Ichthyosis, Follicular Atrophoderma, and Hypotrichosis Caused by Mutations in ST14 Is Associated with Impaired Profilaggrin Processing Thomas Alef, Serena.

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Ichthyosis, Follicular Atrophoderma, and Hypotrichosis Caused by Mutations in ST14 Is Associated with Impaired Profilaggrin Processing Thomas Alef, Serena Torres, Ingrid Hausser, Dieter Metze, Ümit Türsen, Gilles G. Lestringant, Hans Christian Hennies Journal of Investigative Dermatology Volume 129, Issue 4, Pages 862-869 (April 2009) DOI: 10.1038/jid.2008.311 Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Clinical picture and ultrastructural analysis of patients with IFAH. (a–c) Patients from the Arab IFAH family. (a) Dark brown diffuse scaling on the right forearm and follicular atrophoderma on the wrist, hand, and fingers of IV:1 (Figure 2a). (b) Close-up of the phalanx dorsum showing follicular atrophoderma. (c) Unruly, curly scalp hair with the typical receding frontal hairline (IV:3). (d) The Turkish patient IV:1 (Figure 2b) showing light, woolly hair, hypotrichosis of the eyebrows, and the receding frontal hairline. (e–f) Ultrastructural analysis of the upper stratum granulosum and the lower stratum corneum. (e) Patient IV:1 from the Arab family, (f) patient IV:1 from the Turkish family. Dotted lines mark inter- and intralamellar deposits of lamellar body contents in the lower lamellae of the stratum corneum. Amounts of keratohyalin (kh) were reduced. Asterisks denote corneodesmosomes, arrow heads marginal bands of corneocytes (cornified envelopes); n, nucleus; scale bars=1μm. Journal of Investigative Dermatology 2009 129, 862-869DOI: (10.1038/jid.2008.311) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Pedigrees, haplotype analysis, and mutations in ST14. (a) Pedigree of the Arab family with five affected children. The parents were first cousins. Homozygosity defined the critical interval (marked by the box) between D11S4150 and M11TA01. Sequence analysis identified the homozygous mutation c.2269+1G>A in all affected siblings. Exon nucleotides are shown as uppercase, intron nucleotides as lowercase letters. (b) Pedigree of the Turkish family with one affected child. The parents and the paternal grandparents were first cousins. Homozygosity defined the critical interval (marked by the box) between D11S1998 and D11S969. Sequence analysis identified the homozygous mutation c.2034delG. Journal of Investigative Dermatology 2009 129, 862-869DOI: (10.1038/jid.2008.311) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Western blot analysis of matriptase. Primary keratinocytes from the Turkish IFAH patient and control persons were cultivated and differentiated. Differentiation markers keratin 1 and desmoglein 1 were detected in equal amounts in patient and control. Matriptase was completely missing in patient cells as shown with an anti-matriptase antibody recognizing the N-terminal domain of the mature protein. Journal of Investigative Dermatology 2009 129, 862-869DOI: (10.1038/jid.2008.311) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Western blot analysis of prostasin and filaggrin. (a) Proprostasin is activated by proteolytic cleavage after residue Arg-12. Keratinocytes from control persons showed a double band of prostasin zymogen and mature prostasin. Only unprocessed prostasin zymogen was detected in patient samples. (b) Profilaggrin is a large protein of 400–450kDa, composed of 10–12 filaggrin units. Although profilaggrin was almost undetectable in control cells, we observed a massive signal of profilaggrin in patient keratinocytes. (c) Profilaggrin is proteolytically cleaved in terminally differentiating keratinocytes. Only a faint signal is present in patient cells; a significantly larger amount of filaggrin monomers was found in control lysates than in samples from the patient. Probable intermediate products are indicated. Equal protein loading was confirmed by detecting β-actin in patient and control samples. The positions of molecular weight marker signals are shown on the left of each panel. Pa, patient; Co, control. Journal of Investigative Dermatology 2009 129, 862-869DOI: (10.1038/jid.2008.311) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions