Epidermolysis bullosa simplex are a group of inherited disorders characterized primarily by nonscarring intraepidermal blisters that result from lysis of basal cells induced by mechanical trauma. For 3 of the clinical variants, the molecular basis of the skin fragility has been identified as mutations in either one of the basal cell-specific keratins. Keratins 5 and 14 form obligate heterodimers, which assemble in a series of higher ordered interactions to construct the 10 nm keratin intermediate filament. Missense mutations in either keratin 5 or 14 that interfere with molecular assembly or structure result in an abnormal keratin cytoskeletal network and cell fragility. Defects in novel proteins, which either interact with the keratin cytoskeleton, modify the filaments, or mediate filament attachment to cellular components, such as the nuclear envelope, hemidesmosome, desmosome, or other structures, may underlie other disorders of skin fragility. Towards the goals of understanding the normal structure and function of the keratin cytoskeleton, how different mutations in keratin interfere with cytoskeletal assembly and function, and if genomic imprinting influences the incidence of new mutations in keratin genes, we propose to accomplish the following specific aims: 1. To identify and characterize proteins that interact with keratins. 2. To determine if new keratin gene mutations preferentially occur on the paternal or maternal allele. 3. To determine if keratin gene defects underlie either bullous diseases with unusual clinical presentation or other selected disorders of keratinization. 4. To identify and collect patients with an unusual presentation of bullous disease and/or other genetic disorder that may result from defects in-associated proteins. This work may provide new insight into the structure and function of the keratin cytoskeleton, identify novel proteins important in normal keratinocyte function and differentiation, and identify new mutations underlying bullous disorders.
| Chan, Aegean; Godoy-Gijon, Elena; Nuno-Gonzalez, Almudena et al. (2015) Cellular basis of secondary infections and impaired desquamation in certain inherited ichthyoses. JAMA Dermatol 151:285-92 |
| Bunick, Christopher G; Presland, Richard B; Lawrence, Owen T et al. (2015) Crystal Structure of Human Profilaggrin S100 Domain and Identification of Target Proteins Annexin II, Stratifin, and HSP27. J Invest Dermatol 135:1801-1809 |
| Mitchell, Anna L; Judis, LuAnn M; Schwarze, Ulrike et al. (2012) Characterization of tissue-specific and developmentally regulated alternative splicing of exon 64 in the COL5A1 gene. Connect Tissue Res 53:267-76 |
| Chatterjea, Sudeshna M; Resing, Katheryn A; Old, William et al. (2011) Optimization of filaggrin expression and processing in cultured rat keratinocytes. J Dermatol Sci 61:51-9 |
| Mitchell, Anna L; Schwarze, Ulrike; Jennings, Jessica F et al. (2009) Molecular mechanisms of classical Ehlers-Danlos syndrome (EDS). Hum Mutat 30:995-1002 |
| Abrass, C K; Berfield, A K; Ryan, M C et al. (2006) Abnormal development of glomerular endothelial and mesangial cells in mice with targeted disruption of the lama3 gene. Kidney Int 70:1062-71 |
| Kelsell, David P; Norgett, Elizabeth E; Unsworth, Harriet et al. (2005) Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis. Am J Hum Genet 76:794-803 |
| Pirrone, Annalisa; Hager, Barbara; Fleckman, Philip (2005) Primary mouse keratinocyte culture. Methods Mol Biol 289:3-14 |
| Presland, Richard B; Fleckman, Philip (2005) Tetracycline-regulated gene expression in epidermal keratinocytes. Methods Mol Biol 289:273-86 |
| Frank, Diane E; Carter, William G (2004) Laminin 5 deposition regulates keratinocyte polarization and persistent migration. J Cell Sci 117:1351-63 |
Showing the most recent 10 out of 150 publications
