A Mutation in LIPN, Encoding Epidermal Lipase N, Causes a Late-Onset Form of Autosomal-Recessive Congenital Ichthyosis Shirli Israeli, Ziyad Khamaysi,

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A Mutation in LIPN, Encoding Epidermal Lipase N, Causes a Late-Onset Form of Autosomal-Recessive Congenital Ichthyosis Shirli Israeli, Ziyad Khamaysi, Dana Fuchs-Telem, Janna Nousbeck, Reuven Bergman, Ofer Sarig, Eli Sprecher The American Journal of Human Genetics Volume 88, Issue 4, Pages 482-487 (April 2011) DOI: 10.1016/j.ajhg.2011.02.011 Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 1 Family Pedigree, Haplotype Analysis, and PCR-RFLP Analysis The family tree appears in the upper panel (black symbols denote affected individuals and half-filled symbols represent heterozygous carrier of mutation c.399_400delGA). Haplotype analysis using polymorphic markers on chromosome 10q23 is depicted in the middle panel and reveals a homozygous haplotype shared by all patients (boxed in red). The lower panel provides details of the PCR-RFLP analysis that confirm segregation of the mutation in the family: mutation c.399_400delGA abolishes a recognition site for BsmAI; thus, affected patients display a single fragment of 453 bp, healthy individuals show two fragments of 273 and 180 bp, and all fragments are found in heterozygous carriers of the mutation. The American Journal of Human Genetics 2011 88, 482-487DOI: (10.1016/j.ajhg.2011.02.011) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 2 Clinical Features (A and B) Diffuse lamellar ichthyosis over the legs of a 14-year-old affected individual (patient II-1). (C) A skin biopsy shows hyperkeratosis, orthokeratosis, hypergranulosis, and acanthosis (hematoxylin and eosin staining, original magnification 100×). The American Journal of Human Genetics 2011 88, 482-487DOI: (10.1016/j.ajhg.2011.02.011) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 3 Multipoint Analysis of Lod Score Lod scores are plotted against the 15 markers assessed. The American Journal of Human Genetics 2011 88, 482-487DOI: (10.1016/j.ajhg.2011.02.011) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 4 Mutation Analysis Sequence analysis of LIPN reveals a homozygous deletion at cDNA position 399_400 (upper panel, red arrow). The wild-type sequence is given for comparison (lower panel). The American Journal of Human Genetics 2011 88, 482-487DOI: (10.1016/j.ajhg.2011.02.011) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 5 LIPN Expression Analysis (A) Quantitative RT-PCR was performed on mRNA samples extracted from keratinocyte cultures derived from a patient and a nonaffected individual (control). Results are provided as a percentage of LIPN expression in control keratinocytes ± SD. (B) LIPN expression was assessed via Clontech tissue blot cDNA array. Expression of LIPN was normalized to that of ACTB. Results are provided as a percentage of LIPN expression in control keratinocytes ± SD. The following abbreviations are used: ESON = esophagus; S.INT = small intestine; PLACEN = placenta; TRACH = trachea; PROST = prostate; KC = keratinocytes. (C) Total RNA was extracted from organotypic cell cultures at day 0 (green), day 7 (blue), and day 10 (red). LIPN, IVL, and KRT10 expression were compared by using quantitative RT-PCR. Results are provided as a percentage of expression at day 0. The American Journal of Human Genetics 2011 88, 482-487DOI: (10.1016/j.ajhg.2011.02.011) Copyright © 2011 The American Society of Human Genetics Terms and Conditions