Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal dysplasias caused by dominant mutations in KRT14

Abstract

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.

Figure  1.

Clinical features of NFJS. a, Reticulate pigmentation in the left axilla. b, Plantar keratoderma. c, Nail dystrophy. d, Absence of fingerprints in an NFJS patient (right) as compared with normal fingerprints (left).

Figure  2.

Candidate-gene analysis. a, Haplotype analysis of families 3–5, performed using polymorphic markers on chromosome 17q11.2-q21. Blackened symbols represent affected individuals. The disease-associated haplotype found in the three families is boxed in red. b, Direct sequencing of KRT14 reveals pathogenic mutations in all affected individuals. The left panels depict the mutant sequences; wild-type sequences are given for comparison on the right. c, Spectrum of dominant (red) and recessive (black) nonsense/frameshift mutations in KRT14. The mutations are indicated along a schematic representation of the keratin 14 subdomains. The region harboring mutations causing NFJS/DPR, recessive EBS (REBS), and dominant EBS (DEBS) are marked as red, purple, and green bars, respectively.

Figure  3.

Ultrastructural features of NFJS. a, Perinuclear keratin filament retraction without peripheral shell formation in suprabasal cells. Tonofilaments are normally connected to desmosomes (magnification ×3,400). b, Keratin filament condensation in basal cells (magnification ×1,700). c, Amyloid bodies in the papillary dermis underneath the basement membrane (magnification ×3,400). These structures are composed of straight, nonbranching amyloid filaments (insert). d, The location of panels a–c is given along a scheme of the epidermal layers.