Naegeli-Franceschetti-Jadassohn Syndrome and Dermatopathia Pigmentosa Reticularis: Two Allelic Ectodermal Dysplasias Caused by Dominant Mutations in KRT14

Naegeli-Franceschetti-Jadassohn syndrome (NFJS) and dermatopathia pigmentosa reticularis (DPR) are two closely related autosomal dominant ectodermal dysplasia syndromes that clinically share complete absence of dermatoglyphics (fingerprint lines), a reticulate pattern of skin hyperpigmentation, thickening of the palms and soles (palmoplantar keratoderma), abnormal sweating, and other subtle developmental anomalies of the teeth, hair, and skin. To decipher the molecular basis of these disorders, we studied one family with DPR and four families with NFJS. We initially reassessed linkage of NFJS/DPR to a previously established locus on 17q11.2-q21. Combined multipoint analysis generated a maximal LOD score of 8.3 at marker D17S800 at a recombination fraction of 0. The disease interval was found to harbor 230 genes, including a large cluster of keratin genes. Heterozygous nonsense or frameshift mutations in KRT14 were found to segregate with the disease trait in all five families. In contrast with KRT14 mutations affecting the central α-helical rod domain of keratin 14, which are known to cause epidermolysis bullosa simplex, NFJS/DPR-associated mutations were found in a region of the gene encoding the nonhelical head (E1/V1) domain and are predicted to result in very early termination of translation. These data suggest that KRT14 plays an important role during ontogenesis of dermatoglyphics and sweat glands. Among other functions, the N-terminal part of keratin molecules has been shown to confer protection against proapoptotic signals. Ultrastructural examination of patient skin biopsy specimens provided evidence for increased apoptotic activity in the basal cell layer where KRT14 is expressed, suggesting that apoptosis is an important mechanism in the pathogenesis of NFJS/DPR

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