Pachyonychia Congenita Syndrome Disease-causing Mutations

Pachyonychia congenita (PC) is an autosomal dominant genodermatosis characterized by ectodermal dysplasias, of which the hypertrophic nail dystrophy is the most prominent. Based on clinical features, pachyonychia cogenita is mainly divided into two main subsets. PC-1 (Jadassohn-Lewandowsky, 1906, MIM#167200) involves the congenital thickening of the nails, oral leukokeratosis, palmar-plantar hyperkaratosis, hyperhidrosis and follicular keratoses. PC-2 (Jackson-Lawler, 1951, MIM#167210) also has the same features as PC-1, but lacks the oral mucosal involvement and possesses the additional features of multiple epidermal cysts. Individuals with PC-2 may also have natal or neonatal teeth, hair abnormalities (pili torti), angular cheilosis, and hidradenitis suppurativa.The pathogenesis of PC is unknown, but ultrastructural histology shows marked increasing of tonofilaments suggesting that PC may be caused by a keratin defect. Recently, the molecular basis for these two forms of PC has been shown they are to be caused by mutations in four differentiation-specific keratin genes. Specifically, PC-1 is the result of mutations in either keratin 16 or its expression partner, KRT6A.. In contrast, PC-2 results from mutations in either keratin 17 or its expression partner KRT6B. Most of the reported mutations in PC are in the highly conserved 1A helix initiation motifs of these keratin genes. The majority of keratin mutations are dominant acting and mostly involve mis-sense or small insertion/deletion mutations clustering at the ends of the rod domain of the keratin molecule.Keratins are the major structural proteins of the epidermis and associated appendages. They are divided into type I, acidic keratins (cytokeratins K9-20; Hatrichocyte keratins)...