LETTER TO THE EDITOR
A Gain-of-Function Mutation in TRPV3 Causes Focal Palmoplantar Keratoderma in a Chinese Family Journal of Investigative Dermatology advance online publication, 6 November 2014; doi:10.1038/jid.2014.429
a TO THE EDITOR Focal palmoplantar keratoderma (FPPK) is a genetically heterogeneous phenotype characterized by the presence, on the palms and soles, of circumscribed calluses. These can be painful and are usually the most prominent on areas subject to mechanical stress (Kelsell and Stevens, 1999). Recently, we identified two patients with FPPK from a three-generation Chinese family consisting of 29 members (Supplementary Figure S1 online). The proband (Supplementary Figure S1 online, II-7) was a 37-year-old male, who presented with distinct hyperkeratosis lesions on the palms and soles (Figure 1a and b). His son (Supplementary Figure S1 online, III-7) also showed focal hyperkeratosis on the fingers, palms, and toes (Figure 1c–e). Besides the characteristic hyperkeratosis, patients did not present with any other abnormalities. To look for the causative mutation, we conducted whole-genome sequencing on selected family members (Supplementary Figure S1 online). Samples used in this study were obtained according to the principles expressed in the Declaration of Helsinki Princples and were approved by the Institutional Review Board from Guangdong Medical Committee (GMA2012-01) and Western Institutional Review Board (no. 13232). All participants provided written informed consent. A de novo dominant mutation in the transient receptor potential vanilloid 3 (TRPV3) protein that resulted in a p.Gln580Pro amino acid change was identified as the causative mutation for our patients (detailed description of sequence
b
c
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Figure 1. Clinical presentation and histological and Immunohistochemistry results. The proband (II-7) showed large calluses on soles (a, b). The patient, III-7, presented less severe lesions on fingers, palms (c, d), and toes (e). Histopathology study (sole, II-7) revealed prominent hyperkeratosis, thickened stratum spinosum layer with reduced stratum granulosum, disadhesion of cells in the suprabasal layers, elongation of rete ridges, and sparse lymphocyte infiltration in the dermis (f, g). The slide was stained with hematoxylin-eosin and photographed at 40 (f). The yellowed box region was magnified at 100 (g). Panels h–o show results for immunohistochemistry staining on transglutaminase 1 (h, i), filaggrins (j, k), keratin 10 (KRT10; l, m), and KRT14 (n, o), with sections from normal skin and focal palmoplantar keratoderma (sole, II-7) at 200. Scale bars ¼ 100 mm.
Abbreviations: FPPK, focal palmoplantar keratoderma; iTRAQ, isobaric tags for relative and absolute quantitation; OS, Olmsted syndrome; TRPV3, transient receptor potential vanilloid 3 Accepted article preview online 6 October 2014
& 2014 The Society for Investigative Dermatology
www.jidonline.org
1
Y He et al. Mutation in TRPV3 Causes FPPK
Fold change (log2) (involved skin vs. uninvolved skin) –5
0
Fold change (log2) (involved skin vs. uninvolved skin)
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–5.00 –3.00 –1.00 1.00
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DKC1 DSC1 DSC3 DSG1 DSG3 DSP DST
FLG FLG2 LCE1B LCE1C LCE1E LCE2A LCE2B LCE2D LCE3A LCE3B LCE3D LCE3E LCE5A LCE6A LOR S100A7 S100A7A SPRR1A SPRR1B SPRR2A SPRR2B SPRR2C SPRR2D SPRR2E SPRR2F SPRR2G TCHH TGM1 TGM3
Stratum granulosum
Desmosome
GJA1 GJA4 GJB2 GJB3 GJB4 GJB5 GJB6 GJD4 CDH1 CLDN1 CTNNB1 CTNNBIP1 CTNND1 TJP1
Gap junction
Tight junction
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KRT10
Cornified layer
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Stratum basale KRT14 MXD1 MXD3 MXD4
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NOTCH1
KLF4
TP63
ZNF750
OVOL1 MXI1
Transition between proliferation and differentiation basal layer
Figure 2. The effect of transient receptor potential vanilloid 3 mutation on the expression of genes related to keratinocyte differentiation and cell adhesion. The expression level changes of genes that relate to cell adhesion and keratinocyte differentiation were shown in a. The gene identity is listed on the left and the patient ID is listed at the bottom. The changes in gap junction, tight junction, and desmosome-associated genes in focal palmoplantar keratoderma (FPPK) are shown in b. The identity of genes is listed on the left and the patient ID is indicated at the bottom. The expression level changes of several keratinocyte proliferation– and differentiation–associated transcription factors are shown in c. The green circles indicate decreased expression levels in FPPK involved skin, whereas the red circle represents increased levels.
analysis is in Supplementary Information onilne). The mutation was also confirmed by traditional Sanger sequencing (Supplementary Figure S2 online). TRPV3 belongs to a large family of calcium-permeable transient receptor potential ion channel membrane proteins that contain six transmembrane domains (Nilius et al., 2014). The Gln580 residue is located in a conserved cytosolic region linking the fourth and fifth transmembrane domains. (Supplementary Figure S3 online). To study the functional impact of this mutation on TRPV3 activity, we transfected HEK293T cells with wild-type and Gln580 mutation TRPV3 clones (Supplementary Figure S4a and S4b online). Cells with Gln580Pro TRPV3 mutant showed an increased intracellular Ca2 þ concentration compared with cells with wild-type TRPV3, suggesting that the Gln580 mutation in TRPV3 is a gain-of-function change (Supplementary Figure S4c and S4d online). This is 2
further supported by the finding that a pan TRPV antagonist, ruthenium red, can reduce the escalation of intracellular Ca2 þ level induced by TRPV3 mutant (Supplementary Figure S5 online). To understand the molecular changes associated with the pathology, we compared transcriptome and proteome of involved and adjacent uninvolved skin samples from sole (II-7) and palm (III-7) of patients using microarray and iTRAQ (isobaric tags for relative and absolute quantitation). With iTRAQ, we identified 941 unique proteins and quantified 558 of them (Supplementary Table S1 online). The transcriptome and proteome profiling results showed genes/ proteins that are known to be highly expressed in the stratum granulosum and stratum spinosum layers, such as keratin 10 (KRT10), transglutaminases (TGMs), and filaggrins (FLGs) were decreased in the involved skin compared with the uninvolved areas (Figure 2a, Supplementary Table S2 online). The
Journal of Investigative Dermatology (2014), Volume 00
expression level changes of selected mRNAs were also verified by quantitative reverse-transcriptase in real-time PCR (Supplementary Figure S6 online). Immunohistochemistry results showed weaker signals without clear stratum granulosum layer staining with TGM1 (Figure 1h and i) and FLG (Figure 1j and k) in patient sample compared with regular skin. These findings are in agreement with the decreased stratum granulosum layer and increased stratum spinosum observed in histopathology examination (Figure 1f and g). The expression levels of desmocollin 1, desmoglein 1, gap junction protein beta 2, and E-cadherin that encode proteins associated with gap junction, tight junction, and desmosomes were decreased in FPPK involved skin samples (Figure 2b), which is supported by the disadhesion of cells in the suprabasal layers of the epidermis observed under histopathology examination (Figure 1f and g).
Y He et al. Mutation in TRPV3 Causes FPPK
Transcriptomic profiling results also revealed changes in the levels of several keratinocyte proliferation– and differentiation–related transcription factors. For example, the expression level of MYC, a key transcription factor in regulating cell proliferation, was increased in involved skin, whereas its antagonists including MXD1 (MAX dimerization protein 1), MXD3 (MAX dimerization protein 3), MXI1 (MAX interactor 1, dimerization protein), and OVOL1 (Ovo-like 1 protein) were decreased (Rottmann and Luscher, 2006; Wells et al., 2009). In addition, NOTCH1, TP63 (tumor protein p63), ZNF750 (zinc finger protein 750), and KLF4 (Kruppel-like factor 4) that are involved in keratinocyte differentiation were also decreased in the FPPK involved skin (Figure 2c; Nguyen et al., 2006; Chen et al., 2008; Wells et al., 2009; Cohen et al., 2012). This impairment of normal keratinocyte proliferation and development process is further supported by the expression level changes of KRT10 and KRT14, which are preferentially expressed by keratinocytes located in the spinosum and basal layers, respectively (Figure 2a). Immunohistochemistry revealed a broader layer of KRT14-positive cells at the basal layer and weaker KRT10-positive cells in the spinosum layer in FPPK patients (Figure 1l–o). At the pathway and biological process levels, cell differentiation and skin barrier formation–related activities, such as cell cycle and keratinization, were enriched in downregulated genes, whereas cell death–related processes were associated with upregulated genes in involved skin when compared with adjacent uninvolved skin samples (Supplementary Table S3 online). These results are consistent with the observation of distinctly thickened stratum spinosum layer with the reduction or absence of the stratum granulosum in immunohistochemical and histopathological examination. Combining the results of gene expression profiling, pathway analysis and immunohistochemistry suggest that the mutation in TRPV3 disrupts the balance of keratinocyte proliferation and differentiation processes. The epidermis contains highly differentiated keratinocytes that replenish
and form the cornified layer, the outer barrier of the skin. Proper TRPV3 activity is critical in skin development. TRPV3-deficient mice display thermal hyperalgesia, defects in skin barrier formation, wavy hair, and a curly whisker phenotype (Schneider et al., 2008; Cheng et al., 2010; Radtke et al., 2011). Recent reports on several mutations in human TRPV3 involved in the Olmsted syndrome (OS; Lin et al., 2012; Danso-Abeam et al., 2013) further support the importance of TRPV3 activity in keratinocytes development. Compared with OS, our patients with FPPK showed a mild clinical presentation, which might be caused by different mutations leading to functional differences in TRPV3. The finding that a gain-of-function mutation in TRPV3 causes the clinical phenotype in our patients opens the possibility of treating TRPV3-associated FPPK or similar skin conditions with TRPV3 antagonists. Developing a TRPV3-specific inhibitor is an active area of drug discovery for treatment of itching or other sensations (Salat et al., 2013), which may also provide systematic or topical treatments for patients with FPPK. CONFLICT OF INTEREST The authors state no conflict of interest.
ACKNOWLEDGMENTS This study was supported by the National Science Foundation of China (NSFC) grants 81201223 (YH), Guangdong Province Medical Research Foundation of China grants A2012533 (YH) Science and Technology Program of Guangdong 2013B051000080 (YH), Guangdong Medical College Integration of Industry, Education and Research C2013004 (YH), and Guangdong Medical College Research Startup Fund B2013001 (YH). We thank David Baxter, Kelsey Scherler, and Li Gray for technical help.
Yuqing He1,2,3,8, Kang Zeng4,8, Xibao Zhang3,8, Qiaolin Chen5, Jiang Wu6, Hong Li2, Yong Zhou2, Gustavo Glusman2, Jared Roach2, Alton Etheridge7, Shizhen Qing2, Qiang Tian2, Inyoul Lee2, Xin Tian3, Xiaoning Wang5, Zhihua Wu1, Leroy Hood2, Yuanlin Ding1 and Kai Wang2 1
Institute of Medical Systems Biology, Guangdong Medical College, Dongguan, China; 2Institute for Systems Biology, Seattle, Washington, USA; 3Department of Dermatology, Guangzhou Institute of Dermatology, Guangzhou, China; 4Department of Dermatology, Nanfang Hospital, Southern
Medical University, Guangzhou, China; School of Bioscience & Bioengineering, South China University of Technology, Guangzhou, China; 6Department of Dermatology, Guangzhou First Municipal People’s Hospital, Guangzhou, China and 7Pacific Northwest Diabetes Research Institute, Seattle, Washington, USA E-mail: [email protected] or [email protected] 8 These authors contributed equally to this work. 5
SUPPLEMENTARY MATERIAL Supplementary material is linked to the online version of the paper at http://www.nature.com/jid
REFERENCES Chen YJ, Wu CY, Chang CC et al. (2008) Nuclear Kruppel-like factor 4 expression is associated with human skin squamous cell carcinoma progression and metastasis. Cancer Biol Ther 7:777–82 Cheng X, Jin J, Hu L et al. (2010) TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation. Cell 141:331–43 Cohen I, Birnbaum RY, Leibson K et al. (2012) ZNF750 is expressed in differentiated keratinocytes and regulates epidermal late differentiation genes. PLoS One 7:e42628 Danso-Abeam D, Zhang J, Dooley J et al. (2013) Olmsted syndrome: exploration of the immunological phenotype. Orphanet J Rare Dis 8:79 Kelsell DP, Stevens HP (1999) The palmoplantar keratodermas: much more than palms and soles. Mol Med Today 5:107–13 Lin Z, Chen Q, Lee M et al. (2012) Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome. Am J Hum Genet 90:558–64 Nguyen BC, Lefort K, Mandinova A et al. (2006) Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes Dev 20:1028–42 Nilius B, Biro T, Owsianik G (2014) TRPV3: time to decipher a poorly understood family member! J Physiol 15:295–304 Radtke C, Sinis N, Sauter M et al. (2011) TRPV channel expression in human skin and possible role in thermally induced cell death. J Burn Care Res 32:150–9 Rottmann S, Luscher B (2006) The Mad side of the Max network: antagonizing the function of Myc and more. Curr Top Microbiol Immunol 302:63–122 Salat K, Moniczewski A, Librowski T (2013) Transient receptor potential channels-emerging novel drug targets for the treatment of pain. Curr Med Chem 20:1409–36 Schneider MR, Werner S, Paus R et al. (2008) Beyond wavy hairs: the epidermal growth factor receptor and its ligands in skin biology and pathology. Am J Pathol 173:14–24 Wells J, Lee B, Cai AQ et al. (2009) Ovol2 suppresses cell cycling and terminal differentiation of keratinocytes by directly repressing c-Myc and Notch1. J Biol Chem 284: 29125–35
www.jidonline.org
3
A Gain-of-Function Mutation in TRPV3 Causes Focal Palmoplantar Keratoderma in a Chinese Family Journal of Investigative Dermatology advance online publication, 6 November 2014; doi:10.1038/jid.2014.429
a TO THE EDITOR Focal palmoplantar keratoderma (FPPK) is a genetically heterogeneous phenotype characterized by the presence, on the palms and soles, of circumscribed calluses. These can be painful and are usually the most prominent on areas subject to mechanical stress (Kelsell and Stevens, 1999). Recently, we identified two patients with FPPK from a three-generation Chinese family consisting of 29 members (Supplementary Figure S1 online). The proband (Supplementary Figure S1 online, II-7) was a 37-year-old male, who presented with distinct hyperkeratosis lesions on the palms and soles (Figure 1a and b). His son (Supplementary Figure S1 online, III-7) also showed focal hyperkeratosis on the fingers, palms, and toes (Figure 1c–e). Besides the characteristic hyperkeratosis, patients did not present with any other abnormalities. To look for the causative mutation, we conducted whole-genome sequencing on selected family members (Supplementary Figure S1 online). Samples used in this study were obtained according to the principles expressed in the Declaration of Helsinki Princples and were approved by the Institutional Review Board from Guangdong Medical Committee (GMA2012-01) and Western Institutional Review Board (no. 13232). All participants provided written informed consent. A de novo dominant mutation in the transient receptor potential vanilloid 3 (TRPV3) protein that resulted in a p.Gln580Pro amino acid change was identified as the causative mutation for our patients (detailed description of sequence
b
c
f
g
h
i
j
k
l
m
n
o
d
e
Figure 1. Clinical presentation and histological and Immunohistochemistry results. The proband (II-7) showed large calluses on soles (a, b). The patient, III-7, presented less severe lesions on fingers, palms (c, d), and toes (e). Histopathology study (sole, II-7) revealed prominent hyperkeratosis, thickened stratum spinosum layer with reduced stratum granulosum, disadhesion of cells in the suprabasal layers, elongation of rete ridges, and sparse lymphocyte infiltration in the dermis (f, g). The slide was stained with hematoxylin-eosin and photographed at 40 (f). The yellowed box region was magnified at 100 (g). Panels h–o show results for immunohistochemistry staining on transglutaminase 1 (h, i), filaggrins (j, k), keratin 10 (KRT10; l, m), and KRT14 (n, o), with sections from normal skin and focal palmoplantar keratoderma (sole, II-7) at 200. Scale bars ¼ 100 mm.
