine erythrocyte ankyrin cDNA: highly conserved regions of the regulatory domain. Mammaiian Genome 3, 281–285 (1992).

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

White, R., Peters, L., Adkison, L. et al. The murine pallid mutation is a platelet storage pool disease associated with the protein 4.2 (pallidin) gene. Nat Genet 2, 80–83 (1992). https://doi.org/10.1038/ng0992-80

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing