Post Zygotic, Somatic, Deletion in KERATIN 1 V1 Domain Generates Structural Alteration of the K1/K10 Dimer, Producing a Monolateral Palmar Epidermolytic Nevus

Palmoplantar keratodermas (PPKs) are characterized by thickness of stratum corneum and epidermal hyperkeratosis localized in palms and soles. PPKs can be epidermolytic (EPPK) or non epidermolytic (NEPPK). Specific mutations of keratin 16 (K16) and keratin 1 (K1) have been associated to EPPK, and NEPPK. Cases of mosaicism in PPKs due to somatic keratin mutations have also been described in scientific literature. We evaluated a patient presenting hyperkeratosis localized monolaterally in the right palmar area, characterized by linear yellowish hyperkeratotic lesions following the Blaschko lines. No other relatives of the patient showed any dermatological disease. Light and confocal histological analysis confirmed the presence of epidermolityic hyperkeratosis. Genetic analysis performed demonstrates the heterozygous deletion NM_006121.4:r.274_472del for a total of 198 nucleotides, in KRT1 cDNA obtained by a palmar lesional skin biopsy, corresponding to the protein mutation NP_006112.3:p.Gly71_Gly137del. DNA extracted from peripheral blood lymphocytes did not display the presence of the mutation. These results suggest a somatic mutation causing an alteration in K1 N-terminal variable domain (V1). The deleted sequence involves the ISIS subdomain, containing a lysine residue already described as fundamental for epidermal transglutaminases in the crosslinking of IF cytoskeleton. Moreover, a computational analysis of the wild-type and V1-mutated K1/K10 keratin dimers, suggests an unusual interaction between these keratin filaments. The mutation taster in silico analysis also returned a high probability for a deleterious mutation. These data demonstrate once again the importance of the head domain (V1) of K1 in the formation of a functional keratinocyte cytoskeleton. Moreover, this is a further demonstration of the presence of somatic mutations arising in later stages of the embryogenesis, generating a mosaic phenotype.

Epidermal Green Autofluorescence is A Novel Biomarker for Local Inflammation of the Skin

Inflammation of the skin is not only a key pathological factor of multiple major skin diseases, but also a hallmark of the pathological state of the skin. However, there has been significant deficiency in the biomarkers and approaches for non-invasive evaluations of local inflammation of the skin. In our current study, we used a mouse model of skin inflammation to test our hypothesis that the inflammation of the skin can lead to increased epidermal green autofluorescence (AF), which can become a novel biomarker for non-invasive evaluations of the local inflammation of the skin. We found that 12-O-tetradecanoylphorbol-13-acetate (TPA), a widely used inducer of skin inflammation, induced not only inflammation of the skin, but also increased green AF of the skin. The distinct polyhedral structure of the increased AF has indicated that the AF originates from the keratin 1 and/or keratin 10 of the suprabasal keratinocytes. Our Western blot assays showed that TPA produced dose-dependent decreases in the levels of both keratin 1 and keratin 10, suggesting that TPA produced the increased epidermal green AF at least partially by inducing cleavage of keratin 1 and/or keratin 10. Collectively, our study has indicated that epidermal green AF is a novel biomarker for non-invasive evaluations of the local inflammation of the skin. This finding is of profound and extensive significance for non-invasive and efficient diagnosis of multiple inflammation-mediated skin diseases. This biomarker may also be used for non-invasive and rapid evaluations of the health state of the skin.