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 alpha -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.
Dowling-Degos disease (DDD; MIM 179850) is a rare autosomal dominant disorder characterized by reticulate flexural hyperpigmentation associated with hyperkeratotic papules, pitted perioral scars and comedo-like lesions or cysts. 1 Characteristic histopathological features include filiform epithelial downgrowths of the rete ridges, typically involving the follicular infundibulum, basilar hyperpigmentation and dermal melanosis. Follicular retention cysts and perivascular mononuclear infiltrates can also be present. 1 Galli-Galli disease is a term that has been used to describe patients displaying prominent acantholytic changes on histology, in addition to clinical and pathological features resembling those of DDD. 2 Two mutations in KRT5, encoding one of the two major basal epidermal keratin intermediate filaments, were recently reported to underlie DDD in a number of European cases. 3 In the present study, we report a novel mutation in KRT5 in a patient with clinical and histopathological features typical of Galli-Galli disease.
Case and methods
Background: LOXL2 inhibits keratinocyte differentiation. This activity was thought to require LOXL2 enzyme activity. Results: LOXL2 mutants lacking enzyme activity nevertheless inhibit keratinocyte differentiation. The fourth scavenger receptor-cysteine-rich domain of LOXL2 is required for this activity. Conclusion: LOXL2 induces keratinocyte differentiation independently of its enzyme activity. Significance: Our results suggest that LOXL2 may affect diverse biological processes independently of its enzyme activity.
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