and/or aims): This proposal is based on the applicants' recent demonstration that two large kindreds with EBS show linkage of disease phenotype to specific loci on chromosomes 12q and 17q, sites of clusters of type II and I keratin genes, respectively. The investigators now propose to identify the mutated genes at these sites, suggesting that keratin mutations underlie the epidermal fragility in these two kindreds. The strategy will be to establish that these two linkage loci do indeed lie close to the genes for epidermal keratins, and to assess the latter genes for mutations. The etiologic role of mutations, if identified, will be proven by introduction of genes carrying the patients' mutations into cultured keratinocytes or by developing transgenic mice that reproduce the human disease. The investigators also plan to survey other kindreds with EBS for keratin gene mutations so as to identify regions critical for normal protein function. Finally, they propose to test the reported efficacy of retinoid therapy and, if confirmed, investigate the mechanisms responsible for the effect.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR041120-01
Application #
3161534
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1992-06-01
Project End
1996-05-31
Budget Start
1992-06-01
Budget End
1993-05-31
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Ikeda, S; Shigihara, T; Ogawa, H et al. (1998) Narrowing of the Darier disease gene interval on chromosome 12q. J Invest Dermatol 110:847-8
Hu, Z L; Smith, L; Martins, S et al. (1997) Partial dominance of a keratin 14 mutation in epidermolysis bullosa simplex--increased severity of disease in a homozygote. J Invest Dermatol 109:360-4
Peluso, A M; Bonifas, J M; Ikeda, S et al. (1995) Narrowing of the Hailey-Hailey disease gene region on chromosome 3q and identification of one kindred with a deletion in this region. Genomics 30:77-80
Welsh, E A; Ikeda, S; Peluso, A M et al. (1994) Hailey-Hailey disease is not allelic to Darier's disease. J Invest Dermatol 102:992-3
Aberdam, D; Galliano, M F; Vailly, J et al. (1994) Herlitz's junctional epidermolysis bullosa is linked to mutations in the gene (LAMC2) for the gamma 2 subunit of nicein/kalinin (LAMININ-5). Nat Genet 6:299-304
Ikeda, S; Welsh, E A; Peluso, A M et al. (1994) Localization of the gene whose mutations underlie Hailey-Hailey disease to chromosome 3q. Hum Mol Genet 3:1147-50
Bonifas, J M; Bare, J W; Chen, M A et al. (1993) Evidence against keratin gene mutations in a family with ichthyosis hystrix Curth-Macklin. J Invest Dermatol 101:890-1
Chen, M A; Bonifas, J M; Matsumura, K et al. (1993) A novel three-nucleotide deletion in the helix 2B region of keratin 14 in epidermolysis bullosa simplex: delta E375. Hum Mol Genet 2:1971-2