Emmanuelle Bitoun, Stéphane Chavanas, Alan D

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Netherton Syndrome: Disease Expression and Spectrum of SPINK5 Mutations in 21 Families Emmanuelle Bitoun, Stéphane Chavanas, Alan D. Irvine, Lorne Lonie, Christine Bodemer, Mauro Paradisi, Dominique Hamel-Teillac, Shin-ichi Ansai, Yoshihiko Mitsuhashi, Alain Taïeb, Yves de Prost, Giovanna Zambruno, John I. Harper, Alain Hovnanian Journal of Investigative Dermatology Volume 118, Issue 2, Pages 352-361 (February 2002) DOI: 10.1046/j.1523-1747.2002.01603.x Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Schematic representation of the effects of splicing mutations identified in patients 6, 7, and 10. Exons present in the mRNA are denoted by black boxes; exons or parts of exons absent are denoted by hatched boxes. Gray boxes denote novel sequences. Upper case letters denote bases in exons, whereas lower case letters denote bases in introns. The broken V-shaped lines designate regions of pre-mRNA that are removed by normal splicing (N) or by abnormal splicing in the patient. Cryptic splice sites used for aberrant splicing are underlined. “Stop” denotes a PTC. Journal of Investigative Dermatology 2002 118, 352-361DOI: (10.1046/j.1523-1747.2002.01603.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Localization and nature of SPINK5 mutations. Top: schematic genomic organization of SPINK5. The gene comprises 33 exons (numbered boxes) and spans a region of 61 kb. Exons 1 and 33, respectively, contain the initiation (ATG) and stop (TGA) codons of translation. Bottom: schematic representation of the predicted LEKTI protein. The polypeptide contains 1064 amino acids. It is composed of an N-terminal secretory peptide signal (SPS) sequence and 15 domains (plain, dotted, or striped cylinders) separated by linker regions (gray boxes). Typical Kazal-type domains are depicted by striped boxes and Kazal-like domains by plain boxes. Dotted boxes correspond to Kazal-like domains found as proteolytic fragments in the serum (Mägert et al, 1999). SPINK5 mutations identified in this study are indicated by black symbols. Mutations previously reported (Chavanas et al, 2000b;Sprecher et al, 2001) appear in white along the protein. Journal of Investigative Dermatology 2002 118, 352-361DOI: (10.1046/j.1523-1747.2002.01603.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Northern blot analysis of SPINK5 mRNA in cultured epidermal keratinocytes from a control individual (C) and NS patients 14, 17, and 7. A SPINK5 cDNA specific probe shows a strong 3.7 kb hybridization signal in the control, a dramatically reduced signal in keratinocytes from patient 14 (homozygous for 2468insA), and significant levels of SPINK5 mRNAs in keratinocytes from patient 17 (homozygous for 153delT) and patient 7 (compound heterozygous for 2240 + 1G→A and 81 + 5G→A). Exposure time was 8 h. RNA molecular weight markers (Sigma) are represented on the left in kb. Journal of Investigative Dermatology 2002 118, 352-361DOI: (10.1046/j.1523-1747.2002.01603.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions