Prevalent and Rare Mutations in the Gene Encoding Filaggrin Cause Ichthyosis Vulgaris and Predispose Individuals to Atopic Dermatitis Aileen Sandilands,

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Prevalent and Rare Mutations in the Gene Encoding Filaggrin Cause Ichthyosis Vulgaris and Predispose Individuals to Atopic Dermatitis Aileen Sandilands, Gráinne M. O'Regan, Haihui Liao, Yiwei Zhao, Ana Terron-Kwiatkowski, Rosemarie M. Watson, Andrew J. Cassidy, David R. Goudie, Frances J.D. Smith, W.H. Irwin McLean, Alan D. Irvine Journal of Investigative Dermatology Volume 126, Issue 8, Pages 1770-1775 (August 2006) DOI: 10.1038/sj.jid.5700459 Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Clinical features of ichthyosis vulgaris. (a) Fine scaling clearly visible on the neck of the proband in Family 1 (arrows), who is compound heterozygous for loss-of-function mutations in the filaggrin gene. (b) Marked palmar hyperlinearity (arrows) seen here in the proband of Family 1. (c) Acral peeling of the palmar surface of the fingertips was observed in two of the families analyzed here (arrows). Despite this co-incidental finding in unrelated IV families with confirmed FLG defects, this phenotype did not fully co-segregate with filaggrin mutations. Specifically, individual II-4 in Family 3 was wild type for the three known FLG mutations but had the peeling fingertip phenotype (see Figure 2). Journal of Investigative Dermatology 2006 126, 1770-1775DOI: (10.1038/sj.jid.5700459) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Pedigrees of ichthyosis vulgaris families studied. Family trees of the ichthyosis vulgaris families studied, all of which are of Irish ethnicity, showing semidominant inheritance, that is, a subtle phenotype in heterozygotes and a more marked phenotype in homozygotes or compound heterozygotes. Filled symbols denote the full, marked presentation of ichthyosis vulgaris; hatched symbols represent the milder presentation. Filaggrin genotypes are shown for the individuals from whom DNA was obtained for analysis. AD, dermatologist-confirmed atopic dermatitis; PFT, dermatologist-confirmed peeling fingertip phenotype. Journal of Investigative Dermatology 2006 126, 1770-1775DOI: (10.1038/sj.jid.5700459) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Molecular genetic analysis of ichthyosis vulgaris. (a) Schematic diagram of the gene encoding filaggrin (FLG) showing protein domain organization within the three exon gene structure. The extent of the specific PCR used to identify the 3702delG mutation is shown above. The positions of the three known filaggrin mutations are shown below. (b) Direct DNA sequencing of specific FLG PCR products. Top panels show identification of the novel 3702delG mutation in the proband of Family 1. Lower panels show identification of the first 2282del4 homozygous mutation in Family 2. (c) Fluorescent PCR analysis to confirm FLG deletion mutations. Short specific PCR products were end-labelled with the 6-fluorescein phosphoramidite fluorochrome and run on an ABI automated DNA sequencer for accurate sub-base-pair sizing. Left panel shows analysis of a normal control (top) compared to the proband of Family 1 (bottom), who carries the 3702delG mutation. The right panel shows a normal control (top) compared to the proband in Family 2, who is homozygous for 2282del4 (bottom). By this method, the 3702delG mutation was excluded from ~400 ethnically matched controls. Journal of Investigative Dermatology 2006 126, 1770-1775DOI: (10.1038/sj.jid.5700459) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions