Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Jan;91(1):357–361. doi: 10.1172/JCI116193

Epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma). Genetic linkage to chromosome 12q in the region of the type II keratin gene cluster.

L Pulkkinen 1, A M Christiano 1, R G Knowlton 1, J Uitto 1
PMCID: PMC330034  PMID: 7678607

Abstract

Epidermolytic hyperkeratosis (EHK) is an autosomal dominant genodermatosis characterized by hyperkeratosis and blistering of the skin. Histopathology demonstrates suprabasilar blister formation with aggregation of tonofilaments. In this study, we tested the hypothesis that the EHK phenotype is linked to one of the suprabasilar keratins (KRT10 or KRT1) present in the types I and II keratin gene clusters in chromosomes 17q and 12q, respectively. For this purpose, Southern hybridizations were performed with DNA from a large kindred with EHK, consisting of 11 affected individuals in three generations. Segregation analysis with markers flanking the keratin gene clusters demonstrated linkage (Z = 3.61 at theta = 0) to a locus on 12q, while markers on 17q were excluded. These data implicate KRT1, the type II keratin expressed in suprabasilar keratinocytes, as a candidate gene in this family with EHK.

Full text

PDF
357

Images in this article

Selected References

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

  1. Ackerman A. B. Histopathologic concept of epidermolytic hyperkeratosis. Arch Dermatol. 1970 Sep;102(3):253–259. [PubMed] [Google Scholar]
  2. Cheng J., Syder A. J., Yu Q. C., Letai A., Paller A. S., Fuchs E. The genetic basis of epidermolytic hyperkeratosis: a disorder of differentiation-specific epidermal keratin genes. Cell. 1992 Sep 4;70(5):811–819. doi: 10.1016/0092-8674(92)90314-3. [DOI] [PubMed] [Google Scholar]
  3. Chipev C. C., Korge B. P., Markova N., Bale S. J., DiGiovanna J. J., Compton J. G., Steinert P. M. A leucine----proline mutation in the H1 subdomain of keratin 1 causes epidermolytic hyperkeratosis. Cell. 1992 Sep 4;70(5):821–828. doi: 10.1016/0092-8674(92)90315-4. [DOI] [PubMed] [Google Scholar]
  4. Compton J. G., DiGiovanna J. J., Santucci S. K., Kearns K. S., Amos C. I., Abangan D. L., Korge B. P., McBride O. W., Steinert P. M., Bale S. J. Linkage of epidermolytic hyperkeratosis to the type II keratin gene cluster on chromosome 12q. Nat Genet. 1992 Jul;1(4):301–305. doi: 10.1038/ng0792-301. [DOI] [PubMed] [Google Scholar]
  5. Coulombe P. A., Hutton M. E., Letai A., Hebert A., Paller A. S., Fuchs E. Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: genetic and functional analyses. Cell. 1991 Sep 20;66(6):1301–1311. doi: 10.1016/0092-8674(91)90051-y. [DOI] [PubMed] [Google Scholar]
  6. Coulombe P. A., Hutton M. E., Vassar R., Fuchs E. A function for keratins and a common thread among different types of epidermolysis bullosa simplex diseases. J Cell Biol. 1991 Dec;115(6):1661–1674. doi: 10.1083/jcb.115.6.1661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Epstein E. H., Jr Molecular genetics of epidermolysis bullosa. Science. 1992 May 8;256(5058):799–804. doi: 10.1126/science.1375393. [DOI] [PubMed] [Google Scholar]
  8. Goldsmith L. A. The ichthyoses. Prog Med Genet. 1976;1:185–210. [PubMed] [Google Scholar]
  9. Holbrook K. A., Dale B. A., Sybert V. P., Sagebiel R. W. Epidermolytic hyperkeratosis: ultrastructure and biochemistry of skin and amniotic fluid cells from two affected fetuses and a newborn infant. J Invest Dermatol. 1983 Apr;80(4):222–227. doi: 10.1111/1523-1747.ep12534504. [DOI] [PubMed] [Google Scholar]
  10. Ishida-Yamamoto A., McGrath J. A., Chapman S. J., Leigh I. M., Lane E. B., Eady R. A. Epidermolysis bullosa simplex (Dowling-Meara type) is a genetic disease characterized by an abnormal keratin-filament network involving keratins K5 and K14. J Invest Dermatol. 1991 Dec;97(6):959–968. doi: 10.1111/1523-1747.ep12491885. [DOI] [PubMed] [Google Scholar]
  11. Ishida-Yamamoto A., McGrath J. A., Judge M. R., Leigh I. M., Lane E. B., Eady R. A. Selective involvement of keratins K1 and K10 in the cytoskeletal abnormality of epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma). J Invest Dermatol. 1992 Jul;99(1):19–26. doi: 10.1111/1523-1747.ep12611391. [DOI] [PubMed] [Google Scholar]
  12. Lane E. B., Rugg E. L., Navsaria H., Leigh I. M., Heagerty A. H., Ishida-Yamamoto A., Eady R. A. A mutation in the conserved helix termination peptide of keratin 5 in hereditary skin blistering. Nature. 1992 Mar 19;356(6366):244–246. doi: 10.1038/356244a0. [DOI] [PubMed] [Google Scholar]
  13. Lessin S. R., Huebner K., Isobe M., Croce C. M., Steinert P. M. Chromosomal mapping of human keratin genes: evidence of non-linkage. J Invest Dermatol. 1988 Dec;91(6):572–578. doi: 10.1111/1523-1747.ep12477087. [DOI] [PubMed] [Google Scholar]
  14. Mattei M. G., Rivière M., Krust A., Ingvarsson S., Vennström B., Islam M. Q., Levan G., Kautner P., Zelent A., Chambon P. Chromosomal assignment of retinoic acid receptor (RAR) genes in the human, mouse, and rat genomes. Genomics. 1991 Aug;10(4):1061–1069. doi: 10.1016/0888-7543(91)90199-o. [DOI] [PubMed] [Google Scholar]
  15. McKinley-Grant L. J., Idler W. W., Bernstein I. A., Parry D. A., Cannizzaro L., Croce C. M., Huebner K., Lessin S. R., Steinert P. M. Characterization of a cDNA clone encoding human filaggrin and localization of the gene to chromosome region 1q21. Proc Natl Acad Sci U S A. 1989 Jul;86(13):4848–4852. doi: 10.1073/pnas.86.13.4848. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Nakamura Y., Ballard L., O'Connell P., Leppert M., Lathrop G. M., Lalouel J. M., White R. Isolation and mapping of a polymorphic DNA sequence pYNH15 on chromosome 12q [D12S17]. Nucleic Acids Res. 1988 Jan 25;16(2):779–779. doi: 10.1093/nar/16.2.779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Nakamura Y., Martin C., Myers R., Ballard L., Leppert M., O'Connell P., Lathrop G. M., Lalouel J. M., White R. Isolation and mapping of a polymorphic DNA sequence (pCMM86) on chromosome 17q [D17S74]. Nucleic Acids Res. 1988 Jun 10;16(11):5223–5223. doi: 10.1093/nar/16.11.5223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ott J. Estimation of the recombination fraction in human pedigrees: efficient computation of the likelihood for human linkage studies. Am J Hum Genet. 1974 Sep;26(5):588–597. [PMC free article] [PubMed] [Google Scholar]
  19. Polakowska R. R., Eddy R. L., Shows T. B., Goldsmith L. A. Epidermal type I transglutaminase (TGM1) is assigned to human chromosome 14. Cytogenet Cell Genet. 1991;56(2):105–107. doi: 10.1159/000133060. [DOI] [PubMed] [Google Scholar]
  20. Rothnagel J. A., Dominey A. M., Dempsey L. D., Longley M. A., Greenhalgh D. A., Gagne T. A., Huber M., Frenk E., Hohl D., Roop D. R. Mutations in the rod domains of keratins 1 and 10 in epidermolytic hyperkeratosis. Science. 1992 Aug 21;257(5073):1128–1130. doi: 10.1126/science.257.5073.1128. [DOI] [PubMed] [Google Scholar]
  21. Ryynänen M., Knowlton R. G., Uitto J. Mapping of epidermolysis bullosa simplex mutation to chromosome 12. Am J Hum Genet. 1991 Nov;49(5):978–984. [PMC free article] [PubMed] [Google Scholar]
  22. Takahashi E., Hori T., O'Connell P., Leppert M., White R. R-banding and nonisotopic in situ hybridization: precise localization of the human type II collagen gene (COL2A1). Hum Genet. 1990 Nov;86(1):14–16. doi: 10.1007/BF00205165. [DOI] [PubMed] [Google Scholar]
  23. Uitto J., Bauer E. A., Moshell A. N. Symposium on epidermolysis bullosa: molecular biology and pathology of the cutaneous basement membrane zone. Jefferson Medical College, Philadelphia, Pennsylvania, October 4 and 5, 1991. J Invest Dermatol. 1992 Mar;98(3):391–395. doi: 10.1111/1523-1747.ep12499822. [DOI] [PubMed] [Google Scholar]
  24. Uitto J., Christiano A. M. Molecular genetics of the cutaneous basement membrane zone. Perspectives on epidermolysis bullosa and other blistering skin diseases. J Clin Invest. 1992 Sep;90(3):687–692. doi: 10.1172/JCI115938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Vuorio E., de Crombrugghe B. The family of collagen genes. Annu Rev Biochem. 1990;59:837–872. doi: 10.1146/annurev.bi.59.070190.004201. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES