Accepted Article This by is protectedarticle reserved. Allrights copyright. doi: 10.1111/bjd.18033 lead to differences between this version and the throughbeen the copyediting, pagination typesetting, which process, may and proofreading hasThis article been accepted publicationfor andundergone peerfull but review not has # Authors into skin epithelial homeostasis and avenues treatment for Pathophysiology of pachyonychia congenita-associated palmoplantar : New insight Article :Review type Article DR ABIGAIL ZIEMAN (Orcid 0000-0001-8236-207X)ID : topic? this about known already What’s statements Bulleted disclosures interest of Conflict Sources Funding Affiliations

Corresponding author: • • •

complexity. There is no cure or effective treatment for PC. for treatment effective or There isnocure complexity. high and incidence low its of because challenging made is pathophysiology PC study of The leukokeratosis. and dystrophic nails, (PPK), glandular cysts,and oral Individuals PC multiple presentwith with clin following injury. KRT6C, in bycaused isagenodermatosis rare congenita Pachyonychia : A. G. Zieman G. A. : :

School, Ann Arbor, USA; MI AnnArbor, 48109, School, 1 Michigan Medical School, Ann Arbor, MI 48109, USA MI 48109, Arbor, Ann School, Medical Michigan Department of Cell and Developmental Biology, University of Michigan Medical Medical Michigan of University Cell Biology, and Developmental of Department

KRT16 : These studies were supported by grant AR044232 issued to P.A.C. from the from issuedP.A.C. to AR044232 grant by supported were These studies : Institute. Institute. from Cancer from grant T32 CA009110 National support the A.G.Z. received National Institute ofArthritis, Muscul : , 1 and P. A.Coulombe KRT17, KRT17, Pierre A. Coulombe, PhD, 3071 Biomedical Sciences Research Building, Building, Sciences Biomedical Research 3071 PhD, A. Coulombe, Pierre Email: [email protected]. [email protected]. Email: 734-615-7509. USA. Tel: MI 48109, Arbor, Place, Ann Pitcher Zina 109 : None declared. : None declared. which are normally expressed in skin appendages and induced appendages andinduced skin in which expressed are normally 1,2 # 1,2

2 Version of Record. Please Version as this cite of Record. article Department of Dermatology, University of of University of Dermatology, Department ical usually includesymptoms thickened that oskeletal and Skin oskeletal andSkin Disease (NIAMS). KRT6A , KRT6B , Accepted Article of PC of treatment the for cure effective noknown or therapeutics currently There is difficult. everyday tasks making often PPK from daily, lesions severe pain PC plantar experience with individuals instance, While PC does impact not dramatically lifespan, it im (PPK). keratoderma teeth, and palmoplantar natal cysts, sebaceous dystrophies, nail leukokeratosis, oral including appendages ectoderm-derived affecting primarily symptoms of collection homeostasis. tissue skin the controlling of mechanisms understanding our PPK PC-based theand deepens of for treatment explore to newavenues suggests in the ability of the epidermis maintain orto defect aprofound is there PPK, active During signaling. Keap1-Nrf2 hypoactive and stress oxidative Krt16 skin (footpad) palmoplantar the in keratinocytes lesion onset, Ahead of progression. PPKof lesion main stages three PPK, revealed PC-associated of aspects mimic several that lesions footpad develops debilitating ofall PC symptoms. In the particular, study ofthe themostPPK lesions, prevalent of and and pathophysiology the heterogeneity understanding towards made progress recent on focuses review This nature. in palliative and are limited KRT16 This by is protectedarticle reserved. Allrights copyright. genes inany thewound of arise mutations repair-associated from it doesPC affect life lifespan. not can of though quality PCkeratoderma dramatically (PPK). impacts palmoplantar andvery painful dystrophy, nail leukokeratosis, includes oral and appendages typically epithelial ectoderm-derived affects primarily a rare , (PC), congenita Pachyonychia Abstract What study add? does this • •

null mice exhibit specific defects in differentiation. At the time of PPK onset, there is elevated elevated is there onset, PPK of thetime At differentiation. in defects specific exhibit mice null 1 , or , or . Pachyonychia congenita (PC; OMIM #1672000 and 167210) is a rare genodermatosis with a with is a and rare genodermatosis OMIM167210) (PC; #1672000 congenita Pachyonychia complement currentpalliative strategies. This recent progress tonewpossibilities points (PC). congenita pachyonychia with associated (PPK) keratoderma palmoplantar of thepathophysiology studying made when progress This reviews text recent

KRT17 . There is nocure for condition, this and currenttreatment options PC for symptoms return to normalhomeostasis.madereturn to Theprogress pacts quality of life for affected individuals. For individuals. affected for life of quality pacts for devising mayeffective therapeutics that Krt16 null mouse, which spontaneously spontaneously which mouse, null KRT6A , KRT6B , KRT6C ,

of of Accepted Article KRT6A This by is protectedarticle reserved. Allrights copyright. ascertained through sequencing of these keratin genes these of sequencing keratin through ascertained becan only diagnosis a alleles), definitive very similar PC (even with of among presentation patients correspondsmutation tothe PC-K6asubtype. inpartto Owing the heterogeneity in the clinical by example, a - caused etiology for PC genetic PCon subtypes are of based recognized sequence. Until recently, two majors types of PC, type 1 (Jadahsson-Lewandowsky PC, type types of twomajors recently, (Jadahsson-Lewandowsky 1 sequence. Until mall occasional with alleles, missense are mutations Most PC-causing this of disorder. theclinical presentation for part in accounting together stresses, exposure injuryenvironmental or to after e.g., inducible, robustly and are appendages otherwise www.pachyonychia.org. get and Project website involvedto how publicly-available the on can befound the PC about onPC. research basicand clinical More information a plays fostering Project lead in role thePC Finally, effective anddeveloping therapeutics. this disorder understanding together towards working and researchers clinicians patients, for resource a evolvedtransformative into registry has PC This countries. 49 in PC of cases confirmed genetically 864 includes IPCRR the 2019, January PC cases. As of andnotes ongenetically-confirmed photos, questionnaires, datavaluable from extremely gathers which (IPCRR), Registry PC Research the is tothehome PC Project International genetic Further, testing. for meetings and qualify PC support attend with to individuals to assistance condition, andtoclinicians, and translational ba Thiscondition. PC with organization connectsand their families others this individuals to with with PC and individuals both changing for resource Project The Congenita Pachyonychia (Jackson-Lawler (Jackson-Lawler , PC can arise from autosomal dominant mutations in any genes keratin in including five mutations of dominant autosomal PC from can arise The PC Project is a USA public charity that was founded in 2003 and has evolved into a and thatwas life- into Thehas evolved charity in2003 is PC founded Project a USA public KRT6B , KRT6C 7 ), were recognized based on their prevalent clinical features. Nowadays, five Nowadays, features. clinical prevalent ontheir based were ), recognized , KRT16 , or , or KRT17 KRT17 1-5 . These are normally expressed in epithelial epithelial expressed in Theseare . normally keratins sic science researchers. The PC project provides provides PCproject The sic science researchers. insertions or deletions in the keratin coding coding thekeratin in deletions or insertions for clinicians and research and clinicians for 1,8,9 . ers interested this in 6 ) and ) 2 type KRT6A

Accepted Article This by is protectedarticle reserved. Allrights copyright. 25 debilitating most and reportedly penetrant keratoderma palmoplantar on a focus Asserting feature in epidermolytic PPK, is oftencausedwhich in bymutations mutations in either mutations in epidermolysissimplex bullosa (EBS), a caused skin genetically-determined blistering by condition in element a represents predominant latter Thelysis. and/or fragility keratinocyte of display signs nomenclature, human genes are designated using capital lettering (e.g., lettering usingcapital designated genes are human nomenclature, in part because of the extreme pain associated with them them with associated pain extreme the of because part in A short primer on the nomenclature PC-associatedof keratin genes PPK lesions. PC-associated of pathophysiology the deciphering made in progress This focuses PPK(Fig. subtypesrecent on text and of 1B). clinical genetic other developers on and drug clinicians researchers, inform PC andalso with individuals for effective therapeutics the PPK of of of development the pathophysiology might spearhead A understanding deeper details). epidermis volar in keratin differentiation-specific to the low incidence of this orphan disease and the severe pain associated with these lesions these lesions with painassociated and severe the disease this low to the of incidence orphan related limitations at significant reflecting present, understood PPKisonly PC-associated of partially as such genes individual in mutations toma contributes likely involar epidermis expression keratin genes and was underestimated until the advent of whole genome sequencing efforts efforts genome whole of sequencing the until advent wasunderestimated genesand proteins keratin diversity of true the However, I, and as K17 and K16 keratins. K6asaof existencetype of II, type consists removal ofroutine callusesof by moisturizers with followed treatment PPK care of for standard PC-based current PPK.The for isnoeffective there treatment Accordingly, and consisting of dramatic epidermal thickening and andhyperkeratosis thickening epidermal dramaticand of consisting present PPKlesions restricted with prprimarily to , which necessitated a revision of the Moll nomenclature of the Moll nomenclature arevision , necessitated which While PC with individuals present manysymptomswith ofsignificance, highly PPK is The original catalog of human keratin proteins devised by Moll et by et devisedal. Moll proteins The catalog humankeratin original of KRT14 or or KRT5

14-17 KRT6A-C . Keratinocyte fragility alsoa is pathophysiological dominant 1 (Fig. 1A).Virtually all in , KRT16 19,20 essure points in palmar and/or plantar epidermis epidermis plantar and/or palmar in points essure . The greater complexity of keratin gene keratin of complexity greater . The intain structural keratinocyte integrity inspiteintain of and 11-13 26 . Per the internationally accepted . Interestingly, these lesions do not lesionsdonot these Interestingly, . KRT17 . This said, the pathophysiology 3-5,10 KRT9 dividuals with PC (> 90% (> with PC dividuals KRT16 . PPK lesions are debilitating lesions aredebilitating . PPK

18 , the major , themajor 24 ) and mouse genes are and mousegenes ) already recognized the already recognized 23 (see below for for below (see 21,22 1 . ) Accepted Article This by is protectedarticle reserved. Allrights copyright. the human in uncovered (e.g., lettering size normal using designated ( 9 loss keratin adramatic of already, but, tissue histology skin the to there arealterations minimal At this point early time differentiation. terminal of aspects selective defects in exhibit keratinocytes 2). PPK (Fig. and active PPK pre-PPK, onset, signature: of Characterization PPK lesions. skinmimicking lesions PC-associated footpad develops spontaneously Krt6b Krt16 terms of sequence features and regulation, applies to the PC-associated keratin genes the keratin PC-associated to applies and regulation, features sequence terms of and human, in toapplygenes inthemouse orthologous keratin known to high degree conservation of stress phenotype observed at a later stage of progression of PPK-like lesions in this mouse model model mousethis in lesions PPK-like of progression of stage a later at observed phenotype stress this setting setting this marker gene in a and predominant volar represents skin of keratinocytes differentiating in exclusively terminal differentiation unexplained is currently differentiation terminal Lessons learned from transgenicmouse models PC. such as conditions human -based utilizatio discussing theto relevant information is single gene codes for each of K16 eachK16 of codes for gene single and PPK PC study to Table 1) in models (summarized mouse transgenic onthe use of relied researchers have therapeutics, screen or potential PPKpathophysiology underlying and mechanisms molecular Krt9 Krt16 /K9) expression has occurred, which then persists throughout lesion progression progression lesion throughout whichthenpersists has occurred, expression /K9)

null footpad skin, potentially as a compensatory mechanism mechanism compensatory a as potentially skin, footpad null 28 , and three functional K6 genes in the human, K6genes, andthree inthe human, functional In 2-weeks old old In 2-weeks As there are no no are there As null mice has revealed three phases in PPK, each with a somewhat unique molecular molecular unique a somewhat with each PPK, in phases three revealed mice has null 34 . Among the models available, the available, the models Among . 19,20,36 . In contrast to to contrast In . Krt16 in vitro 27 . Currently, we know of two functional genes . mouse, inthe of we two know functional Currently, null mice, corresponding to the “pre-PPK stage”, footpad skin skin footpad stage”, “pre-PPK the to corresponding mice, null human cell culture models that can be used to investigate the cellular cellular the modelsthatcan culture humanbe used investigate to cell Krt9 30,31 , several differentiation markers appear to in markersbe upregulated to appear , several differentiation andK17proteins Krt16 Krt16 35 n of transgenic mouse models to study keratin study models to transgenic of mouse n ). The ofK6sequences multiplicity was originally , it occurs independent and ahead of the oxidative the oxidative of ahead and occurs it independent , null mouse strainnull is the onlyone that KRT6A 32,33 in the human and mouse genomes. The genomes. mouse human and inthe , KRT6B 35 . While this partial defect in , and , KRT6C

2,29 29,31,32 35 Krt6a . By contrast, a . Krt9 . This and and occurs occurs 35,37 . Accepted Article evidence of reduced Nrf2 activity in PC-PPK lesions of individuals with with individuals PC-PPK lesionsof in activity reduced of Nrf2 evidence is there PC patients, from plantarbiopsies skin access to to given ascertain Whilerestricted difficult ineffective in isupregulated though factor, a transcription itself, Nrf2 while time at that markedly attenuated to compared genes synthesis glutathione of expression glutathione anddecreased antioxidant cell master the levelsof decreased including stress, oxidative of features displays epidermis several skin footpad This by is protectedarticle reserved. Allrights copyright. innate immunity effectors including DAMPsincluding effectors innate immunity (DAMPs) and barrier homeostasis genes, which mimics human PC-based PPK lesions PPK lesions whichmimics PC-based human genes, homeostasis (DAMPs) barrier and Patterns Molecular of many Associated Danger a gross exhibit misregulation footpad lesions both at baseline and in response to TPA, which acts as a chemical irritant irritant achemical as acts which TPA, to response in and baseline at both skin, tail in genes inflammation and homeostasis barrier of expression with correlated significantly response to barrier-compromising stresses stresses barrier-compromising to response for a role to genes pointed homeostasis barrier belongsof a network to inflammation and barrier function function and barrier inflammation systemsgenetics dataset that related the risk of developing skin tumors to the regulation of skin apowerful Re-analyzing stress. to response skin’s the regulating in K16 of the role explore to used been genetics has PC-based of thepathophysiology PPK. into Systems insight significant provided Lessons learnedcomputational endeavors from stress, they are not associated with keratinocyte fragility fragility keratinocyte with are theyassociated not stress, experiencing mechanical thus and tothe exposed substratum inareas arise thesepreferentially lesions timeall this By maintain skin return to normalhomeostasis. or defect tissue the to in profound ability footpad of WT controls. Keap1-Nrf2 signaling, a central regulator of the cellular antioxidant response, is response, ofantioxidant the cellular regulator acentral signaling, Keap1-Nrf2 controls. In one-month old In one-month old Along with targeted molecular analyses, computational analysis of genomic data sets has also sets has genomic analysis of data computational analyses, Along targeted molecular with In two-months old In old two-months Krt16 Krt16 null mice have spontaneously developed PPK-like lesions on their paws, and while paws,and while their on lesions PPK-like nullmicedeveloped have spontaneously null footpad skin (likely reflecting an attempt to restore redox homeostasis). homeostasis). torestore an redox skin(likely reflecting attempt footpad null Krt16 Krt16 null mice, corresponding to “onset stage” of PPK-like lesions, null lesions, PPK-like stage” to“onset of mice, corresponding null mice, corresponding to isa PPK,there stage” of to an “active mice,null corresponding 40 revealed a tight link between 39 , which converged nicely with the phenotype of PPK-like PPK-like of phenotype the , which converged with nicely 39,41 . In this data set, moreover,. In thisdata set, 38,39 . At a the molecular level, Krt16 Krt16 , skin barrier genes, genes, and barrier , skin KRT16 41 . The discovery that that discovery The . Krt16 incalibrating theskin’s mutations mutations expression is expression 39 Krt16 . 37 null . Krt16

