Nature Genetics
6, 299 - 304 (1994)
doi:10.1038/ng0394-299
Herlitz's junctional epidermolysis bullosa is linked to mutations in the gene (LAMC2) for the  2 subunit of nicein/kalinin (LAMININ−5)Daniel Aberdam1, Marie-Florence Galliano1, Joëlle Vailly1, Leena Pulkkinen2, 5, Jeannette Bonifas3, Angela M. Christiano2, Karl Tryggvason4, Jouni Uitto2, Ervin H. Epstein Jr3, Jean-Paul Ortonne1
& Guerrino Meneguzzi1
1INSERM U385, Faculté de Médecine, 06107 Nice cedex 2, France
2Department of Dermatology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
3Department of Dermatology, University of California, San Francisco General Hospital, San Francisco, California 94110, USA
4Biocenter and Department of Biochemistry, University of Oulu, 90570 Oulu, Finland
5L.P. is on leave of absence from Department of Obstetrics & Gynecology, Section of Prenatal Diagnosis, Kuopio University Hospital, Kuopio, Finland Correspondence should be addressed to G.M. We have linked Herlitz's junctional epidermolysis bullosa (H−JEB) to the gene (LAMC2) encoding the  2 subunit of nicein/kalinin, an isolaminin (laminin−5) expressed by basal keratinocytes. In four H−JEB kindreds, a maximum two−point lod score of 5.33 at  =0 was observed between a microsatellite near LAMC2 at 1 q25−31 and the disease. In one family, a homozygous point mutation leading to a premature stop codon (CGA to TGA) was identified in exon 3 of the gene. The segregation of the mutated allele implicates the mutation in the pathology of the disorder and corroborates the linkage results.
REFERENCES
- Fine, J.D. et al. Revised clinical and laboratory criteria for subtypes of inherited epidermolysis bullosa. J. Am. Acad. Dermatol. 24, 119−135 (1991).
- Epstein, E.H. Molecular genetics of epidermolysis bullosa. Science 256, 799−804 (1992).
- Fine, J.D. Epidermolysis bullosa: clinical aspects, pathology and recent advances in research. Int. J. Dermatol. 25, 143−157 (1986).
- Verrando, P. et al. Monoclonal antibody GB3, a new probe for the study of human basement membranes and hemidesmosomes. Exp. cell Res. 170, 116−128 (1987).
- Kallunki, P. et al. A truncated laminin chain homologous to the B2 chain: structure, spatial expression and chromosomal assignement. J. cell Biol. 119, 679−693 (1992).
- Vailly, J. et al. The 100-kDa chain of nicein/kalinin is a laminin B2 chain variant. Eur. J. Blochem. 219, 209−218 (1994).
- Gerecke, D., Wagman, D.W., Champliaud, M.F. & Burgeson, R.E. The complete primary structure for a novel lamin chain, the laminin B1 k chain. J. biol. Chem. (in the press).
- Baudoin, C. et al. The 150 kD subunit of the basement membrane component BM600/nicein shares homologies with the chain A of human laminin. J. invest. Dermatol. (in the press).
- Engel, J. Laminins and other strange proteins. Biochemistry 31, 10643−10651 (1992).
- Burgeson, R.E. et al. A new nomenclature for laminins. Matrix Biol. (in the press).
- Baudoin, C. et al. Herlitz junctional epidermolysis bullosa keratinocytes display heterogeneous defects of nicein gene expression. J. clin. Invest. (in the press).
- Vailly, J., et al. The genes for nicein/kalinin 125kDa and 100kDa subunits, candidates for junctional epidermolysis bullosa, map to chromosome 1q32 and 1 q25−q31. Genomics (in the press).
- Aberdam, D. et al. Assignement of mouse nicein (laminin 5) genes to chromosome 1 and 18. Mamm. Genome (in the press).
- Rousselle, P., Lunstrum, G.P., Keene, D.R. & Burgeson, R.E. Kalinin: an epithelium-specific basement membrane adhesion molecule that is a component of anchoring filaments. J. cell Biol. 114, 567−576 (1991).
