Mutations in AQP5, Encoding a Water-Channel Protein, Cause Autosomal-Dominant Diffuse Nonepidermolytic Palmoplantar Keratoderma Diana C. Blaydon, Lisbet K.

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Mutations in AQP5, Encoding a Water-Channel Protein, Cause Autosomal-Dominant Diffuse Nonepidermolytic Palmoplantar Keratoderma Diana C. Blaydon, Lisbet K. Lind, Vincent Plagnol, Kenneth J. Linton, Francis J.D. Smith, Neil J. Wilson, W.H. Irwin McLean, Colin S. Munro, Andrew P. South, Irene M. Leigh, Edel A. O’Toole, Anita Lundström, David P. Kelsell The American Journal of Human Genetics Volume 93, Issue 2, Pages 330-335 (August 2013) DOI: 10.1016/j.ajhg.2013.06.008 Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 1 Mutations in AQP5 Underlie Autosomal-Dominant Diffuse NEPPK (A) The clinical phenotype of a British individual affected by diffuse NEPPK (with the c.529A>T mutation in AQP5) shows some transgradiens onto the dorsal surface of the fingers and a livid, red edge. (B) The clinical phenotype of a Swedish individual affected by diffuse NEPPK (with the c.113C>A mutation in AQP5). The hand on the right shows palmar skin with mild diffuse hyperkeratosis prior to water exposure. The hand on the left shows the white, spongy appearance of the palmar skin after 15 min of water exposure. (C) The pedigree of the British family (affected by the c.529A>T mutation) shows how the mutant AQP5 allele segregates with disease in this family. Genotypes were confirmed in available individuals by Sanger sequencing: A/A represents two wild-type alleles, and A/T represents one mutant allele and one wild-type allele. The individual highlighted in red was used for exome sequencing. (D) Sanger sequence traces of the five missense mutations identified in AQP5 in families affected by diffuse NEPPK. The American Journal of Human Genetics 2013 93, 330-335DOI: (10.1016/j.ajhg.2013.06.008) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 2 AQP5 Variants Appear to Demonstrate Normal Trafficking to the Plasma Membrane (A–C) Immunofluorescent staining of AQP5 with an antibody raised against the C terminus of human AQP5 (green) in frozen sections from an unaffected, control palm (A) and a British diffuse NEPPK (with the p.Ile177Phe substitution) palm (B). The primary antibody was omitted in the negative control (C). Nuclei were counterstained with DAPI (blue). AQP5 appears to be present throughout the palmar epidermis and shows strong localization to the plasma membrane of the keratinocytes of the stratum granulosum. A similar AQP5 distribution is seen in the diffuse NEPPK palm compared to the unaffected control. (D–I) Monolayers of Neb1 HpV-immortalized keratinocyte cells transfected with constructs expressing wild-type or variant AQP5 and then fixed in 4% paraformaldehyde and stained with rabbit monoclonal AQP5 antibody (ab92320, green). The levels of cell-membrane localization in all four AQP5 variants tested—p.Ala38Glu (D), p.Ile45Ser (E), p.Ile177Phe (G), and p.Arg188Cys (H)—are similar to that seen for wild-type AQP5 (F). Primary antibody was omitted in the negative control (I). Nuclei are counterstained with DAPI (blue). Scale bars represent 40 μm. The American Journal of Human Genetics 2013 93, 330-335DOI: (10.1016/j.ajhg.2013.06.008) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 3 The Five AQP5 Variants Most Likely Affect the Water Conductance of the AQP5 Channel (A) A side view of the AQP5 monomer shows the half helices formed by loops B and E. The cartoon is transparent so that the side chains of the residues substituted in diffuse NEPPK can be visualized. Residues Ile45, Ile177, and Arg188 line the water channel one helical turn extracellular to the ar/R constriction point, which is defined in AQP5 by Arg188, Phe49, and His173. Residues Ala38 and Asn123 are located on the extracellular surface of AQP5. (B) A close-up view of the tripeptide consisting of Ile177, Tyr178, and Phe179 of the extracellular end of helix 5 (gold) shows the intramolecular hydrogen bond formed with Asn123 in extracellular loop C (green) and the intermolecular hydrogen bond formed with Ala38′ in extracellular loop A′ (blue) of the adjacent monomer. The intrachannel water molecules (which are in the foreground) are shown as light-blue transparent spheres. Structural models were generated in MacPyMOL (Delano Scientific). Despite the fact that the AQP5 variants display a wide distribution of the primary sequence of AQP5, they are clustered in the tertiary structure of the protein and either line the extracellular end of the water channel or are situated in extracellular loops important for stabilizing the tertiary structure of AQP5. The American Journal of Human Genetics 2013 93, 330-335DOI: (10.1016/j.ajhg.2013.06.008) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 4 Microtubules in Diffuse NEPPK Palm Skin Show Evidence of Increased Stabilization Immunofluorescent staining of α-tubulin (green) (A–D) and acetylated α-tubulin (green) (E–H) in paraffin-wax-embedded sections from an unaffected, control palm (A and E), a British diffuse NEPPK (with the p.Ile177Phe substitution) palm (B and F), and a Swedish diffuse NEPPK (with the p.Ala38Glu substitution) palm (C and G). Primary antibody was omitted in negative controls (D and H). Nuclei were counterstained with DAPI (blue). There appears to be a slight increase in the level of α-tubulin and a more pronounced increase in the level of acetylated α-tubulin in the diffuse NEPPK palmar biopsy samples compared to the control palm, indicating an increase in microtubule stabilization in the diffuse NEPPK palmar skin. Scale bars represent 40 μm. The American Journal of Human Genetics 2013 93, 330-335DOI: (10.1016/j.ajhg.2013.06.008) Copyright © 2013 The American Society of Human Genetics Terms and Conditions