Accepted Article This by is protectedarticle reserved. Allrights copyright. both from expression gene of surveys genome-wide of availability The skin lesions lesions. PPK PC-based in elevated often is expression PC to as be applicable could response stress skin’s how K16 the of understanding calibrates by lesions exhibited by genetic strain background background bystrain genetic R127C) can elicit a presentation of focal non-epidermolytic PPK vs. full-blown PC PPK vs. full-blown of non-epidermolytic focal cana presentation R127C) elicit in alleles similar Remarkably, condition. this of pathophysiology the in modifiers comparisons of global transcriptional changes in changesin transcriptional global of comparisons human-mouse orthologous gene pairings, enabled multiple computational analyses computational enabledmultiple gene pairings, human-mouse orthologous murine the with PPK datasets human Merging the the of limitations and strengths the test further several phenotypic aspects of of aspects phenotypic several miceand humans, between differences immunological the this with despite notion, effects. Consistent suggesting thatthe consequences in alterations associated with Krt6a/Krt6b (3 or the allele or same mutatedkeratin PPK of thepathophysiology in background geneticimbalances keratin and for A role lesions. PPK PC-associated of pathogenesis of the study modelfor an mouse is appropriate the the notion extending that and level, reinforcing PPKgene expression at aglobal lesions casethatlesional astrong comparisons provided these Altogether (Fig. 3C). allele keratin samemutated the cases andbetween with mutations, keratin different cases involving between degreehighlight individual high heterogeneity the of changes further transcriptional global of comparisons pairwise Additionally, 3A-B). cases (Fig. KRT6

Since the ofPC presentation symptomsvariesgreatly even similar individuals between with cases, 3 cases, 35 double-null mice double-null PCand PPK individuals with lesions from KRT16 Krt16 cases) generated statistically significant positive correlation values in all all in values correlation positive significant statistically generated cases) null mice. These efforts lent strong support to support strong athe notion better that lent mice. null These efforts 47 Krt16 49 . Interestingly, select phenotypic traits in traits phenotypic select . Interestingly, also exhibit a dependence on genetic background. background. genetic on adependence exhibit also 1,42-44 null mice including the PPK-like lesions are modestly impacted modestly impacted are lesions PPK-like the mice including null , there likely is a role for genetic background and gene background genetic for a role is likely , there Krt16 Krt16 Krt16 Krt16 null mouseas avalid model forPC-based PPK. null mouse footpad skin mimics PC-associated skin mimics mousePC-associated null footpad null footpad lesions and individual PC cases cases PC individual and lesions footpad null null footpad lesions dataset, based upon upon based dataset, lesions footpad null 22 has provided an excellent opportunity to opportunity to has an excellent provided KRT16 are subject to modifier gene(s) gene(s) modifier to subject are Krt17 null mice Krt16 KRT16 35 44-46 . Pairwise . Pairwise null footpad null footpad (Fig. 1C), 48 (N125S and and (N125S and and Krt16 KRT16 null

Accepted Article keratins keratins the differentiation-specific PC-basedFor example, of PPK. role pathophysiology in a significant This by is protectedarticle reserved. Allrights copyright. 22,35,50 pleiotropic and context-dependent properties properties pleiotropic and context-dependent inflammation pose a risk for infection and can infection pose for patients be for inflammation a painful risk of the development of ectodermal appendages, including the tooth tooth including the the of ectodermal appendages, development of keratoderma-like phenotype on footpad skin skin footpad on phenotype keratoderma-like genetic variants inthe PC-associated genes to keratin tooth susceptibility increase decay usually lost within the first few months of life life of months few first the within usually lost PPK that closely resembles the corresponding human disorder human disorder corresponding the PPKclosely resembles that sensitive regulation of these genes wound- and stress- the given expected as PPK, PC-based in increased dramatically is alleles) mutated alterations (see KRT17 in mutations individuals with in over all preferentially and and body the canoccur glands arise which fromsebaceous originate to filled cysts believed benignare fluid which PC patients, in #184510) and #184500 seeOMIMentries multiplex; or cysts occurrence individual multiple (steatocystoma of intrigui as particularly remaining out them stand PCother features PPKand unknownsclinical Pathophysiological of in lesions. of PPK and evolution development the on impact have striking to are amongbalance poised a them associatedwith mutations in preferentially and isalso innewborns teeth of whichreferspresence to is natal teeth, manifestation PC. with associated natalteeth and phenomenon of study lesions to skin model no cystic the currently . Of note, mice that are double-null for the differentiation-specific differentiation-specific for the double-null are micethat note, Of .

57-59 In addition to genetic background, imbalances in keratin expression also appear likely to play play to likely appear also expression keratin imbalances in background, genetic to addition In While all clinical manifestations associated with PC are worth a deep investigation, twoof a PCare worth deep investigation, associated with clinical Whileall manifestations KRT2 . These cysts often require surgical drainage or removal as their rupture and/or and/or removalrupture or astheir drainage surgical These require . often cysts and and 35 and KRT9 22 ), the expression of of the), expression are both decreased in are both KRT17 22 . Given the knowledge that K6, K16 and K17 proteins have proteins K17 and K16 K6, that knowledge Giventhe . 1,59 . Natal teeth are soft, friable and prone to caries, and are and caries, to prone and friable soft, are teeth Natal . KRT6A 51 35,37,39,52-56 1,60-63 while mice null for while micenull Krt16 ng at a cellular and molecular level. level. One isthe ng and molecular at a cellular , . Of note, KRT6B null lesions andhuman footpad null PPK PC-based , such alterations in keratin levelsand protein keratin in such alterations , , KRT16 Krt17 36 . Aside from these (and other) . Aside these from other) (and 32 Krt9 is expressed at a very early stage atastage early very expressed is , and/or . Recent studies have shown that 1 . Another intriguing. Another develop develop an epidermolytic Krt2 KRT17 and and Krt10 (including the the (including develop a develop 64 . There is Accepted Article This by is protectedarticle reserved. Allrights copyright. calluses of removal mechanical and orthotics, PC for strategies andcurrent therapeutic of past Limitations in a trialof the siRNA whichtargetsTD101, the some promise hasshown It expression. allelestheir and keratin reduce mutant target that specifically are highlighted here. The strategy first involves th strategies distinct Two these lesions. of the management for therapeutics effective new and develop systemic treatment the of toxicity PC-PPK without improved K6a two patients of treatment sirolimus Recently, topical PC. for treatment long-term beingviable a from it prevent treatment rapamycin systemic with most satisfying treatment forindividuals PC with has the been cutting grinding, or calluses filing, of by removal mechanical Routine underlying PPK. andPain medication custom alleviate orthotics butcan do discomfort, partially not treat the PC-PKK. most cases of with associated overgrowth the significant control cannot they calluses, soften long-term treatment for PC long-term treatment for a from viable being retinoids prevent oral pain increased including effects adverse side rapamycin, ca reduced successfully retinoids Oral treatment. based therapeutics that involves topical applic thatinvolves topical based therapeutics deliver siRNA- to method a Accordingly, corneum. stratum the through penetration improve does not botulinum toxin (Botox) into plantar callusesimprove plantar into (Botox) toxin botulinum expression and, when taken orally, improves PC symptoms K6a suppresses rapamycin/sirolimus The mTOR gene inhibitor expression. keratin reducing mutant rosuvastatin has been shown to be effective in a single case of K6a based PC K6a of case PC based a in be single effective to shown has been rosuvastatin self-delivery siRNAs for mutant keratin alleles improves the uptake of siRNAs by keratinocytes keratinocytes siRNAs of by alleles uptake the keratin mutant improves for siRNAs self-delivery therapeutics requires that injections intradermal cau acid-based such nucleic delivery of that limitation the this from suffers form, approach In itscurrent PC-associated PPK has been treated with a combination of keratolytics, pain medication, medication, pain keratolytics, of a combination with treated PPKhasbeen PC-associated The second strategy to treat PC-based PPK consists of drug-based interventions aimed at drug-based of treat interventions PC-basedstrategy The PPKconsists to second 71 but requires additional studies to confirm the safety and efficacy of this this of the andefficacy safety confirm to studies but requires additional 72 . Statins can also downregulate . can downregulate Statins also ation of therapeutic agents is sorely needed sorely is oftherapeutic agents ation 23,65 llus thickness in some PC individuals, but like but PC individuals, some in thickness llus KRT6A . While . While the keratolytics salicylic acid and urea 23 e development of short interfering RNAs (siRNAs) interfering short RNAs of (siRNAs) e development . Significant efforts are currently under way under are currently efforts to . Significant se intense to the pain Thepatient. of generation d plantar blistering and pain associated with PC- with associated and blistering pain plantar d N171K allele, albeit in a allele,in albeit N171K single patient 70 KRT6A . However, severe side-effects associated associated However,side-effects severe . expression expression 74 . Finally, injections of 73 , but sofar only oral 69 . 21,66,67 68 but but . Accepted Article This by is protectedarticle reserved. Allrights copyright. PPK lesions therapeutics for any disease anytherapeutics for disease developing when consideration isan important differences sex-based micethat isareminder the SF treatment regimen is necessaryregimenthe SFtreatment is natural molecule sulforaphane (SF), which activates Nrf2 signaling by modifying Keap1 Keap1 signaling by modifying Nrf2 activates which (SF), molecule natural sulforaphane In of normal epidermal differentiation. restoration the promoting of capable pathways and/or pathways response stress target to be would PPK PC-based Opportunities for noveltherapies PPK. PC-based for strategies treatment provide long-term them viable none of form provide inpresent relief, some interventions drug-based induction of male open question. PC-associated PPK. PPK. PC-associated for trea the attractive prospect an lesions represent In the treatment theprospectend, ofcombining prevent PPK-like lesions in male mice lesions in female mice. SF is available in pure form or as part of broccoli sprout extract mutations eitherin keratins K5 orK14 of inthe EBS treatment from promise arising has and shown therapeutic safelytopically, delivered Krt16 A promising opportunity to complement ongoing efforts to develop effective therapeutics for for therapeutics effective develop to efforts ongoing complement to opportunity A promising Another strategy worth considering is to normalize terminal differentiation volar In in skin. differentiation terminal isnormalize to considering strategy Another worth

null mice treated with SF prior to lesion onset, restoration of Nrf2 activity coincided with with activity coincided Nrf2 of restoration onset, lesion to SF prior with treated mice null 75 Krt9 , but injections are costly and must be performed under anesthesia. While each of these eachof While anesthesia. under andmustbe costly , but areperformed injections expression expression 81 35 . Whether there is a sexual dimorphism in the setting of PC remains an remains PC of setting the in dimorphism sexual a is there Whether . . Additional efforts should be focused on testing this specific strategy. strategy. specific this shouldbe focusedtesting on efforts Additional . for successful activation of Nrf2 of Nrf2 activation successful for 37 79,80 . Addition of theER- of Addition . . The sexual dimorphism in response to SF treatment in in SF treatment to response in dimorphism Thesexual . modalities that act to modalities actto prevent treatthat and/or active tment ofa condition featuring the complexity of Krt16 nullmice, topical treatmentthe with small β agonist Diarylpropionitrile (DPN) to to (DPN) Diarylpropionitrile agonist 77 and prevention of PPK-like of PPK-like andprevention 78 76 , can be , can , can Accepted Article This by is protectedarticle reserved. Allrights copyright. Health. Institutes of National the from AR044232 grant by supported was work This support. their for the laboratory thank of Coulombe members to wish The authors Acknowledgements that control skin tissue homeostasis. mechanisms the understand better to an opportunity provides also but PC, treat to therapeutics devise to paves PC.researchers The only PPK with the of way study for not pathophysiology individuals for symptoms debilitating the most of one PPK, PC-based of thepathophysiology into insight novel and provided beeninvaluable biology computational has of and mousetransgenic models use of the disease, studying this thatarise challenges in of Despite theplethora presentation. Future directions a polygenic disease complex, isawith (PC) skin monogenic congenita Pachyonychia 2012 2011 2008 2005 2002 2000 2000 1999 1999 1996 Accepted Article References Main phenotype(s) Genetic modification Mouse model Year This by is protectedarticle reserved. Allrights copyright. 1 Table Krt16 skin Humanized N171K KRT6A knock-in Krt75 Krt6a/Krt6b Krt17 Krt6a Krt6a/Krt6b transgenic Krt6a transgenic Krt6a Krt6a Krt1 7 - -/- - - Δ / / / - - - : Mouse models with phenotypes that are potentially relevant to pachyonychia congenita (PC). (PC). congenita pachyonychia to relevant potentially are that phenotypes with models Mouse : 21P

- - / / - - ; Deletion of of Deletion Deletion of of Deletion of Deletion of Deletion of Deletion engrafted onto mice immunodeficient onto engrafted mutation with N171K PC individuals from derived skin equivalents Bioengineered case) PC in N171 mutation to (corresponding mutation codon N158 of Point and late- Hyperkeratosis E2 HK1-tag by of Replacement domain rod central the of 2B region the deleting Truncation helix betweendomain head176) and1A 52 of amino acids 125- Deletion (residues Krt6a Krt16 Krt6a Krt17 Krt6a and locus Oral lesions, footpad lesions lesions footpad lesions, Oral locus dependent strain Ageand reepithelialization of Delay , locus locus Krt6b Krt6b , and , and lcs rllsos 4984 Oral lesions locus Krt17 lcs Severe lysis cell bed innail locus epitheliu alopecia wounding after resembling humanPPK fragility 87 Defects inhairshaft, nail onset alopecia Lethal orblister alopecia blistering Intraepidermal blistering 88 blistering epidermal and Acanthosis m 48 85 38,47 38,47 83 83 82 86 Accepted Article This by is protectedarticle reserved. Allrights copyright. central “head” domain, struct domain the tripartite FNEPPK.exhibits K16 both or PPK PC PC, and (FNEPPK), non-epidermolytic focal for proteinare that causative (K16) for. Additional tableare references 18,89-111. for PPK subtypes of are accounted clinical Various presentation. PPK clinical a canelicit when mutated, genes of which, the diversity Table summarizing (B) (www.pachyonychia.org). Project Congenita a with from an individual based PPK lesions 1 Figure Legends Figure at 2-, 4-, and 8-weeks of age in of and at 4-, 8-weeks 2-, occur Summary (B) that changes key molecular Zen of using software. 2.3 attachment andprocessed Apotome Images with aZeiss using microscope acquired µm. = corneum. Scale stratum 100 bar SC= Epi = Dermepidermis, = dermis. junction. isepidermal/dermal line Dotted lysis. cell suprabasal thickening ofthe living epidermis and the stratum isdramatic there 8 By isobserved. weeks, thickening epidermal mild lesions, appearance of macroscopic to prior can be 4 weeks, At seen. of keratinocytes basal aspect ratio nuclear decreased a and keratinocytes, basal of crowding layer, granular the of appearance abnormal the including alterations upon inspection, closer but, architecture and thickness overall a normal epidermis shows of histology Representative (A) 4 8weeks). Active-PPKPPK (at (at of weeks), and age), PPK 2weeks of Onset (at 2 Figure FNEPPK text. both and purple for PC are in are causative causative for FNEPPKare in blue text, mutations causative for PC are in gold text, and mutations that thatare mutations Representative IF among element proteins. asignature and represent conserved highly are bars) red (see domain rod central the of attributes Many L12). and (L1 linkers repeat repeat-containing heptad of is comprised : Palmoplantar keratoderma, a genetically heterogeneous disorder. (A) Photograph of PC- of Photograph (A) disorder. a heterogeneous genetically keratoderma, : Palmoplantar : Development of PPK-like lesions in PPK-like lesions of : Development α -helical “rod” domain, and C-terminal “tail” domain. The central rod domain domain rod central The domain. “tail” C-terminal and domain, “rod” -helical Krt16 Krt16 null footpad skin at 2-, 4-, and 8-weeks of age. At 2 weeks, the age. At of at 8-weeks and 4-, skin 2-, footpad null null footpad skin. nullfootpad Potentia (C) α -helical coils (1A, 1B, Coil non-heptad by 1B, separated Coil 2) (1A, coils -helical KRT16 Krt16 corneum, infiltration of immune cells, and limited limited of cells, and immunecorneum, infiltration (C) Schematic of select mutations in 16 keratin in mutations (C) select Schematic of ure shared by all IF proteins, with a N-terminal IFure byall shared proteins, L124R mutation. Source: Pachyonychia Source: mutation. L124R null footpad skin proceeds in three stages: Pre- stages: three in proceeds skin footpad null l therapeutic interventions for for interventions l therapeutic Accepted Article Jackson AD, Lawler PachyonychiaSD. congenita; reporta ofcases six inone family, with note a 7 8 Liao H, Sayers JM, Wilson NJ Wilson JM, Sayers H, Liao 8 Lewandowski). and (Jadassohn Congenita Pachyonychia J. Franklin 6 Bowden PE, Haley JL, Kansky A 5 Goor H van MF, Jonkman FJ, Smith 4 11 Krupiczojc MA, O'Toole EA. Plantar pain in pachyonychia congenita. congenita. pachyonychia in pain Plantar EA. O'Toole MA, Krupiczojc 11 NJ Wilson SA, Leachman T, Fu 9 DP Lunny EL, Rugg WH, McLean 3 Wilson NJ, Messenger AG, Leachman SA 2 microarray data from from data microarray of comparisons pairwise from (R) calculated coefficients Correlation (A-B) based PPK lesions. 10 Lin MT, Levy ML, Bowden PE Bowden LevyML, Lin MT, 10 This by is protectedarticle reserved. Allrights copyright. 3 Figure Diarylpropionitrile. = DPN sulforaphane. = SF 35,37,39,77). refs. (see development lesion of each stage 1 Leachman SA, Kaspar RL, Fleckman P Fleckman RL, Kaspar SA, Leachman 1 References mutations in in mutations corresponding R values. Figure adapted from Zieman et al. (2019) Zieman etal. (2019) from Figure adapted R values. corresponding the text areunderneath purple in denoted each correlation P values for between samples. correlation perfect conveys 1 of value R a whereas correlation, negative perfect convey would -1 of value either PPK with cases PC-based of individual comparisons between on linkage data. Medicine of Society causing pachyonychia congenita. congenita. pachyonychia causing congenita. 1998; 2. type congenita pachyonychia disorder K17 the of phenocopy congenita. keratoderma. keratoderma. dermatology spot. hot keratinmotif of 6in pachyonychiatwo congenita patients: further mutationalevidence for a congenita patients withmutations. K16 1025-8. congenita. : Correlation of transcriptional changes between between changes transcriptional of Correlation : 7 KRT6 : 1143-8. Experimental dermatology Experimental Nature genetics Nature genetics Nature The journal of investigative dermatology. Symposium proceedings Symposium dermatology. ofinvestigative journal The (A) or (A) 2018; 2018; The Journal of investigative dermatology investigative of Journal The Krt16 Annals of eugenics of Annals 1939; 179 KRT16 null footpad lesions lesions footpad null : 11-2. 32 1995; 1995; (B). (C) Correlation coefficients calculated from pairwise etal. et al. et : 263-5. etal. etal. et al. Journal of dermatological science dermatological of Journal 10 9 A spectrum of mutations in keratins K6a, K16 and K17 K17 and K16 K6a, keratins in mutations of spectrum A Identificationof sporadic mutations inhelix the initiation etal. : 273-8. 1951; Genotype-phenotype correla Genotype-phenotype 1999; 1999; Mutation of a type II keratin gene (K6a) in pachyonychia pachyonychia in (K6a) gene keratin II type of a Mutation : 363-5. et al. et Keratin 16 and mutations cause pachyonychia pachyonychia cause mutations 17 keratin and 16 Keratin The Journal of investigative dermatology investigative of Journal The et al. et A mutation in human keratin K6b produces a produces K6b keratin human in mutation A 16 35 Clinical and pathological features of pachyonychia pachyonychia of features pathological and Clinical 8 and human PC-based PPK lesions : 115-9. : 142-6. Keratin K6c Keratin mutations cause palmoplantarfocal Krt16 2010; 2010; null footpad lesions and human PC- and human lesions footpad null 35 KRT6 . 130 Human molecular genetics tions among pachyonychia : 425-9. 2007; Proceedings of the Royal Royal the of Proceedings or or The British journal of of journal British The KRT16 48 : 199-205. 2005; mutations. mutations. A R 22 resultingfrom 2011; 10 : 3-17. 131

: Accepted Article 17 Coulombe PA, Kerns ML, Fuchs E. simplex: a paradigm for disorders of of disorders for paradigm a simplex: bullosa Epidermolysis E. Fuchs ML, Kerns PA, Coulombe 17 4 Moll R, Franke WW, Schiller DL 24 Goldberg Fruchter I, D,Meilick A 23 Cao YA, Hickerson RP, Seegmiller BL 22 ME Schwartz RP, Hickerson SA, Leachman 21 Kim D, Hossain MZ, NievesA 20 I Moll HW, Heid L, Langbein 19 L Langbein HC, Hennies A, Reis 18 R Vassar ME, Hutton PA, Coulombe 16 A Letai ME, Hutton PA, Coulombe 15 1 Bernot KM, Coulombe PA, McGowan KM. Kerati 31 TB Shows A, RayChaudhury M, Rosenberg 30 This by is protectedarticle reserved. Allrights copyright. Coulombe PA, Fuchs Epidermolysis E. bullosa simplex. 14 heriditary in mechanisms Pain M.J. Caterina, M., Polydefkis, P.A., Coulombe, RL, Weinberg 13 FJD Smith E, Sprecher S, Brill 12 29 Takahashi K, Paladini RD, Coulombe PA. Clonin PA. Coulombe RD, Paladini K, Takahashi 29 during expressed keratins of the regulation posttranscriptional for Evidence E. Fuchs TynerAL, 27 draft the and proteins filament intermediate for Genes K. Weber TM, M, Magin Hesse 25 28 Takahashi K, Yan B, K Yamanishi K, Takahashi Yan 28 PA Coulombe PE, Bowden J, Schweizer 26 different types of epidermolysis bullosa simplex diseases. diseases. simplex bullosa epidermolysis of types different expression in normal epithelia, tumors and cultured cells.cultured expression and in normal tumors epithelia, JEADV : Venereology and Dermatology of Academy European the of Journal Therapy Gene Ib trial of an inherited skindisorder. American journal of pathology MimicsParacrine Canonical WntSignalingActivatedIs Ectopically and Skin Disease. in expression. epidermal cytokeratin 9:cDNA tissue fragility. 1661-74. skin. (EPPK). keratoderma 11. analyses. functional and genetic patients: simplex bullosa epidermolysis 90. 36. chromosome characterization17: and expression. chemistry isoforms. 6 keratin II type related highly encoding cDNAs and 2002; cycle. hair andthe morphogenesis skin during cells Palmoplantar Keratoderma. Keratoderma. Palmoplantar origin. neuropathic 1998; orthologs. human their from independently evolved and regulated differentially biology epidermis. human in transformation malignant and hyperproliferation keratins. pseudogeneskeratin related to genes 8and 18. keratin novel genome: human the of sequence Journal of dermatological science of dermatological Journal 119 53 1986; : 170-83. The Journal of cell biology cell of The Journal 1995; : 1137-49. Differentiation; research in biological diversity biological in research Differentiation; 2010; 103 J ClinInvest 270 : 1945-55. The British journal of dermatology of journal British The : 18581-92. 18 Nature genetics Nature : 442-6. 2009; et al. et al. et The British journal of dermatology et al. 2016; et al. et et al. et cloning, amino acid sequence, and tissue specificity of gene etal. et al. Molecularcharacterization body the site-specific of human 119 et al. et Chronic pain in pachyonychia congenita: evidence for for evidence congenita: pachyonychia in pain Chronic To Control Site-Specific Skin Gene Expression, Autocrine Autocrine GeneExpression, Skin Site-Specific Control To 2006; et al. etal. Keratin 9 gene Keratin 9 mutations in epidermolyticpalmoplantar Molecular therapy the: journal of the American Society of catalogThe of human cytokeratins: patterns of 1994; 186 : 1784-93. The two functionalThe keratin 6genes are of mouse Besttreatment practices pachyonychiafor congenita. 2015; etal. Point mutations in human keratin 14 genes of genes 14 keratin human in mutations Point A function for keratins and a common thread amongthreadcommon keratinsa and function for A : 1140-50. Gene expression profiling in pachyonychia congenita congenita pachyonychia in profiling expression Gene etal. etal. 174 6 consensusNew nomenclature for mammalian : 174-9. 77 : 169-74. g and characterization of multiple human genes First-in-human mutation-targeted siRNA phase phase siRNA mutation-targeted First-in-human genes and a surprisingly high number of of number high surprisingly a and genes A group of type I keratin genes on human human on genes keratin I type of group A : 156-65. n 16 expression defines a subset of epithelial epithelial of a subset defines expression n 16 Journal of cell science cell of Journal Molecular and cellular biology cellular and Molecular The Journal of investigative dermatology 2018; Seminars in dermatology in Seminars 1993; The Journal biology of cell Cell 179 The Journal of biological biological of Journal The 1982; 1982; 2019; 2019; : 154-62. 55 : 57-71. 31 In press. In 2001; The Journal of cell of Journal The : 11-24. Cell 2014; 1991; 1991; 114 1993; : 2569-75. Genomics 1988; 28 66 1991; : 279-85. : 1301- 12 The The 8 : 173- : 722-

