KRT14 haploinsufficiency results in increased susceptibility of keratinocytes to TNF-alpha-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 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-alpha (TNF-alpha)-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-alpha-induced apoptosis. This phenomenon was not observed when cells were cultured in the presence of doxycycline, a known negative regulator of TNF-alpha-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.
Laboratory of Molecular Dermatology and Department of Dermatology, Rambam Health Care Campus, Haifa, Israel.
Jennie
J
Lugassy
John A
JA
McGrath
Peter
P
Itin
Revital
R
Shemer
Julian
J
Verbov
Helen R
HR
Murphy
Akemi
A
Ishida-Yamamoto
John J
JJ
Digiovanna
Dani
D
Bercovich
Nathan
N
Karin
Alon
A
Vitenshtein
Jouni
J
Uitto
Reuven
R
Bergman
Gabriele
G
Richard
Eli
E
Sprecher
D017209:Apoptosis; D002460:Cell Line; D002648:Child; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D053547:Keratin-14 / Q000235:genetics* / Q000502:physiology; D015603:Keratinocytes / Q000378:metabolism*; D007633:Keratins / Q000378:metabolism; D009154:Mutation; D012868:Skin Abnormalities / Q000378:metabolism; D012871:Skin Diseases / Q000235:genetics*; D013577:Syndrome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D053547:Keratin-14; D014409:Tumor Necrosis Factor-alpha; D007633:Keratins