Exome Sequencing Reveals Mutations in TRPV3 as a Cause of Olmsted Syndrome Zhimiao Lin, Quan Chen, Mingyang Lee, Xu Cao, Jie Zhang, Donglai Ma, Long Chen,

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Exome Sequencing Reveals Mutations in TRPV3 as a Cause of Olmsted Syndrome Zhimiao Lin, Quan Chen, Mingyang Lee, Xu Cao, Jie Zhang, Donglai Ma, Long Chen, Xiaoping Hu, Huijun Wang, Xiaowen Wang, Peng Zhang, Xuanzhu Liu, Liping Guan, Yiquan Tang, Haizhen Yang, Ping Tu, Dingfang Bu, Xuejun Zhu, KeWei Wang, Ruoyu Li, Yong Yang The American Journal of Human Genetics Volume 90, Issue 3, Pages 558-564 (March 2012) DOI: 10.1016/j.ajhg.2012.02.006 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Phenotypic Characteristics of OS (A) Bilateral mutilating palmoplantar keratoderma, flexion deformities and constriction of digits in individual 1. (B) Keratotic plaques involving periorificial, neck and axillary areas in individual 1. (C) Diffused alopecia with follicular papules in individual 2. (D) Skin biopsy section demonstrating psoriasiform hyperplasia, orthohyperkeratosis and parakeratosis in individual 1 (hematoxylin-eosin staining; the scale bar represents 100 μm). (E) Individual 1, skin biopsy section showing profound mast cell infiltration in upper dermis (toluidine blue staining; the scale bar represents 100 μm). (F) The pedigree of individual 3 (arrow indicates individual 3). The American Journal of Human Genetics 2012 90, 558-564DOI: (10.1016/j.ajhg.2012.02.006) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 Mutations and Schematic Structure of TRPV3 (A)Sequencing results demonstrating heterozygous TRPV3 mutation of c.1717G>A (amino acid change of p.Gly573Ser) in individuals 1, 3, 4, and 6; c.1717G>T (p.Gly573Cys) in individual 2; and c.2074T>G (p.Trp692Gly) in individual 5. (B) Schematic structure of TRPV3 protein and multiple alignment of the linker region between S4 and S5 and the TRP domain, with the alignments of corresponding segments of human TRPV1-2 and 4-6 proteins. Gly573 and Trp692 are highly conserved residues. The mutation sites that produce p.Gly573Ser (M1), p.Gly573Cys (M2), and p.Trp692Gly (M3) are also aligned with the substitution positions (black highlighted). The American Journal of Human Genetics 2012 90, 558-564DOI: (10.1016/j.ajhg.2012.02.006) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 Whole-Cell and Inside-Out Recordings of TRPV3 Currents from Transfected HEK293 Cells (A–D) Representative whole-cell current traces in HEK293 cells expressing TRPV3 or mutant channels in response to the voltage step protocol (left panels), and respective current-voltage plots from the steady-state currents (right panels). (E–H) Representative currents from inside-out patches in HEK293 cells expressing TRPV3 or mutant channels in response to stimulation by 300 μM 2-APB or inhibition by 130 mM Ba2+ to assess the level of leak currents, at −80 mV and +80 mV. WT TRPV3 current is activated by 2-APB and followed by a characteristic decay. Note that the mutants Gly573Ser, Gly573Cys, and Trp692Gly show little activation, then inhibition in the presence of 2-APB, and a robust block by Ba2+. (I) Comparison of ratios of currents evoked by 2-APB (300 μM) over basal currents between the TRPV3 WT and mutant channels. (t test, n = 3–7. p = 0.00001). Error bars represent SEM. The American Journal of Human Genetics 2012 90, 558-564DOI: (10.1016/j.ajhg.2012.02.006) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 4 Cell Death of Transfected HEK293 Cells and Apoptosis of Affected Individuals' Keratinocytes (A) Merged images of transfected HEK293 cells stained with PI (red) and Hoechst 33342 (blue). Mutants show significantly more PI-positive cells compared to wild-type TRPV3. (B) Quantification of cell death rates in transfected HEK293 cells (red nuclei/blue nuclei × 100%). Data are averaged from three independent experiments. ∗p < 0.05, ∗∗p < 0.01. (C) Fluorescence microscope images (TUNEL method) of palm skin biopsy sections from an unrelated control, individuals 1, 2, and 6. Large amount of apoptotic cells (with fluorescent nuclei) are seen in individuals with OS. The scale bars represent 50 μm. (D) Quantification of apoptotic keratinocytes in the skin sections. The mean proportion of apoptotic cells are significantly higher in the group of OS patients than in the group of normal controls (t test, n = 3, p = 0.000005). Error bars represent SEM. The American Journal of Human Genetics 2012 90, 558-564DOI: (10.1016/j.ajhg.2012.02.006) Copyright © 2012 The American Society of Human Genetics Terms and Conditions