- Carter, W.G., Ryan, M.C. & Gahr, P.J. Epilligrin, a new cell adhesion ligand for integrin
 3 1 in epithelial basement membranes. Cell. 65, 599−610 (1991).
- Sakai, L.I., Keene, D.R., Morris, N.P. & Burgeson, R.E. Type VII collagen is a major structural component of anchoring fibrils. J. cell Biol. 114, 1567−1586 (1986).
- Burgeson, R.E. Type VII collagen, anchoring fibrils and epidermolysis bullosa. J. invest. Dermatol. 101, 252−255 (1993).
- Verrando, P. et al. Monoclonal antibody GB3 defines a widespread defect of several basement membranes and a keratinocyte dysfunction in patient with lethal junctional epidermolysis bullosa. Lab. Invest. 64, 85−92 (1991).
- Meneguzzi, G., Marinkovich, M.P., Aberdam, D., Burgeson, R. & Ortonne, J.P. Abnormal expression of kalinin in the Herlitz's JEB epithelial basement membrane. Exp. Dermatol. 1, 221−229 (1992).
- Fine, J.D. 19-DEJ-1, a monoclonal antibody to the hemidesmosome-anchoring filament complex, is the only reliable immunohistochemical probe for all major forms of junctional epidermolysis bullosa. Arch. Dermatol. 126, 1187−1190 (1990).
- Welssenbach, J. et al. A second-generation linkage map of the human genome. Nature 359, 794−801 (1992).
- Group, N.C.C.M. A comprehensive genetic linkage map of the human genome. Science 258, 148−162 (1992).
- Bare, J.W., Lebo, R.V. & Epstein, E.H.Jr. Loss of heterozygosity at chromosome 1q22 in basal cell carcinomas and exclusion of the basal cell nevus syndrome gene from this site. Cancer Res. 52, 1494−1498 (1992).
- Verrando, P. et al. Differential immunoreactivity of antibodies to the basement membrane protein nicein (BM600) in Junctional Epidermolysis Bullosa. J. invest. Dermatol. 101, 738−743 (1993).
- Woodley, D.T. & McNutt, S. In Epidermolysis bullosa. Basic and clinical aspects. (eds Lin, A.N. & Carter, D.M.) 19−36 (Springer-Verlag, New York, 1992).
- 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).
- Marinkovich, M.P., Lunstrum, G.P., Keene, D.R. & Burgeson, R.E. The dermal-epidermal junction of human skin contains a novel laminin variant. J. cell Biol. 119, 695−703 (1992).
- Christiano, A. M. et al. A missense mutation in type VII collagen in two affected siblings with recessive dystrophic epidermolysis bullosa. Nature Genet. 4, 62−66 (1993).
- Uitto, J. & Christiano, A. M. Dystrophic forms of epidermolysis bullosa. Sem. Dermatol. 12, 191−201 (1993).
- Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular cloning: A laboratory manual. (Cold Spring Harbor Laboratory Press, New York, 1989).
- Ortonne, J.P. et al. The epidermal antigen recognized by monoclonal antibody GB36 is very late antigen 6 (VLA-6). J. invest. Dermatol. 94, 400A (1990).
- Browne, D.L. & Litt, M. Characterization of (CA)n microsatellites with degenerate sequencing primers. Nucl. Acids Res. 200, 141 (1992).
- Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Strategies for multilocus linkage analysis in humans. Proc. natn. Acad. Sci. U.S.A. 81, 3443−3446 (1984).
- Rheinwald, J.G. & Green, H. Serial cultivation of strains of human epidermal keratinocytes; the formation of keratinocyte colonies from single cells. Cell 6, 331−344 (1975).
- Simon, M. & Green, H. Enzymatic cross-linking of involucrin and other proteins by keratinocytes particulates in vitro. Cell 40, 677−683 (1985).
- Chomzynski, P. & Sacchi, N. Single step method of RNA isolation by acid guanidium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156−159 (1987).
|
