Diana C. Blaydon, Sarah L. Etheridge, Janet M

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RHBDF2 Mutations Are Associated with Tylosis, a Familial Esophageal Cancer Syndrome Diana C. Blaydon, Sarah L. Etheridge, Janet M. Risk, Hans-Christian Hennies, Laura J. Gay, Rebecca Carroll, Vincent Plagnol, Fiona E. McRonald, Howard P. Stevens, Nigel K. Spurr, D. Timothy Bishop, Anthony Ellis, Janusz Jankowski, John K. Field, Irene M. Leigh, Andrew P. South, David P. Kelsell The American Journal of Human Genetics Volume 90, Issue 2, Pages 340-346 (February 2012) DOI: 10.1016/j.ajhg.2011.12.008 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Mutations in RHBDF2 Underlie Tylosis Clinical images of a tylosis patient showing the focal nonepidermolytic palmoplantar keratoderma (A) and oral leukokeratosis (B). Sanger sequence traces (C) displaying the c.557T>C mutation identified in the UK and USA families and the c.566C>T mutation identified in the German family. (D) Schematic illustrating of the structure of RHBDF2, a seven-transmembrane-domain protein, and the approximate location of the alterations identified in tylosis patients. Protein alignment with ClustalW illustrates that the amino acid residues mutated in the tylosis patients (in p.Ile186Thr and p.Pro189Leu) are highly conserved across a wide range of eukaryotic species as well as in RHBDF1, a closely related member of the iRhom family. The American Journal of Human Genetics 2012 90, 340-346DOI: (10.1016/j.ajhg.2011.12.008) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 RHBDF2 Localization is Altered in Tylotic Skin Immunofluorescence staining of frozen sections from normal skin (A) and tylotic skin (B). RHBDF2 appears to localize predominantly to the cell membrane in sections from normal skin, whereas the localization is mostly cytoplasmic in skin sections from patients with tylosis. Plasma-membrane staining with an antibody against the desmosomal cadherin proteins desmogleins 1 and 2 is shown in normal skin (C) and tylotic skin (D) and reveals that the localization of at least one other plasma-membrane protein remains the same in the tylotic-skin sections as it is in the normal-skin sections. Scale bars represent 20 μm. (E) Immunoblotting of lysates from control keratinocyte cell lines K1 and K16 and tylotic cell lines TYLK1 and TYLK2 cultured in the presence of exogenous EGF with anti-RHBDF2 shows a reduction in RHBDF2 levels in tylotic keratinocytes. The use of anti-actin demonstrated equal loading. The American Journal of Human Genetics 2012 90, 340-346DOI: (10.1016/j.ajhg.2011.12.008) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 Tylosis Cell Lines Show Increased Migration and Are Less Responsive to Exogenous EGF (A) Immunoblotting of lysates from control cells K1 and K16 and tylotic cells TYLK1 and TYLK2 blotted with anti-phospho-EGFR and anti-EGFR (total) shows a reduction in the levels of total EGFR in the lysates from tylotic cells. The use of anti-β-actin demonstrated equal loading. Cells were grown in the absence of exogenous EGF. (B) An MTS proliferation assay shows proliferation levels in two tylotic cell lines, TYLK1 and TYLK2, and two control cell lines, K1 and K16, after a 72 hr culture in the presence and absence of exogenous EGF. The assay was carried out in quadruplicate (p = 0.00035). (C) Light-microscopy images of cells 2 days after we scraped them in the absence of exogenous EGF. The experiment was carried out in triplicate, and a representative image is shown from each experiment for control cell lines K1 and K16 and for tylotic cell lines TYLK1 and TYLK2. (D) Quantification of migration of control cells and tylotic cells: (1) after 1 day in the presence of EGF (p = 0.025, experiments in duplicate, control cells n = 2, tylosis cells n = 1) and (2) after 3 days in the absence of EGF (p = 2.13 × 10−6, experiments in triplicate, n = 2 in each case). The American Journal of Human Genetics 2012 90, 340-346DOI: (10.1016/j.ajhg.2011.12.008) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 4 Squamous Esophageal Tumors Show Cytoplasmic Localization of RHBDF2 Immunohistochemical staining of formalin-fixed, paraffin-embedded sections from a control esophagus with esophagitis (A), tylotic (B), and sporadic (C) squamous cell tumors. The localization of RHBDF2 in both tumor types is strongly cytoplasmic compared to the control tissue. Scale bars represent 20 μm. The American Journal of Human Genetics 2012 90, 340-346DOI: (10.1016/j.ajhg.2011.12.008) Copyright © 2012 The American Society of Human Genetics Terms and Conditions