115

: Accepted Article 4 Smith FJ, Fisher MP, E Healy 44 This by is protectedarticle reserved. Allrights copyright. Smith FJ, LD, Corden EL Rugg 43 LessardPina-Paz JC, S, Rotty JD 39 of definition the with coincides expression 17 keratin of Onset PA. Coulombe KM, McGowan 32 2 Covello SP, SmithFJ, SillevisSmitt JH 42 P Huang E, Kandyba DA, Quigley 41 Quigley DA,ToMD, Perez-Losada J 40 mice 16-null Keratin PA. Coulombe JC, Lessard 38 Kerns ML,Hakim RG Lu JM, 37 encoding gene human of the Characterization WW. Franke Leube RE, SM, Troyanovsky 33 45 Shamsher MK, Navsaria HA, Stevens HP Stevens HA, MK, Navsaria Shamsher 45 36 Fu DJ, Thomson C, Lunny DP Lunny C, Fu Thomson DJ, 36 ZiemanPoll A, BG, Ma J 35 Chen J, Roop DR. Mouse models in preclinical studies for pachyonychiacongenita. 34 47 Zieman A, Coulombe PA. The keratin 16 null phe null 16 keratin The PA. Coulombe A, Zieman 47 Smith FJ, LiaoH, Cassidy AJ 46 52 Tong X, Coulombe PA. Keratin 17 modulates hair follicle cycling in a TNFalpha-dependent TNFalpha-dependent a in cycling follicle hair modulates 17 Keratin PA. Coulombe X, Tong 52 Wong P, Colucci-Guyon E,Takahashi K 49 E Colucci-Guyon X, Tong KM, McGowan 48 51 Fischer H, Langbein L, Reichelt J Reichelt L, Langbein H, Fischer 51 Rice RH, Durbin-Johnson Salemi BP, M 50 dermatology pachyonychiacongenita type 1and focalpalmoplantar keratoderma. dermatology investigative of Journal multiplex. steatocystoma resembling phenotype a or 2 type congenita pachyonychia 475-80. breach. barrier epidermal dermatology disorders. related and congenita pachyonychia of feature phenotypes. congenita pachyonychia major epithelial lineages during skin development. multiplex or pachyonychia congenita type 2. 2. type congenita orpachyonychia multiplex 65. Cancer. and inInflammation Differences Skin Reveals Functional tumour susceptibility. 134 epidermis. palmoplantar the of differentiation cytokeratin 17and itsexpression pattern. 86. investigative dermatology. Symposium proceedings genetics non-epidermolytic palmoplantar keratoderma (NEPPK) in two families. mutation-based palmoplantar keratoderma. proceedings Symposium dermatology. investigative of background in mice. mice. in background fashion. fashion. biology essential their reveals genes and K6beta alopecia. dependent integrity of plantar skin. plantar callus. : 754-63. 2000; 1995; 1995; Genes & development & Genes 2000; 2000; 2012; 2012; 150 Journal of proteomics 4 : 1875-81. : 921-8. 132 9 Experimental dermatology Experimental : 170-7. Genes & development & Genes Nature : 1384-91. et al. et Journal of dermatological science ofdermatological Journal Proc Natl Acad Sci U S A Proc SciU Acad Natl et al. etal. et al. et etal. etal. Altered keratinocyte Altered differentiation is keratin early of an driver 2009; 2009; 2006; etal. et al. et et al. The genetic basis of pachyonychia congenita. congenita. pachyonychia of basis genetic The Oxidative stress and dysfunctional NRF2 underlie underlie NRF2 dysfunctional and stress Oxidative Novel keratin Novel 16mutations and protein expression studies in Keratin 9 is required for the structural integrity and terminal terminal integrity and structural the for required 9is Keratin Missense mutations in keratin 17 cause either cause keratin either 17 in mutations Missense et al. et 2017; 2017; 458 1997; et al. et Keratin 16 regulates innate immunity in response to to response in immunity innate regulates 16 Keratin Keratins K2 and K10 are essential for essential theepidermal K10are Keratins and K2 20 Gene Expression DorsalTail and Architecture Mouse of J Clin Invest et al. et etal. etal. etal. : 1353-64. : 505-8. Genetic architecture of mouse skin inflammation and structural role in the oral mucosa. mucosa. oral inthe role structural Keratin 17 mutations Keratin 17 cause either steatocystoma European journal of cell biology cell of journal European 165 2002; 108 Introducing mutationnull a the in mouse K6alpha Proteomicprofiling of Pachyonychiacongenita Human molecular genetics The British journal of dermatology of journal British The Novel mutations in keratin 16 gene underly focal underly focal gene 16 keratin in mutations Novel Keratin 17 null mice exhibit age- and strain- and age- exhibit mice null 17 Keratin develop palmoplantar keratoderma, a hallmark hallmark a keratoderma, palmoplantar develop : 132-7. The Journal of investigative dermatology ofinvestigative Journal The : 220-3. 2018; notype is modestly impacted by genetic strain strain genetic by impacted modestly is notype 2016; 16 2013; The Journal of cell biology cell of Journal The 2005; 2005; : 1412-22. 2005; 27 126 : 672-4. 110 2016; The Journal of investigative investigative of Journal The 10 : 2356-66. : 21-30. : 19537-42. 10 : 37-46. 81 Cell reports Cell : 10-6. Experimental Experimental Human molecular molecular Human 2019; 1992; 1992; The Journal of cell cell of Journal The 2016; 1998; 1998; In Press In The journal of of journal The 1998; 59 The journal journal The 16 : 127-37. 143 The : 1153- 139 . 2014; : 469- : Accepted Article 73 Zhao Y, Gartner U, Smith FJ Smith U, Gartner Y, Zhao 73 V Patel FB, Bartholomew JMC, Teng 71 HickersonLeake RP, PhoLN D, 70 8 Wilson NJ, Leachman SA, Hansen CD 58 McLean Hansen EliasonWH, CD, MJ 57 72 Gruber R, Edlinger M, Kaspar RL Kaspar M, Edlinger GruberR, 72 WH McLean SA, Leachman RL, Kaspar 69 61 Feinstein A, Friedman J, Schewach-Millet M. Pachyonychia congenita. congenita. Pachyonychia M. Schewach-Millet J, Friedman A, Feinstein 61 Dei Rossi E, C ClementiM, deStefani Cardin 60 BJ Feng SA, Leachman MJ, Eliason 59 JT Jacob DJ, DePianto RP, Hobbs 56 8 Hickerson RP, D MA, Flores Leake 68 Hickerson RP, Smith FJ, Reeves RE 67 2 Munro CS, Bryce S, S Carter 62 66 Leachman SA, Hickerson RP, Hull PR Hull RP, Hickerson SA, Leachman 66 This by is protectedarticle reserved. Allrights copyright. Porter RM, Bravo AA, Smith FJD. Management of Plantar KeratodermasLessons from 65 CM Karacz JC, Carlson Duverger O, 64 B Didona FJ, Smith A, Terrinoni 63 E Ilagan A, Arutyunov BM, Chung 55 AA Dlugosz ML, Kerns D, Depianto 53 54 Rotty JD, Coulombe PA. A wound-induced keratin inhibits Src activity during keratinocyte keratinocyte during activity Src inhibits keratin wound-induced A PA. Coulombe JD, Rotty 54 patients. congenita pachyonychia in symptoms improves and keratinocytes human in (K6a) keratin pachyonychia congenita. congenita. pachyonychia 2011; congenita. pachyonychia avenuefor therapeutic congenita. pachyonychia pachyonychiacongenita using topical sirolimus. dermatology investigative of Journal meeting. Consortium Congenita Pachyonychia International Annual 7th the on report expressionkeratinocytes. tumor in skin The Journal of investigative dermatology investigative of Journal The 43 131 model. congenita pachyonychia organotypic an 27. Academy of Dermatology of Academy syndrome. malformation distinct type: a Dermatology congenita. pachyonychia confirmed genetically dominant-negative skin model. model. skin dominant-negative congenita. pachyonychia including disorders keratin gene cluster on 17q12-q21. 17q12-q21. on cluster gene keratin keratinocytes. tumor skin in K hnRNP and 17 keratin 428-35. Pachyonychia Congenita. associated keratins increase susceptibility to toothdecay. dermatology congenita. pachyonychia of cases 13 in K17 and K16 K6a, keratins growth by polarizing the immune response inskin. migration and tissue repair. repair. tissue and migration : 968-71. : 1037-44. 131 Journal of dermatological science dermatological of Journal : 1045-52. 2001; 2001; 2012; 117 67 : 680-6. : 1391-6. The Journal of investigative dermatology ofinvestigative Journal The Journal of the American Academy of Dermatology of Academy American of the Journal 1988; Journal of the American Podiatric Medical Association Medical Podiatric American ofthe Journal et al. et etal. The Journal of cell biology cell of Journal The et al. et al. The Journal of investigative dermatology investigative of Journal The etal. et al. 19 Statins downregulate K6a promoter activity: a possible possible a activity: promoter K6a downregulate Statins etal. A gene for pachyonychia congenita is closely linked to the the to linked closely is congenita pachyonychia for gene A et al. et al. et et al. etal. et al. et : 705-11. Journal of medical genetics medical of Journal et al. Rapamycin selectively inhibits expression of an inducible an inducible of expression inhibits selectively Rapamycin etal. et al. et et al. et Novel recurrent and mutations theencoding genesin 2011; An appraisal of oral retinoids in the treatment of of treatment the in retinoids oral of appraisal An et al. et Keratin-dependent regulation of Aire and gene gene and Aire of regulation Keratin-dependent Regulationof C-X-C chemokine gene expression by Use of Use of self-delivery gene expression siRNAs toinhibit in A review of the clinical ph clinical the of review A Single-nucleotide-specific siRNA targetingin a Keratin 17 promotes epithelial proliferation and tumor tumor and proliferation epithelial promotes 17 Keratin Nature genetics Genetic variants in pachyonychia congenita- pachyonychia in variants Genetic 2011; The British journal of dermatology of journal British The Novel ofpainful treatment keratoderma plantar in Therapeutic siRNAs for dominant genetic skin skin genetic dominant for siRNAs Therapeutic The phenotypic and molecular genetic features of features genetic molecular and phenotypic The A large mutational study in pachyonychia congenita. congenita. pachyonychia in study mutational Alarge 2009; Toward a treatment for pachyonychia congenita: congenita: pachyonychia for treatment a Toward 131 et al. Journal of dermatological science dermatological of Journal : 1011-4. 131 Journal of the American Academyof The Journal of investigative dermatology ofinvestigative Journal The Clinical and experimental dermatology experimental and Clinical The Journal of investigative dermatology investigative of Journal The Pachyonychia congenita Jackson-Lawler Jackson-Lawler congenita Pachyonychia 56 Nature genetics : 1018-24. : 82-8. 82-8. : The Journal of cell biology ofcell Journal The 2012; 2012; 2015; PLoS genetics PLoS 197 47 1994; : 381-9. : 933-8. enotype of 254 withpatients 254 enotype of The JournalThe of investigative 2011; 2010; 31 Journalthe ofAmerican 2018; : 675-8. 2008; 131 42 1986; 2012; 2012; : 910-4. : 1015-7. 2008; 2008; 14 2015; 128 2017; : e1007168. : e1007168. 114 66 : 594-605. : e193-9. : e193-9. 51 208 : 367-70. The The 107 2018; 2018; : 151-7. 2011; : 613-

: Accepted Article 84 Wojcik SM, Longley MA, Roop DR. Discovery of a novel murine keratin 6 (K6) isoform explains explains isoform (K6) 6 keratin murine novel a of Discovery DR. Roop MA, Longley SM, Wojcik 84 Kerns ML,Guss L, Fahey J 80 87 Chen J, Jaeger K, Den Z Den K, Jaeger J, Chen 87 pachyonychia elicit to redundancy functional Overcoming PA. Coulombe R, Domergue P, Wong 86 Wojcik SM, Bundman DS, Roop DR. Delayed wound healing inkeratinknockout 6a mice. 85 Wojcik SM, Imakado S, Seki T 83 disease blistering skin inducible an with model mouse Atransgenic PA. Coulombe K, Takahashi 82 Leube RE, SchwarzMatters: Interfering Sex N. with Oxidativethe Response Stress in 81 Kerns ML,DePianto D, Dinkova-Kostova AT 79 78 Zhang Y, Talalay P, Cho CG Cho P, Talalay Y, Zhang 78 7 Kerns ML,Hakim JMC, Zieman A 77 Hu C.Modificationof Cysteine Keap1 Residues by Sulforaphane. 2011; 76 92 Armstrong DK, McKenna KE, Purkis PE Purkis KE, McKenna DK, Armstrong 92 Lugassy J,P, Itin Ishida-YamamotoA 91 Arin MJ, Longley Kuster MA, W 90 RP Hickerson F, Larcher M, Garcia 88 This by is protectedarticle reserved. Allrights copyright. Swartling C, Karlqvist Hymnelius M, K 75 M Shahidi-Dadras F, Rajabi F, Abdollahimajd 74 89 Kimonis V, DiGiovanna JJ, Yang JM Yang JJ, DiGiovanna V, Kimonis 89 128 congenita. pachyonychia resembling defects biology K6b. and K6a for deficient mice in defects nail and hair of absence the follicle. hair and epidermis the in consequences phenotypic distinct has inmice transgenes mutant Dermatology of Academy American the disorders. keratin-based in use of its feasibility the Assessing extract: sprout broccoli 2007; sulforaphane restores skinintegrity in epidermolysis bullosa simplex. 205. congenita-like nail lesions transgenicin mice. Molecularcellular and biology phenotype. Pachyonychia Congenita. structure. of elucidation and isolation broccoli: 100. Model for PachyonychiaModel for Congenita. subtype of palmoplantar keratoderma. keratoderma. palmoplantar of subtype mutations inKRT14. dominant by caused dysplasias ectodermal allelic two reticularis: pigmentosa dermatopathia dermatology hyperkeratosis. epidermolytic causes that mutation anovel 1: keratin of congenita. congenita. ep worsened with foot in patients problems 103 epidermolytic palmar-plantar keratoderma. congenita. pachyonychia of dermatology of successful treatment with rosuvastatinpatient mutation. with a in KRT6A a : 270-9. : 764-9. 104 2001; Differentiation; research in biological diversity biological in research Differentiation; : 14460-5. The British journal of dermatology Proc Natl Acad Sci U S A S U Sci Acad Natl Proc 1999; 1999; 154 2018. : 619-30. 8 American journal of human genetics human of journal American : 124-7. et al. et etal. The Journal of investigative dermatology ofinvestigative Journal The The Journal of investigative dermatology investigative of Journal The et al. Mice expressing a mutant Krt75 (K6hf) allele develop hair and nail nail and hair develop allele (K6hf) Krt75 mutant a expressing Mice etal. 2000; Randomized, split-body,single-blinded clinicaltopical trial of etal. A major inducer of anticarcinogenic protective enzymes from from enzymes protective anticarcinogenic of inducer major A et al. et etal. et al. et Expression of MK6a dominant-negative and C-terminal C-terminal and dominant-negative MK6a of Expression 1996; The Journal of investigative dermatology investigative of Journal The et al. et An asparagine to threonine substitution in the 1A domain domain 1A the in substitution threonine to asparagine An 20 etal. Sexual Dimorphism in Response to an NRF2 Inducer in a a in Inducer NRF2 an to Response in Dimorphism Sexual et al. Development of skin-humanized mouse models of models mouse of Development skin-humanized 2017; : 5248-55. Human moleculargenetics A mutation A V1 the in end domain keratinof 1in non- Naegeli-Franceschetti-Jadassohn syndrome and 93 of toxin treatment Botulinum the sweat- in et al. et Haploinsufficiency of desmoplakin causes a striate astriate causes desmoplakin of Haploinsufficiency idermolysis bullosa simplex and pachyonychia et al. et The Journal of investigative dermatology The Journal of investigative dermatology investigative of Journal The : 14776-81. 2010; Molecular and cellular biology cellular and Molecular 76 Proc Natl Acad Sci U S A Reprogramming of keratin biosynthesis by by biosynthesis keratin of Reprogramming : 449-53.e1. Pachyonychiacongenita: case a report of a 163 1999; : 1072-6. 2006; 65 : 97-112. 79 2011; 1999; : 724-30. 2018; Proc Natl Acad Sci U SA SciU Proc Natl Acad The Journal of cell 24 1992; Experimental Experimental 131 8 138 : 515-21. : 143-8. The British journal journal British The 2005; : 1053-60. 2018; : 1019-22. 89 : 2399-403. 25 138 1994; Journal of of Journal : 197- 2008; : 1094-

Accepted Article 1 Toomes C, James J, Wood AJ 111 97 Kubo A, Shiohama A, Sasaki T Sasaki A, Shiohama A, Kubo 97 1 Blaydon DC, EtheridgeRisk SL, JM 110 H Megarbane E, Chouery L, Adaimy 109 101 Blaydon DC, Lind LK, Plagnol V Plagnol LK, Lind DC, Blaydon 101 PA A, Hofer Lundstrom L, Lind 100 LeeM Q, Chen Lin Z, 99 Maestrini E, Monaco AP, McGrath JA 98 A Crosby N, Protonotarios G, McKoy 96 0 Nagy N, Wedgeworth E,Hamada T 108 This by is protectedarticle reserved. Allrights copyright. CS Lounsbury Q, Shao XQ, Gong 104 I Burgt vander L, MA, Spruijt vanSteensel 103 Richard G, White TW,Smith LE 102 H Wan FJ, Smith NV, Whittock 95 McGrathJA, McMillan JR, Shemanko CS 94 HP Stevens D, Simrak L, Rickman 93 107 Vanderhooft SL, Francis JS, Holbrook KA Holbrook JS, Francis SL, Vanderhooft 107 Fischer J, Bouadjar Heilig R B, 106 SM Pasternack GN, Eckstein KA, Giehl 105 periodontal disease and palmoplantar keratosis. keratosis. palmoplantar and disease periodontal familial esophageal cancer syndrome. hair (Naxos disease). disease). (Naxos hair woolly and keratoderma palmoplantar with cardiomyopathy ventricular right arrhythmogenic genetics type found in northern Sweden is localized chromosometo 12q11-q13. human genetics human recessive :odonto-onycho-dermal the dysplasia. 2. WNT10A. in mutation nonsense homozygous mutation causing oculodentodigital dysplasia and palmoplantar keratoderma. keratoderma. palmoplantar and dysplasia oculodentodigital causing mutation A Part genetics. medical keratoderma. palmoplantar with dysplasia oculo-dento-digital with nonepi diffuse autosomal-dominant cause syndrome. Olmsted 7. ofcornified the cell envelope, underlies Vohwinkel's syndrome. journalof human genetics keratosis. palmoplantar Nagashima-type cause superfamily, inhibitor protease 118 results in striate palmoplantar keratoderma. genetics keratoderma. palmoplantar striate disease skin dominant autosomal the dermatology chemistry biological Human genetics Human keratoderma. palmoplantar and deaf-mutism dominant with family a in mutation missense journalof human genetics ectodermal dysplasia/skin fragility syndrome. Human molecular genetics molecular Human 2012; keratoderma type Buschke-Fischer-Brauer. palmoplantar : 838-44. 91 1994; 1994; 1999; 1999; : 754-9. 1995; 1995; 3 8 2007; 2007; 1998; : 1789-93. : 971-6. 131 2006; 2006; American journal of human genetics human of journal American et al. Lancet (London, England) (London, Lancet 81 103 : 448-53. 448-53. : 2005; 2005; : 821-8. Exome sequencingmutations reveals incause TRPV3as of a 2013; 2013; 2001; 2001; : 393-9. 281 et al. et al. et et al. et et al. etal. et al. et : 31801-11. et al. et 132a et al. et et al. 93 93 10 et al. et Loss-of-function mutationscathepsin the in gene resultC in et al. et Mutationsin gene encodingthe SLURP-1 in deMal Meleda. Mutations in SERPINB7, encodi et al. et : 945-56. : 330-5. The gene for diffuse palmoplantar keratoderma of the the of keratoderma palmoplantar diffuse for gene The Frameshift mutation Frameshift domainkeratin the of human V2 in 1 Mutations in AQP5, encoding a water-channel protein, protein, water-channel a encoding AQP5, in Mutations : 171-4. : 875-80. et al. et Functional defects of Cx26 resulting from a heterozygous heterozygous a from resulting ofCx26 defects Functional etal. Functional characterization of a GJA1 frameshift GJA1 frameshift a of characterization Functional et al. et N-terminal deletion in a desmosomal cadherin causes causes cadherin desmosomal a in deletion N-terminal American journal of human genetics human of journal American RHBDF2mutations are associated with tylosis, a et al. et etal. Schopf-Schulz-Passarge syndrome resulting from a a from resulting syndrome Schopf-Schulz-Passarge MutationWNT10A is in associated autosomalwith an Identification of a deletion in plakoglobin in in plakoglobin in deletion a of Identification et al. dermolytic palmopla A molecular A defect in loricrin, majorcomponent the Nonsense mutations in AAGAB cause punctate punctate cause AAGAB in mutations Nonsense The Journal of investigative dermatology investigative of Journal The Mutations in the plakophilin 1 gene result in in result gene 1 plakophilin the in Mutations Familial pityriasis rubra pilaris. pilaris. rubra pityriasis Familial Journal of dermatological science dermatological of Journal Nature genetics 2000; A 2-bp deletion in the GJA1 gene is associated associated is gene GJA1 the in deletion 2-bp A Nature genetics 355 2012; : 2119-24. American journalhuman of genetics 1997; ntar keratoderma. keratoderma. ntar 90 Nature genetics 1999; : 558-64. ng a member of the serine serine the of member a ng American journal of of journal American 17 American journal of journal American : 240-4. 23 Human molecular Human molecular : 421-4. 2012; Archives of Archives of The Journal of of Journal The American 2010; 1996; 90 American American : 340-6. 2002; 58 13 : 220- : 70-

Accepted Article This by is protectedarticle reserved. Allrights copyright.

Accepted Article This by is protectedarticle reserved. Allrights copyright.

Accepted Article This by is protectedarticle reserved. Allrights copyright.