Integrin 4 mutations associated with junctional epidermolysis bullosa with pyloric atresia

Pyloric atresia associated with junctional epidermolysis bullosa (PA−JEB), is a rare inherited disorder characterized by pyloric stenosis and blistering of the skin as primary manifestations. We demonstrate that in one PA−JEB patient the disease resulted from two distinct mutations in the 4 integrin gene alleles. The paternal mutation consists of a one base pair deletion causing a shift in the open reading frame, and a downstream premature termination codon. The maternal mutation occurs in a donor splice site, and results in in−frame exon skipping involving the cytoplasmic domain of the polypeptide. Our results implicate mutations in the 4 integrin gene in some forms of PA−JEB.

1. Hynes, R.O. Integrins: versatility, modulation and signaling in cell adhesion. Cell. 69, 11–25 (1992). | Article | PubMed  | ISI | ChemPort |
2. Anderson, D.C. & Springer, T.A. Leukocyte adhesion deficiency: an inherited defect in the Mac-1, LFA-1, and p150,95 glycoproteins. A. Rev. Med. 38, 175–194 (1987). | Article | ISI | ChemPort |
3. George, J.N., Caen, J.P. & Nurden, A.T. Glanzmann's thrombasthenia: the spectrum of clinical disease. Blood. 75, 1383–1395 (1990). | PubMed  | ISI | ChemPort |
4. De Luca, M. et al. Polarized integrin mediates human keratinocyte adhesion to basal lamina. Proc. natn. Acad. Sci. U.S.A. 87, 6888–6892 (1990). | ChemPort |
5. Marchisio, P.C., Bondanza, S., Cremona, O., Cancedda, R. & De Luca, M. Polarized expression of integrin receptors ( 64, 21 and v5) and their relationship with the cytoskeleton and basement membrane matrix in cultured human keratinocytes. J. Cell Biol. 112, 761–773 (1991). | Article | PubMed  | ISI | ChemPort |
6. Larjava, H. et al. Novel function for 1 integrins in keratinocyte cell-cell interactions. J. Cell Biol. 110, 803–815 (1990). | Article | PubMed  | ISI | ChemPort |
7. Carter, W.G., Wayner, E.A., Bouchard, T.S. & Kaur, P. The role of integrins 21 and 31 in cell-cell and cell-substrate adhesion of human epidermal cells. J. Cell Biol. 110, 1387–1404 (1990). | Article | PubMed  | ISI | ChemPort |
8. Carter, W.G., Kaur, P., Gil, S.G., Gahr, P.J. & Wayner, E.A. Distinct functions for integrins 31 in focal adhesions and 64/bullous pemphigoid antigen in a new stable anchoring contact (SAC) of keratinocytes: relation to hemidesmosomes. J. Cell Biol. 111, 3141–3154 (1990). | Article | PubMed  | ISI | ChemPort |
9. Sonnenberg, A. et al. Integrin 64 complex is located in hemidesmosomes, suggesting a major role in epidermal cell-basement membrane adhesion. J. Cell Biol. 113, 907–917 (1991). | Article | PubMed  | ISI | ChemPort |
10. Stepp, M.A., Spurr-Michaud, S., Tisdale, A., Elwell, J. & Gipson, I.K. 64 integrin heterodimer is a component of hemidesmosomes. Proc. natn. Acad. Sci. U.S.A. 87, 8970–8974 (1990). | ChemPort |
11. Jones, J.C.R., Kurpakas, M.A., Cooper, M.H. A function for the integrin 64 in the hemidesmosome. Cell Regul. 2, 427–438 (1991). | PubMed  | ISI | ChemPort |
12. Garrod, D.R. Desmosomes and hemidesmosomes. Curr. Op. Cell Biol. 5, 30–40 (1993). | PubMed  | ChemPort |
13. Spinardi, L., Ren, Y.-L, Sanders, R. & Giancotti, F.G. The 4 subunit cytoplasmic domain mediates the interaction of 64 integrin with the cytoskeleton of hemidesmosomes. Mol. Biol. Cell. 4, 871–684 (1993). | PubMed  | ISI | ChemPort |
14. Tamura, R.N. et al. Epithelial 64: complete primary structure of 6 and variant forms of 4. J. Cell Biol. 111, 1593–1604 (1990). | Article | PubMed  | ISI | ChemPort |
15. Suzuki, S. & Naitoh, Y. Amino acid sequence of a normal integrin 4 subunit and primary expression of the mRNA in epithelial cells. EMBO J. 9, 757–763 (1990). | PubMed  | ISI | ChemPort |
16. Hogervorst, F., Kuikman, I., Von Dem Borne, A.E. & Sonnenberg, A. Cloning and sequence analysis of 4 cDNA: an integrin subunit that contains a unique 118 kD cytoplasmic domain. EMBO J. 9, 765–770 (1990). | PubMed  | ISI | ChemPort |
17. Jonkman, M.F., de Jong, M.C.J.M., Heeres, K. & Sonnenberg, A. Expression of integrin 64 in junctional epidermolysis bullosa. J. invest. Dermatol. 99, 489–496 (1992). | PubMed  | ISI | ChemPort |
18. Phillips, R.J., Aplin, J.D. & Lake, B.D. Antigenic expression of integrin 64 in junctional epidermolysis bullosa. Histopathology. 24, 571–576 (1994). | PubMed  | ISI | ChemPort |
19. Fine, J.D., Bauer, E.A., Briggaman, R.A. & Carter, D.M Revised clinical and laboratory criteria for subtypes of inherited epidermolysis bullosa. J. Am. Acad. Dermatol. 24, 119–135 (1991). | PubMed  | ISI | ChemPort |
20. Baudoin, C., Miquel, C., Blanchet-Bardon, C., Gambini, C., Meneguzzi, G. & Ortonne, J.P. Herlitz junctional epidermolysis bullosa keratinocytes display heterogenous defects of nicein/kalinin gene expression. J. din. Invest. 93, 862–869 (1994). | ChemPort |
21. Aberdam, D. et al. Herlitz's junctional epidermolysis bullosa is genetically linked to mutations in the nicein/kalinin (laminin 5) LAMC2 gene. Nature Genet. 6, 299–304 (1994). | Article | PubMed  | ISI | ChemPort |
22. Pulkkinen, L. et al. Mutations in the 2 chain gene (LAMC2) of kalinin/laminin 5 in the junctional forms of epidermolysis bullosa. Nature Genet. 6, 293–298 (1994). | Article | PubMed  | ISI | ChemPort |
23. Pulkkinen, L. et al. A homozygous nonsense mutation in the 3 chain gene of laminin 5 (LAMBS) in Herlitz junctional epidermolysis bullosa. Genomics. 24, 357–360 (1994). | Article | PubMed  | ISI | ChemPort |
24. Lacour, J.P. et al. Lethal junctional epidermolysis bullosa with normal expression of BM 600 and antro-pyloric atresia: a new variant of junctional epidermolysis bullosa? Eur. J. Pediatr. 151, 252–257 (1992). | PubMed  | ISI | ChemPort |
25. Lestringant, G.G., Akel, S.R. & Qayed, K.I. The pyloric atresia-junctional epidermolysis bullosa syndrome. Arch. Dermatol. 128, 1083–1086 (1992). | Article | PubMed  | ISI | ChemPort |
26. McKusick, V.A. Mendelian inheritance in man. (Johns Hopkins University Press, Baltimore, 1992).
27. Mueller, S., Klaus-Kovtun, V. & Stanley, J.R. A 230-kD basic protein is the major bullous pemphigoid antigen. J. Invest. Dermatol. 92, 33–38 (1989). | PubMed  | ISI | ChemPort |
28. Hieda, Y., Nishizawa, Y., Uematsu, J. & Owaribe, K. Identification of a new hemidesmosomal protein, HD1: A major, high molecular mass component of isolated hemidesmosomes. J. Cell Biol. 116, 1497–1506 (1992). | Article | PubMed  | ISI | ChemPort |
29. Green, M.R. Biochemical mechanisms of constitutive and regulated pre-mRNA splicing. A. Rev. Cell Biol. 7, 559–599 (1991). | ISI | ChemPort |
30. Dietz, H.C. et al. The skipping of constitutive exons in vivo induced by nonsense mutations. Science 259, 680–683 (1993). | PubMed  | ISI | ChemPort |
31. Mclntosh, I., Hamosh, A. & Dietz, H.C. Nonsense mutations and diminished mRNA levels. Nature Genet. 4, 219 (1993). | Article | PubMed  | ISI | ChemPort |
32. Solowska, J., Edelman, J.M., Albelda, S.M. & Buck, C.A. Cytoplasmic and transmembrane domains of integrin 1 and 2 subunits are functionally interchangeable. J. Cell Biol. 114, 1079–1088 (1991). | Article | PubMed  | ISI | ChemPort |
