Molecular Analysis of 250 Patients with Autosomal Recessive Congenital Ichthyosis: Evidence for Mutation Hotspots in ALOXE3 and Allelic Heterogeneity.

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Molecular Analysis of 250 Patients with Autosomal Recessive Congenital Ichthyosis: Evidence for Mutation Hotspots in ALOXE3 and Allelic Heterogeneity in ALOX12B Katja-Martina Eckl, Silvia de Juanes, Janine Kurtenbach, Marc Nätebus, Jenny Lugassy, Vinzenz Oji, Heiko Traupe, Marie-Luise Preil, Francisco Martínez, Josef Smolle, Avikam Harel, Peter Krieg, Eli Sprecher, Hans C. Hennies Journal of Investigative Dermatology Volume 129, Issue 6, Pages 1421-1428 (June 2009) DOI: 10.1038/jid.2008.409 Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Analysis of the transcription of mutation c.434G>A in ALOXE3 using a mini-gene assay. Genomic DNA of patient ISA spanning intron 1 to exon 5 was cloned and expressed. RNA analysis revealed a shortened fragment from exon 2 to exon 4 (upper panel). Sequence analysis showed complete skipping of exon 3 (lower panel). Pa, patient; Co, control; D, DNA template; N, negative control; M, molecular weight standard. Journal of Investigative Dermatology 2009 129, 1421-1428DOI: (10.1038/jid.2008.409) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Clinical presentation of patients with epidermal lipoxygenase deficiency. (a and b) Clinical presentation of adults: the light scaling (a) and hyperlinearity of the hands (b) in a patient with mutations in ALOXE3 were reminiscent of ichthyosis vulgaris but the ichthyosis was present at birth, and the patient showed a mild keratotic lichenification of the overall integument (patient FE3). (c–e) Clinical presentation of children: the keratotic lichenification also included the elbow fossa and dorsa of the extremities (c, patient FE1; d, FE4). Additionally, there was a peculiar kink of the external ear helix in patient FE4 (e). Journal of Investigative Dermatology 2009 129, 1421-1428DOI: (10.1038/jid.2008.409) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 RP-HPLC analysis of the products formed by wild-type or mutant LOX. Homogenates from HEK-293 cells transiently transfected with pcDNA3 constructs containing wild-type or mutant 12R-LOX and eLOX-3 or the β-galactosidase (lacZ) coding region were incubated in TE buffer with (a) 100μM arachidonic acid or (b) 50μM 12R-HPETE for 15minutes at 37°C. Products were extracted with methanol/dichloromethane, dried under vacuum, redissolved in methanol/water/acetic acid (82:18:0.01 by volume), injected on a 4μm YMC-Pack ODS-H80 column, and eluted at 0.5mlmin−1. The eluates were monitored at 235 and 205nm, respectively. Authentic 12-HETE and 8R-hydroxy-11R,12R-epoxyeicosatrienoc acid (8R,11R(12R)-HepEtrE) were used as standards. The retention times of 12-HETE and 8R,11R(12R)-HepEtrE were 32.2 and 19.3minutes, respectively. Journal of Investigative Dermatology 2009 129, 1421-1428DOI: (10.1038/jid.2008.409) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Schematic representation of the domain organization of 12R-LOX and eLOX-3 and survey of known mutations associated with ARCI. The amino-acid sequences of 12R-LOX and eLOX-3 are very similar to each other. 12R-LOX and eLOX-3 contain an N-terminal β-barrel LH2 domain (dark gray), a C-terminal catalytic lipoxygenase domain (white) from position 126, and an inserted specific extra domain (black). Putative iron ligands of the active site are shown in black (Gillmor et al., 1997; Boeglin et al., 1998; Krieg et al., 2001). Mutation sites are represented by arrowheads (upper part: 12R-LOX; lower part: eLOX-3); missense (white) and truncating (gray) mutations are differentiated. Previously unreported mutations described here are checkered. The two mutational hotspots in eLOX-3 are marked by asterisks. Journal of Investigative Dermatology 2009 129, 1421-1428DOI: (10.1038/jid.2008.409) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions