Keratin disorders: from gene to therapy

• Published in: Human molecular genetics 2011-10, Vol.20 (2), p.R189-R197
• Main Authors: IRWIN MCLEAN, W. H, TARA MOORE, C. B
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Biotechnology; Ectodermal Dysplasia - genetics; Ectodermal Dysplasia - metabolism; Ectodermal Dysplasia - therapy; Fundamental and applied biological sciences. Psychology; Gene therapy; Genetic Therapy; Genetics of eukaryotes. Biological and molecular evolution; Hair Diseases - genetics; Hair Diseases - metabolism; Hair Diseases - therapy; Health. Pharmaceutical industry; Humans; Industrial applications and implications. Economical aspects; Keratins - genetics; Keratins - metabolism; Molecular and cellular biology; Mutation; RNA, Small Interfering - genetics; RNA, Small Interfering - therapeutic use
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddr379

The term 'keratin' is generally accepted to refer to the epithelial keratins of soft and hard epithelial tissues such as: skin, cornea, hair and nail. Since their initial characterization, the total number of mammalian keratins has increased to 54, including 28 type I and 26 type II keratins. Inherited defects that weaken the keratin load-bearing cytoskeleton produce phenotypes characterized by fragility of specific subsets of epithelial tissues. The vast majority of mutations are either missense or small in-frame in-del mutations and disease severity often relates to the position of the mutation in relation to the rod domain. The most complex epithelial structure in humans, the hair follicle, contains trichocyte ('hard') keratin filaments and approximately half of the 54 functional human keratin genes are trichocyte keratins. So far, only four of these have been linked to human genetic disorders: monilethrix, hair-nail ectodermal dysplasia, pseudofolliculitis barbae and woolly hair, while the majority of the hair keratins remain unlinked to human phenotypes. Keratin disorders are a classical group of dominant-negative genetic disorders, representing a large healthcare burden, especially within dermatology. Recent advances in RNA interference therapeutics, particularly in the form of small-interfering RNAs, represent a potential therapy route for keratin disorders through selectively silencing the mutant allele. To date, mutant-specific siRNAs for epidermolysis bullosa simplex, pachyonychia congenita and Messmann epithelial corneal dystrophy-causing missense mutations have been developed and proven to have unprecedented specificity and potency. This could herald the dawn of a new era in translational medical research applied to genetics.