Abbreviations: FPPK, focal palmoplantar keratoderma; iTRAQ, isobaric tags for relative and absolute quantitation; OS, Olmsted syndrome; TRPV3, transient receptor potential vanilloid 3 Accepted article preview online 6 October 2014
& 2014 The Society for Investigative Dermatology
www.jidonline.org
1
Y He et al. Mutation in TRPV3 Causes FPPK
Fold change (log2) (involved skin vs. uninvolved skin) –5
0
Fold change (log2) (involved skin vs. uninvolved skin)
b
5
–5.00 –3.00 –1.00 1.00
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DKC1 DSC1 DSC3 DSG1 DSG3 DSP DST
FLG FLG2 LCE1B LCE1C LCE1E LCE2A LCE2B LCE2D LCE3A LCE3B LCE3D LCE3E LCE5A LCE6A LOR S100A7 S100A7A SPRR1A SPRR1B SPRR2A SPRR2B SPRR2C SPRR2D SPRR2E SPRR2F SPRR2G TCHH TGM1 TGM3
Stratum granulosum
Desmosome
GJA1 GJA4 GJB2 GJB3 GJB4 GJB5 GJB6 GJD4 CDH1 CLDN1 CTNNB1 CTNNBIP1 CTNND1 TJP1
Gap junction
Tight junction
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Stratum spinosum
KRT10
Cornified layer
C-Myc
Stratum basale KRT14 MXD1 MXD3 MXD4
II-7
III-7
Differentiation
a
NOTCH1
KLF4
TP63
ZNF750
OVOL1 MXI1
Transition between proliferation and differentiation basal layer
Figure 2. The effect of transient receptor potential vanilloid 3 mutation on the expression of genes related to keratinocyte differentiation and cell adhesion. The expression level changes of genes that relate to cell adhesion and keratinocyte differentiation were shown in a. The gene identity is listed on the left and the patient ID is listed at the bottom. The changes in gap junction, tight junction, and desmosome-associated genes in focal palmoplantar keratoderma (FPPK) are shown in b. The identity of genes is listed on the left and the patient ID is indicated at the bottom. The expression level changes of several keratinocyte proliferation– and differentiation–associated transcription factors are shown in c. The green circles indicate decreased expression levels in FPPK involved skin, whereas the red circle represents increased levels.
analysis is in Supplementary Information onilne). The mutation was also confirmed by traditional Sanger sequencing (Supplementary Figure S2 online). TRPV3 belongs to a large family of calcium-permeable transient receptor potential ion channel membrane proteins that contain six transmembrane domains (Nilius et al., 2014). The Gln580 residue is located in a conserved cytosolic region linking the fourth and fifth transmembrane domains. (Supplementary Figure S3 online). To study the functional impact of this mutation on TRPV3 activity, we transfected HEK293T cells with wild-type and Gln580 mutation TRPV3 clones (Supplementary Figure S4a and S4b online). Cells with Gln580Pro TRPV3 mutant showed an increased intracellular Ca2 þ concentration compared with cells with wild-type TRPV3, suggesting that the Gln580 mutation in TRPV3 is a gain-of-function change (Supplementary Figure S4c and S4d online). This is 2
further supported by the finding that a pan TRPV antagonist, ruthenium red, can reduce the escalation of intracellular Ca2 þ level induced by TRPV3 mutant (Supplementary Figure S5 online). To understand the molecular changes associated with the pathology, we compared transcriptome and proteome of involved and adjacent uninvolved skin samples from sole (II-7) and palm (III-7) of patients using microarray and iTRAQ (isobaric tags for relative and absolute quantitation). With iTRAQ, we identified 941 unique proteins and quantified 558 of them (Supplementary Table S1 online). The transcriptome and proteome profiling results showed genes/ proteins that are known to be highly expressed in the stratum granulosum and stratum spinosum layers, such as keratin 10 (KRT10), transglutaminases (TGMs), and filaggrins (FLGs) were decreased in the involved skin compared with the uninvolved areas (Figure 2a, Supplementary Table S2 online). The
Journal of Investigative Dermatology (2014), Volume 00
expression level changes of selected mRNAs were also verified by quantitative reverse-transcriptase in real-time PCR (Supplementary Figure S6 online). Immunohistochemistry results showed weaker signals without clear stratum granulosum layer staining with TGM1 (Figure 1h and i) and FLG (Figure 1j and k) in patient sample compared with regular skin. These findings are in agreement with the decreased stratum granulosum layer and increased stratum spinosum observed in histopathology examination (Figure 1f and g). The expression levels of desmocollin 1, desmoglein 1, gap junction protein beta 2, and E-cadherin that encode proteins associated with gap junction, tight junction, and desmosomes were decreased in FPPK involved skin samples (Figure 2b), which is supported by the disadhesion of cells in the suprabasal layers of the epidermis observed under histopathology examination (Figure 1f and g).
Y He et al. Mutation in TRPV3 Causes FPPK
Transcriptomic profiling results also revealed changes in the levels of several keratinocyte proliferation– and differentiation–related transcription factors. For example, the expression level of MYC, a key transcription factor in regulating cell proliferation, was increased in involved skin, whereas its antagonists including MXD1 (MAX dimerization protein 1), MXD3 (MAX dimerization protein 3), MXI1 (MAX interactor 1, dimerization protein), and OVOL1 (Ovo-like 1 protein) were decreased (Rottmann and Luscher, 2006; Wells et al., 2009). In addition, NOTCH1, TP63 (tumor protein p63), ZNF750 (zinc finger protein 750), and KLF4 (Kruppel-like factor 4) that are involved in keratinocyte differentiation were also decreased in the FPPK involved skin (Figure 2c; Nguyen et al., 2006; Chen et al., 2008; Wells et al., 2009; Cohen et al., 2012). This impairment of normal keratinocyte proliferation and development process is further supported by the expression level changes of KRT10 and KRT14, which are preferentially expressed by keratinocytes located in the spinosum and basal layers, respectively (Figure 2a). Immunohistochemistry revealed a broader layer of KRT14-positive cells at the basal layer and weaker KRT10-positive cells in the spinosum layer in FPPK patients (Figure 1l–o). At the pathway and biological process levels, cell differentiation and skin barrier formation–related activities, such as cell cycle and keratinization, were enriched in downregulated genes, whereas cell death–related processes were associated with upregulated genes in involved skin when compared with adjacent uninvolved skin samples (Supplementary Table S3 online). These results are consistent with the observation of distinctly thickened stratum spinosum layer with the reduction or absence of the stratum granulosum in immunohistochemical and histopathological examination. Combining the results of gene expression profiling, pathway analysis and immunohistochemistry suggest that the mutation in TRPV3 disrupts the balance of keratinocyte proliferation and differentiation processes. The epidermis contains highly differentiated keratinocytes that replenish
and form the cornified layer, the outer barrier of the skin. Proper TRPV3 activity is critical in skin development. TRPV3-deficient mice display thermal hyperalgesia, defects in skin barrier formation, wavy hair, and a curly whisker phenotype (Schneider et al., 2008; Cheng et al., 2010; Radtke et al., 2011). Recent reports on several mutations in human TRPV3 involved in the Olmsted syndrome (OS; Lin et al., 2012; Danso-Abeam et al., 2013) further support the importance of TRPV3 activity in keratinocytes development. Compared with OS, our patients with FPPK showed a mild clinical presentation, which might be caused by different mutations leading to functional differences in TRPV3. The finding that a gain-of-function mutation in TRPV3 causes the clinical phenotype in our patients opens the possibility of treating TRPV3-associated FPPK or similar skin conditions with TRPV3 antagonists. Developing a TRPV3-specific inhibitor is an active area of drug discovery for treatment of itching or other sensations (Salat et al., 2013), which may also provide systematic or topical treatments for patients with FPPK. CONFLICT OF INTEREST The authors state no conflict of interest.
ACKNOWLEDGMENTS This study was supported by the National Science Foundation of China (NSFC) grants 81201223 (YH), Guangdong Province Medical Research Foundation of China grants A2012533 (YH) Science and Technology Program of Guangdong 2013B051000080 (YH), Guangdong Medical College Integration of Industry, Education and Research C2013004 (YH), and Guangdong Medical College Research Startup Fund B2013001 (YH). We thank David Baxter, Kelsey Scherler, and Li Gray for technical help.
Yuqing He1,2,3,8, Kang Zeng4,8, Xibao Zhang3,8, Qiaolin Chen5, Jiang Wu6, Hong Li2, Yong Zhou2, Gustavo Glusman2, Jared Roach2, Alton Etheridge7, Shizhen Qing2, Qiang Tian2, Inyoul Lee2, Xin Tian3, Xiaoning Wang5, Zhihua Wu1, Leroy Hood2, Yuanlin Ding1 and Kai Wang2 1
Institute of Medical Systems Biology, Guangdong Medical College, Dongguan, China; 2Institute for Systems Biology, Seattle, Washington, USA; 3Department of Dermatology, Guangzhou Institute of Dermatology, Guangzhou, China; 4Department of Dermatology, Nanfang Hospital, Southern
Medical University, Guangzhou, China; School of Bioscience & Bioengineering, South China University of Technology, Guangzhou, China; 6Department of Dermatology, Guangzhou First Municipal People’s Hospital, Guangzhou, China and 7Pacific Northwest Diabetes Research Institute, Seattle, Washington, USA E-mail: [email protected] or [email protected] 8 These authors contributed equally to this work. 5
SUPPLEMENTARY MATERIAL Supplementary material is linked to the online version of the paper at http://www.nature.com/jid
REFERENCES Chen YJ, Wu CY, Chang CC et al. (2008) Nuclear Kruppel-like factor 4 expression is associated with human skin squamous cell carcinoma progression and metastasis. Cancer Biol Ther 7:777–82 Cheng X, Jin J, Hu L et al. (2010) TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation. Cell 141:331–43 Cohen I, Birnbaum RY, Leibson K et al. (2012) ZNF750 is expressed in differentiated keratinocytes and regulates epidermal late differentiation genes. PLoS One 7:e42628 Danso-Abeam D, Zhang J, Dooley J et al. (2013) Olmsted syndrome: exploration of the immunological phenotype. Orphanet J Rare Dis 8:79 Kelsell DP, Stevens HP (1999) The palmoplantar keratodermas: much more than palms and soles. Mol Med Today 5:107–13 Lin Z, Chen Q, Lee M et al. (2012) Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome. Am J Hum Genet 90:558–64 Nguyen BC, Lefort K, Mandinova A et al. (2006) Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes Dev 20:1028–42 Nilius B, Biro T, Owsianik G (2014) TRPV3: time to decipher a poorly understood family member! J Physiol 15:295–304 Radtke C, Sinis N, Sauter M et al. (2011) TRPV channel expression in human skin and possible role in thermally induced cell death. J Burn Care Res 32:150–9 Rottmann S, Luscher B (2006) The Mad side of the Max network: antagonizing the function of Myc and more. Curr Top Microbiol Immunol 302:63–122 Salat K, Moniczewski A, Librowski T (2013) Transient receptor potential channels-emerging novel drug targets for the treatment of pain. Curr Med Chem 20:1409–36 Schneider MR, Werner S, Paus R et al. (2008) Beyond wavy hairs: the epidermal growth factor receptor and its ligands in skin biology and pathology. Am J Pathol 173:14–24 Wells J, Lee B, Cai AQ et al. (2009) Ovol2 suppresses cell cycling and terminal differentiation of keratinocytes by directly repressing c-Myc and Notch1. J Biol Chem 284: 29125–35
www.jidonline.org
3