33. Pytela, R., Pierschbacher, M.D. & Ruoslahti, E. Identification and isolation of a 140 kD cell surface glycoprotein with properties expected of a fibronectin receptor. Cell 40, 191–196 (1985). | Article | PubMed  | ISI | ChemPort |
34. Benian, G.M., Kiff, J.E., Neckelmann, N., Moerman, U.G. & Waterston, R.H. Sequence of an unusually large protein implicated in regulation of myosin activity in C. elegans. Nature 342, 45–50 (1989). | Article | PubMed  | ISI | ChemPort |
35. Morla, A. & Ruoslahti, E. A fibronectin self-assembly site involved in fibronectin matrix assembly: reconstruction in a synthetic peptide. J. Cell Biol. 118, 421–429 (1992). | Article | PubMed  | ISI | ChemPort |
36. Giancotti, F.G., Stepp, M.A., Suzuki, S., Engvall, E. & Ruoslahti, E. Proteolytic processing of endogenous and recombinant 4 integrin subunit. J. Cell Biol. 118, 951–959 (1992). | Article | PubMed  | ISI | ChemPort |
37. Chang, C.H., Perrin, E.V. & Bove, K.E. Pyloric atresia associated with epidermolysis bullosa: special reference to pathogenesis. Pediatr. Pathol. 1, 449–457 (1983). | PubMed  | ChemPort |
38. Frieden, I.J. Aplasia cutis congenita: a clinical review and proposal for for classification. J. Am. Acad. Dermatol. 14, 646–660 (1986). | PubMed  | ISI | ChemPort |
39. Kurpakus, M.A., Quaranta, V. & Jones, J.C. Surface relocation of 64 integrins and assembly of hemidesmosomes in an in vitro model of wound healing. J. Cell Biol. 115, 1737–1750 (1991). | Article | PubMed  | ISI | ChemPort |
40. Gipson, I.K., Spurr-Michaud, S., Tisdale, A., Elwell, J. & Stepp, M.A. Redistribution of the hemidesmosome component 64 integrin and bullous pemphigoid antigens during epithelial wound healing. Exp. Cell Res. 207, 86–98 (1993). | Article | PubMed  | ISI | ChemPort |
41. Hertle, M.D., Kubler, M.D., Leigh, I.M. & Watt, F.M. Aberrant integrin expression during epidermal wound healing and in psoriatic epidermis. J. din. Invest. 89, 1892–1901 (1992). | ChemPort |
42. Larjava, H., Salo, T., Haapasalmi, K., Kramer, R.H. & Heino, J. Expression of integrins and basement membrane components by wound keratinocytes. J. din. Invest. 92, 1425–1435 (1993). | ChemPort |
43. Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular cloning. A laboratory manual. (Cold Spring Harbor Laboratory Press, NY, 1989).
44. Ortonne, J.P. et al. The epidermal antigen recognized by monoclonal antibody GB36 is very late antigen 6 (VLA-6). J. invest. Dermatol. 94, 400 (1990). | ISI |
45. Sonnenberg, A., Modderman, P.W. & Hogervorst, F. Laminin receptor on platelets is the integrin VLA-6. Nature 336, 487–489 (1988). | Article | PubMed  | ISI | ChemPort |
46. Kennel, S.J. et al. Second generation monoclonal antibodies to human integrin 64. Hybridoma 9, 243–255 (1990). | PubMed  | ISI | ChemPort |
47. Niessen, C.M. et al. Expression of the integrin 64 in peripheral nerves: localization in Schwann and perineural cells and different variants of the 4 subunit. J. Cell Sci. 107, 543–552 (1994). | PubMed  | ISI | ChemPort |
48. Tanaka, T. et al. Production of rabbit antibodies against carboxy-terminal epitopes encoded by bullous pemphigoid cDNA. J. invest Dermatol. 94, 617–623 (1989). | ISI |
49. Owaribe, K., Nishizawa, Y. & Franke, W.W. Isolation and characterization of hemidesmosomes from bovine corneal epithelial cells. Exp. Cell Res. 192, 622–630 (1991). | PubMed  | ISI | ChemPort |
50. Hogervorst, F., Kuikman, I., van Kessel, G.A. & Sonnenberg, A. Molecular cloning of the human 6 integrin subunit. Alternative splicing of 6 mRNA and chromosomal localization of the 6 and 4 genes. Eur. J. Biochem. 199, 425–433 (1991). | PubMed  | ISI | ChemPort |

	Top

	Top