KRT14 Haploinsufficiency Results in Increased Susceptibility of Keratinocytes to TNF-α-Induced Apoptosis and Causes Naegeli–Franceschetti–Jadassohn Syndrome

Naegeli–Franceschetti–Jadassohn syndrome (NFJS) is a rare autosomal dominant disorder characterized by loss of dermatoglyphics, reticulate hyperpigmentation of the skin, palmoplantar keratoderma, abnormal sweating, and other developmental anomalies of the teeth, hair, and skin. We recently demonstra...

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Published in:Journal of investigative dermatology 2008-06, Vol.128 (6), p.1517-1524
Main Authors: Lugassy, Jennie, McGrath, John A., Itin, Peter, Shemer, Revital, Verbov, Julian, Murphy, Helen R., Ishida-Yamamoto, Akemi, DiGiovanna, John J., Bercovich, Dani, Karin, Nathan, Vitenshtein, Alon, Uitto, Jouni, Bergman, Reuven, Richard, Gabriele, Sprecher, Eli
Format: Article
Language:English
Subjects:
Apoptosis
Biological and medical sciences
Cell Line
Child
Dermatology
Female
Gene Expression Regulation
Genetic Predisposition to Disease
Hair and nails disorders
Humans
Keratin-14 - genetics
Keratin-14 - physiology
Keratinocytes - metabolism
Keratins - metabolism
Medical sciences
Mutation
Skin Abnormalities - metabolism
Skin Diseases - genetics
Skin involvement in other diseases. Miscellaneous. General aspects
Syndrome
Tumor Necrosis Factor-alpha - metabolism
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Summary:Naegeli–Franceschetti–Jadassohn syndrome (NFJS) is a rare autosomal dominant disorder characterized by loss of dermatoglyphics, reticulate hyperpigmentation of the skin, palmoplantar keratoderma, abnormal sweating, and other developmental anomalies of the teeth, hair, and skin. We recently demonstrated that NFJS is caused by heterozygous nonsense or frameshift mutations in the E1/V1-encoding region of KRT14, but the mechanisms for their deleterious effects in NFJS remain elusive. In this study, we further expand the spectrum of NFJS-causing mutations and demonstrate that these mutations result in haploinsufficiency for keratin 14 (K14). As increased apoptotic activity was observed in the epidermal basal cell layer in NFJS patients and as previous data suggested that type I keratins may confer resistance to tumor necrosis factor-α (TNF-α)-induced apoptosis in epithelial tissues, we assessed the effect of down-regulation of KRT14 expression on apoptotic activity in keratinocytes. Using a HaCaT cell-based assay, we found that decreased KRT14 expression is associated with increased susceptibility to TNF-α-induced apoptosis. This phenomenon was not observed when cells were cultured in the presence of doxycycline, a known negative regulator of TNF-α-dependant pro-apoptotic signaling. Collectively, our results indicate that NFJS results from haploinsufficiency for K14 and suggest that increased susceptibility of keratinocytes to pro-apoptotic signals may be involved in the pathogenesis of this ectodermal dysplasia syndrome.
ISSN:0022-202X
1523-1747
DOI:10.1038/sj.jid.5701187