Identification and mutation analysis of the complete gene for Chediak–Higashi syndrome

Abstract

Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder characterized by hypopigmentation, severe immunologic deficiency with neutropenia and lack of natural killer (NK) cells, a bleeding tendency and neurologic abnormalities1–4. Most patients die in childhood. The CHS hallmark is the occurrence of giant inclusion bodies and organelles in a variety of cell types, and protein sorting defects into these organelles5–8. Similar abnormalities occur in the beige mouse6,7,9–13, the proposed model for human CHS. Two groups have recently reported the identification of the beige gene14,15, however the two cDNAs were not at all similar. Here we describe the sequence of a human cDNA homologous to mouse beige, identify pathologic mutations and clarify the discrepancies of the previous reports. Analysis of the CHS polypeptide demonstrates that its modular architecture is similar to the yeast vacuolar sorting protein, VPS15.

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References

  1. 1

    Beguez-Cesar, A.B. Neutropenia cronica maligna familiar congranulaciones atipicas de los leucocitos. Bol. Soc. Cubana Pediatr. 15, 900–922 (1943).

    Google Scholar 

  2. 2

    Steinbrinck, W. Uber eine neue Granulationsanomalie der Leukocyten. Dtsch. Arch. Klin. Med. 193, 577–581 (1948).

    Google Scholar 

  3. 3

    Chediak, M. Nouvelle anomalie leukocytaire de caractere constitutionnel et familiel. Rev. Hematol. 7, 362–367 (1952).

    CAS  PubMed  Google Scholar 

  4. 4

    Higashi, O. Congenital gigantism of peroxidase granules. Tohoku J. Exp. Med. 59, 315–332 (1954).

    CAS  Article  Google Scholar 

  5. 5

    Jones, K.L., Stewart, R.M., Fowler, M., Fukuda, M. & Holcombe, R.F. Chediak-Higashi lymphoblastoid cell lines: granule characteristics and expression of lysosome-associated membrane proteins. Clin. Immunol. Immunopath. 65, 219–226 (1992).

    CAS  Article  Google Scholar 

  6. 6

    Burkhardt, J.K., Wiebel, F.A., Hester, S. & Argon, Y. The giant organelles in Beige and Chediak-Higashi fibroblasts are derived from late endosomes and mature lysosomes. J. Exp. Med. 178, 1845–1856 (1993).

    CAS  Article  Google Scholar 

  7. 7

    Holcombe, R.F., Jones, K.L. & Stewart, R.M. Lysosomal enzyme activities in Chediak-Higashi syndrome: evaluation of lymphoblastoid cell lines and review of the literature. Immunodeficiency 5, 131–140 (1994).

    CAS  Google Scholar 

  8. 8

    Zhao, H. et al. On the analysis of the pathophysiology of Chediak-Higashi syndrome. Lab. Investig. 71, 25–34 (1994).

    CAS  PubMed  Google Scholar 

  9. 9

    Lutzner, M.A., Lowrie, C.T. & Jordan, H.W. Giant granules in leukocytes of the beige mouse. Heredity 58, 299–300 (1966).

    Article  Google Scholar 

  10. 10

    Brandt, E.J., Elliott, R.W. & Swank, R.T. Defective lysosomal enzyme secretion in kidneys of Chediak-Higashi (beige) mice. J. Cell Biol. 67, 774–788 (1975).

    CAS  Article  Google Scholar 

  11. 11

    Swank, R.T. & Brandt, E.J. Turnover of kidney β-glucuronidase in normal and Chediak-Higashi (beige) mice. Am. J. Pathol. 92, 755–771 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Willingham, M.C., Spicer, S.S. & Vincent, R.A., The origin and fate of large dense bodies in beige mouse fibroblasts. Exp. Cell Res. 136, 157–168 (1981).

    CAS  Article  Google Scholar 

  13. 13

    Penner, J.D. & Prieur, D.J. A comparative study of the lesions in cultured fibroblasts of humans and four species of animals with Chediak-Higashi syndrome. Am. J. Med. Genet. 28, 445–454 (1987).

    CAS  Article  Google Scholar 

  14. 14

    Perou, C.M. et al. Identification of the murine beige gene by YAC complementation and positional cloning. Nature Genet. 13, 303–308 (1996).

    CAS  Article  Google Scholar 

  15. 15

    Barbosa, M.D.F.S. et al. Identrtication of the homologous beige and Chediak-Higashi syndrome genes. Nature 382, 262–265 (1996).

    CAS  Article  Google Scholar 

  16. 16

    Stein, L., Kruglyak, L., Slonim, D. & Lander, E. Unpublished software, Whitehead Institute/MIT Center for Genome Research (1995).

  17. 17

    Fukai, K. et al. Homozygosity mapping of the gene for Chediak-Higashi syndrome to chromosome 1q42–q44 in a segment of conserved synteny that includes the mouse beige locus (bg). Am. J. Hum. Genet., 59, 620–624 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Barret, F.J. et al. Genetic and physical mapping of the Chediak-Higashi syndrome on chromosome 1q42–43. Am. J. Hum. Genet. 59, 625–632 (1996).

    Google Scholar 

  19. 19

    Bork, P. & Koonin, E.V. Protein sequence motifs. Curr. Opin. Struct. Biol. 6, 366–376 (1996).

    CAS  Article  Google Scholar 

  20. 20

    Peifer, M., Berg, S. & Reynolds, A.B. A repeating amino acid motif shared by proteins with diverse cellular roles. Cell 76, 789–791 (1994).

    CAS  Article  Google Scholar 

  21. 21

    Andrade, M.A. & Bork, P. HEAT repeats in the Huntington's disease protein. Nature Genet. 11, 115–116 (1995).

    CAS  Article  Google Scholar 

  22. 22

    DiFiglia, M. et al. Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron 14, 1075–1081 (1995).

    CAS  Article  Google Scholar 

  23. 23

    Sabatini, D.M., Erdjument-Bromage, H., Lui, M., Tempst, P. & Snyder, S.H. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78, 35–43 (1994).

    CAS  Article  Google Scholar 

  24. 24

    Zheng, X.F., Florentine, D., Chen, J., Crabtree, G.R. & Schreiber, S.L. TOR kinase domains are required for two distinct functions, only one of which is inhibited by rapamycin. Cell 82, 121–130 (1995).

    CAS  Article  Google Scholar 

  25. 25

    Hemmings, B.A. et al. α-and β-forms of the 65-kDa subunit of protein phosphatase 2A have a similar 39 amino acid repeating structure. Biochemistry 29, 3166–3173 (1990).

    CAS  Article  Google Scholar 

  26. 26

    Neer, E.J., Schmidt, C.J., Nambudripad, R. & Smith, T.F. The ancient regulatory-protein family of WD-repeat proteins. Nature 371, 297–300 (1994).

    CAS  Article  Google Scholar 

  27. 27

    Sondek, J., Bohm, A., Lambright, D.G., Hamm, H.E. & Sigler, P.B. Crystal structure of a GA protein beta gamma dimer at 2.1A resolution. Nature 379, 369–374 (1996).

    CAS  Article  Google Scholar 

  28. 28

    Wall, M.A. et al. The structure of the G protein heterotrimer Gi α1β1γ2. 83, 1047–1058 (1995).

  29. 29

    Belmont, L.D. & Mitchison, T.J. Identification of a protein that interacts with tubulin dimers and increases the catastrophe rate of microtubules. Cell 84, 623–631 (1996).

    CAS  Article  Google Scholar 

  30. 30

    Lupas, A.N. et al. Predicting coiled coils from protein sequences. Science 252, 1162–1164 (1991).

    CAS  Article  Google Scholar 

  31. 31

    Klionsky, D.J. & Emr, S.D. A new class of lysosomal/vacuolar protein sorting signals. J. Biol. Chem. 265, 5349–5352 (1990).

    CAS  PubMed  Google Scholar 

  32. 32

    Herman, P.K., Stack, J.H. & Emr, S.D. A genetic and structural analysis of the yeast Vps15 protein kinase: evidence for a direct role of VPS15p in vacuolar protein delivery. EMBO J. 10, 4049–60 (1991).

    CAS  Article  Google Scholar 

  33. 33

    Stack, J.H., Herman, P.K., Schu, P.V. & Emr, S.D. A membrane-associated complex containing the Vps15 protein kinase and the VPS34 PI 3-kinase is essential for protein sorting to the yeast lysosome-like vacuole. EMBO J. 12, 2195–204 (1993).

    CAS  Article  Google Scholar 

  34. 34

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

    CAS  Google Scholar 

  35. 35

    Altschul, S.F., Boguski, M.S., Gish, W. & Wootton, J.C. Issues in searching molecular sequence databases. Nature Genet. 6, 119–129 (1994).

    CAS  Article  Google Scholar 

  36. 36

    Wootton, J.C. & Federhen, S. Analysis of compositionally biased regions in sequence databases. Meth. Enz. 266, 554–571 (1996).

    CAS  Article  Google Scholar 

  37. 37

    Rost, B., Sander, C. & Schneider, R. PHD—an automatic mail server for protein secondary structure prediction. Comput. Appl. Biosci. 10, 53–60 (1994).

    CAS  PubMed  Google Scholar 

  38. 38

    Bork, P. & Gibson, T. Applying motif and profile searches. Meth. Enz. 266, 162–184 (1996).

    CAS  Article  Google Scholar 

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Nagle, D., Karim, M., Woolf, E. et al. Identification and mutation analysis of the complete gene for Chediak–Higashi syndrome. Nat Genet 14, 307–311 (1996). https://doi.org/10.1038/ng1196-307

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