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

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Item Type:	Article
Title:	Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis: Two allelic ectodermal dysplasias caused by dominant mutations in KRT14
Creators Name:	Lugassy, J., Itin, P., Ishida-Yamamoto, A., Holland, K., Huson, S., Geiger, D., Hennies, H.C., Indelman, M., Bercovich, D., Uitto, J., Bergman, R., McGrath, J.A., Richard, G. and Sprecher, E.
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.
Keywords:	Apoptosis, Biopsy, Dermatoglyphics, Dominant Genes, Ectodermal Dysplasia, Frameshift Mutation, Keratin-14, Keratins, Lod Score, Microsatellite Repeats, Mutation, Nonsense Codon, Pedigree, Polymerase Chain Reaction, Sweat Glands, Syndrome, Tertiary Protein Structure
Source:	American Journal of Human Genetics
ISSN:	0002-9297
Publisher:	University of Chicago Press
Volume:	79
Number:	4
Page Range:	724-730
Date:	October 2006
Official Publication:	https://doi.org/10.1086/507792
PubMed:	View item in PubMed

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