A New Case of Keratin 14 Functional Knockout Causes Severe Recessive EBS and Questions the Haploinsufficiency Model of Naegeli–Franceschetti–Jadassohn.

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A New Case of Keratin 14 Functional Knockout Causes Severe Recessive EBS and Questions the Haploinsufficiency Model of Naegeli–Franceschetti–Jadassohn Syndrome Matthias Titeux, Audrey Décha, Nathalie Pironon, Laure Tonasso, Géraldine Gasc, José Enrique Mejía, Catherine Prost-Squarcioni, Alain Hovnanian Journal of Investigative Dermatology Volume 131, Issue 10, Pages 2131-2133 (October 2011) DOI: 10.1038/jid.2011.166 Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Clinical features of the patient with recessive EBS, with clarification of basal keratinocytes and lack of keratin 14 staining. (a) Clinical appearance of the patient, pedigree of the family, and fingerprints of the patient (II.1) and his sons (III.1 and III.2). Patient presents with widespread skin blistering more prominent on the hands, wrists and forearms, feet, ankles, and legs. Blisters were often hemorrhagic and led to erythematous and slightly atrophic scars without milia. Nails were dystrophic or absent. Hyperkeratosis was predominant on the soles. (b) Electron microscopy analysis showing cytoplasm clarification (*) of basal keratinocytes. Note the thin meshwork (arrows) made of thin protofilaments (arrowheads) connected to the inner plate of hemidesmosomes near the basement membrane (inset). Bars=1μm. (c) Immunohistochemistry analyses showing absence of keratin 14 staining in the patient skin sections, whereas keratin 5 staining was slightly enhanced and keratin 15 was slightly reduced compared with control skin. Bars=130μm. EBS, epidermolysis bullosa simplex. Journal of Investigative Dermatology 2011 131, 2131-2133DOI: (10.1038/jid.2011.166) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Keratin 14 is not detectable and KRT14 transcripts are dramatically reduced in cultured keratinocytes from the patient. (a) Western blot analysis showing complete absence of keratin 14 (K14) on protein extracts from cultured keratinocytes of the patient, whereas the levels of keratin 5 (K5) and keratin 15 (K15) were similar to that observed in normal human keratinocytes (NHK). No truncated K14 protein of ∼30kDa predicted by the p.Pro276LeufsX4 mutation could be detected using the AE1 antibody recognizing the amino-terminal head domain of type I keratins (Chan et al., 1994) on protein extracts from the soluble or insoluble fractions. The faint bands around 45kDa present in the epidermolysis bullosa simplex (EBS) extract probably correspond to degradation products. (b) Quantitative reverse transcription PCR measurements demonstrating a 15- to 19-fold reduction of the amount of KRT14 mRNA in the patient's keratinocytes compared with NHK, whereas levels of KRT5 and KRT15 mRNA are not significantly changed. (See Supplementary Table S2 online for primer sequences.) Journal of Investigative Dermatology 2011 131, 2131-2133DOI: (10.1038/jid.2011.166) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions