Autosomal Recessive Ichthyosis with Hypotrichosis Caused by a Mutation in ST14, Encoding Type II Transmembrane Serine Protease Matriptase Lina Basel-Vanagaite,

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Autosomal Recessive Ichthyosis with Hypotrichosis Caused by a Mutation in ST14, Encoding Type II Transmembrane Serine Protease Matriptase Lina Basel-Vanagaite, Revital Attia, Akemi Ishida-Yamamoto, Limor Rainshtein, Dan Ben Amitai, Raziel Lurie, Metsada Pasmanik-Chor, Margarita Indelman, Alex Zvulunov, Shirley Saban, Nurit Magal, Eli Sprecher, Mordechai Shohat The American Journal of Human Genetics Volume 80, Issue 3, Pages 467-477 (March 2007) DOI: 10.1086/512487 Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 1 Clinical features of the patients. A and B, Hair of patients III-1 and III-8, respectively. Sparse and curly hair is observed. C and D, Ichthyotic skin of patient III-1 on the trunk and of patient III-5 on the upper limb, respectively. The American Journal of Human Genetics 2007 80, 467-477DOI: (10.1086/512487) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 2 Light microscopy (A–C) and SEM (D–F) examination of hair obtained from affected patients. A and B, Dysplastic hair. Hair shafts are irregular, flaky, and undulating (A). B, Magnified undulation of panel A. C, Pili torti. Affected shaft is twisted on its own axis. D and E, Pili bifurcati. Each bifurcation produces two separate parallel branches that fuse again to form a single shaft; each branch is covered with its own cuticle. F, Central pili mono bifurcati: bifurcation that does not fuse again to the hair shaft and is located in the middle of the hair shaft. A minimum of 50 hairs from each patient were examined. The American Journal of Human Genetics 2007 80, 467-477DOI: (10.1086/512487) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 3 Family tree, candidate region, and mutation analysis. A, Pedigree of the family and segregation analysis of the mutation. Segregation was assayed by PCR amplification of the genomic DNA and restriction by BpmI. The wild-type allele is uncut. Blackened symbols represent affected individuals. An arrow shows informative recombination. B, Candidate region. C, Mutation analysis of ST14. Sequence chromatogram from wild-type (WT), carrier (C), and affected (M) genotypes on genomic DNA. The American Journal of Human Genetics 2007 80, 467-477DOI: (10.1086/512487) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 4 Multiple alignment and conservation analysis of human ST14 with its orthologues. A, Multiple sequence alignment, performed by ClustalW (Clustal Alignment), with use of 10 protein sequences of matriptase, including vertebrates from fish to human: Homo sapiens (human) ST14, (GenBank accession number NP_068813), Homo sapiens (human) prostamin (GenBank accession number BAB20376), Homo sapiens (human) serine protease (GenBank accession number AAG15395), Pan troglodytes (chimpanzee) homologue (GenBank accession number XP_508863), Mus musculus (mouse) matriptase (GenBank accession number BAE38987), Rattus norvegicus (rat) matriptase (GenBank accession number AAH97271), Gallus gallus (chicken) matriptase (GenBank accession number XP_417872), Canis familiaris(dog) matriptase (GenBank accession number XP_546396), Xenopus laevis (frog) matriptase (GenBank accession number AAH71077), and Danio rerio (zebrafish) hypothetical protein (GenBank accession number NP_001035441). G827 is marked with an arrow. Residue colors represent amino acid biochemical properties according to Zappo colors. Conservation scale is shown below the alignment (yellow bars). B, Sequence conservation analysis, performed using the ConSeq Server, with internal MSA alignment serving as input. Residue G827 is circled in red. Conserved regions are marked with dark magenta, and variable regions are marked with green. Exposed (e) and functional (f) residues can be seen. The American Journal of Human Genetics 2007 80, 467-477DOI: (10.1086/512487) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 5 Cornified cell envelope–protein expression (original magnification ×400). Skin-biopsy sections obtained from a control individual (A, C, E, and G) and a patient (B, D, F, and H) were stained with antibodies directed against filaggrin (A and B), loricrin (C and D), involucrin (E and F), and keratin 1 (G and H) and were examined by light microscopy. Note the marked acanthosis (H) and thickened stratum corneum (indicated by an asterisk [*] in panel D) in affected skin. The American Journal of Human Genetics 2007 80, 467-477DOI: (10.1086/512487) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 6 Normal-looking lamellar granules with immunoreactivity to LEKTI and CDSN in the skin of a patient. Skin-biopsy samples from a patient were examined by electron microscopy. The top panel is an unlabeled Lowicryl HM20-embedded section stained with uranyl acetate and lead citrate, showing laminated internal structures within lamellar granules (arrowheads). The lower panels are 5-nm immunogold-labeled (arrows) sections with antibodies against LEKTI and CDSN. The American Journal of Human Genetics 2007 80, 467-477DOI: (10.1086/512487) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 7 Impaired degradation of corneodesmosomes in affected skin. Skin-biopsy samples from a patient (left panels) and a healthy individual (right panels) were examined by electron microscopy. Stratum corneum is greatly thickened in the patient’s skin compared with that of the control individual (top panels, with the same magnification). The rectangular areas marked in the top panels are shown at higher magnifications in the middle panels. Corneodesmosomes are intact in the upper layer, with many CDSN labels (arrows) in the patient (left, middle), whereas they are degraded with only a few CDSN labels remaining in the upper stratum corneum in normal skin (right, middle). The lower panels show desmosomes between the uppermost stratum granulosum (G) and the first cornified cells positively labeled with CDSN in both patient and control skin. The American Journal of Human Genetics 2007 80, 467-477DOI: (10.1086/512487) Copyright © 2007 The American Society of Human Genetics Terms and Conditions