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Overview of genes involved in Epidermodysplasia verruciformis

Sobia Munir, Ayub kakar, Saliha Samiullah

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Int. J. Biosci.15(4), 188-202, October 2019

DOI: http://dx.doi.org/10.12692/ijb/15.4.188-202


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Epidermodysplasia verruciformis also known as EV is a rare skin disorder caused by genetic mutations. These mutations can lead to susceptibility of beta human papilloma virus infection in which body having clinical manifestations of flat warts, macules and pityriasis versicolor-like lesions. Normal population is asymptomatic for HPV but genetically affected EV individuals may develop cutaneous malignancy especially squamous cell carcinoma in third or fourth decade of life. Cancer may be progressive towards UV rays and sun exposed regions of the body. Disease can be designated as typical or atypical type. Typical EV as keratinocyte intrinsic immunity defects leading to develop lesions by beta HPVs infection, atypical EV as T cells deficiency to cause immunosuppression. Most of typical EV cases involve alteration of transmembrane channel like genes family named as EVER1 and EVER2 genes. Another recently discovered CIB1 mutation also performing crucial role in developing typical EV manifestations. Atypical EV cases involve different genes like LCK, RHOH, STK4, DOCK8, COROIA, IL7, DCLRE1C, CARMIL2, ITK, RASGRP1, ANKRD26 and TPP2. Most of atypical mutations can be loss of function mutation and patients are immunodeficient. This review comprises of role of these genes, their mutations and their role in leukocyte and keratinocyte immunity to develop EV disease.


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Overview of genes involved in Epidermodysplasia verruciformis

Abdollahpour H, Appaswamy G, Kotlarz D, Diestelhorst J, Beier R, Schäffer AA, Gertz EM, Schambach A, Kreipe HH, Pfeifer D, Engelhardt KR, Rezaei N, Grimbacher B, Lohrmann S, Sherkat R, Klein C. 2012. The phenotype of human STK4 deficiency. Blood 119(15), 3450-3457.  http://dx.doi.org/10.1182/blood-2011-09-378.158.

Androphy EJ, Dvoretzky I, Lowy DR. 1985. X-linked inheritance of epidermodysplasia verruciformis: genetic and virologic studies of a kindred. Archives of dermatology 121(7), 864-868. http://dx.doi.org/10.1001/archderm.1985.01660070054014

Aochi S, Nakanishi G, Suzuki N, Setsu N, Suzuki D, Aya K, Iwatsuki K. 2007. A novel homozygous mutation of the EVER1/TMC6 gene in a Japanese patient with epidermodysplasia verruciformis. British Journal of Dermatology 157(6), 1265-1266. https://doi.org/10.1111/j.1365-2133.2007.08206.x

Burger B, Itin PH. 2014. Epidermodysplasia verruciformis In Human Papillomavirus Karger Publishers (45), 123-13. https://doi.org/10.1159/000356068

Cockayne EA. 1933. Inherited abnormalities of the skin and its appendages. Oxford University Press, Humphrey Milford [Oxford, Printed by John Johnson at the University Press].

Crequer A, Picard C, Patin E, D’Amico A, Abhyankar A, Munzer M, Abel L. 2012b. Inherited MST1 deficiency underlies susceptibility to EV-HPV infections. Public Library Of Science One 7(8), e44010. https://doi.org/10.1371/journal.pone.0044010

Crequer A, Picard C, Pedergnana V, Lim A, Zhang SY, Abel L, Jouanguy E. 2013. EVER2 deficiency is associated with mild T-cell abnormalities. Journal of clinical immunology 33(1), 14–21. http://dx.doi.org/10.1007/s10875-012-9749-1

Crequer A, Troeger A, Patin E, Ma CS, Picard C, Pedergnana V, Mueller-Fleckenstein I. 2012a. Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections. The Journal of clinical investigation 122(9), 3239-3247.  http://dx.doi.org/10.1172/JCI62949

Dallery-Prudhomme E, Roumier C, Denis C, Preudhomme C, Kerckaert JP, Galiegue-Zouitina S. 1997. Genomic Structure and Assignment of the RhoH/TTF Small GTPase Gene (ARHH) to 4p13 byin SituHybridization. Genomics 43(1), 89-94. https://doi.org/10.1006/geno.1997.4788

de Jong SJ, Créquer A, Matos I, Hum D, Gunasekharan V, Lorenzo L, Casanova JL. 2018b. The human CIB1-EVER1-EVER2 complex governs keratinocyte-intrinsic immunity to β-papillomaviruses. The Journal of experimental medicine 215(9), 2289–2310. http://dx.doi.org/10.1084/jem.20170308.

de Jong SJ, Imahorn E, Itin PH, Uitto J, Orth G, Jouanguy E, Burger B. 2018a. Epidermodysplasia verruciformis: inborn errors of immunity to human beta-papillomaviruses. Frontiers in microbiology 9, 1222. https://doi.org/10.3389/fmicb.2018.01222

Fouéré S, Aubin F, Péré H, Galicier L, Gheit T, Tommasino M, Bagot M. 2018. Epidermodysplasia verruciformis in an adult patient with a germline Interleukin‐2 inducible T‐Cell Kinase mutation and lymphoma: the case of inherited versus acquired. Journal of the European Academy of Dermatology and Venereology 32(6), 240-241. https://doi.org/10.1111/jdv.14756

Germani A, Malherbe S, Rouer E. 2003. The exon 7-spliced Lck isoform in T lymphocytes: a potential regulator of p56lck signaling pathways. Biochemical and biophysical research communications 301(3), 680-685. https://doi.org/10.1016/S0006-291X(02)03000-0

Ghosh S, Bienemann K, Boztug K,  Borkhardt A. 2014. Interleukin-2-inducible T-cell kinase (ITK) deficiency – clinical and molecular aspects. Journal of clinical immunology 34(8), 892–899. http://dx.doi.org/10.1007/s10875-014-0110-8

Ghosh S, Drexler I, Bhatia S, Adler H, Gennery AR, Borkhardt A. 2018. Interleukin-2-Inducible T-Cell Kinase Deficiency-New Patients, New Insight?. Frontiers in immunology 9, 979. http://dx.doi.org/10.3389/fimmu.2018.00979

Horev L, Unger S, Molho-Pessach V, Meir T, Maly A, Stepensky P, Ramot Y. 2015. Generalized verrucosis and HPV-3 susceptibility associated with CD4 T-cell lymphopenia caused by inherited human interleukin-7 deficiency. Journal of the American Academy of Dermatology 72(6), 1082-1084. https://doi.org/10.1016/j.jaad.2015.02.1118.

Huang S, Wu JH, Lewis DJ, Rady PL, Tyring SK. 2018. A novel approach to the classification of epidermodysplasia verruciformis. International journal of dermatology 57(11), 1344-1350. https://doi.org/10.1111/ijd.14196.

Hahn Y, Bera TK, Pastan IH, Lee B. 2006. Duplication and extensive   remodeling shaped POTE family genes encoding proteins containing ankyrin repeat and coiled coil domains. Gene 366(2), 238-245. https://doi.org/10.1016/j.gene.2005.07.045

Imahorn E, Yüksel Z, Spoerri I, Gürel G, Imhof C, Saraçoğlu ZN, Itin PH. 2017. Novel TMC 8 splice site mutation in epidermodysplasia verruciformis and review of HPV infections in patients with the disease. Journal of the European Academy of Dermatology and Venereology 31(10), 1722-1726. https://doi.org/10.1111/jdv.14431

Kalińska-Bienias A, Kowalewski C, Majewski S. 2016. The EVER genes–the genetic etiology of carcinogenesis in epidermodysplasia verruciformis and a possible role in non-epidermodysplasia verruciformis patients. Advances in Dermatology and Allergology 33(2), 75. http://dx.doi.org/10.5114/ada.2016.59145

Kawase M. 2013. Genetics of epidermodysplasia verruciformis. In Current Genetics in Dermatology. Intech Open. http://dx.doi.org/10.5772/55340

Keresztes G, Mutai H, Heller S. 2003. TMC and EVER genes belong to a larger novel family, the TMC gene family encoding transmembrane proteins. BMC genomics 4(1), 24. https://doi.org/10.1186/1471-2164-4-24

Kurima K, Yang Y, Sorber K, Griffith AJ. 2003. Characterization of the transmembrane channel-like (TMC) gene family: functional clues from hearing loss and epidermodysplasia verruciformis. Genomics  82(3), 300-308. https://doi.org/10.1016/S0888-7543(03)00154-X

Lazarczyk M, Cassonnet P, Pons C, Jacob Y, Favre M. 2009. The EVER proteins as a natural barrier against papillomaviruses: a new insight into the pathogenesis of human papillomavirus infections. Microbial and Moleccular Biology Review 73(2), 348-370. http://dx.doi.org/10.1128/MMBR.00033-08

Lazarczyk M, Dalard C, Hayder M, Dupre L, Pignolet B, Majewski S,  Liblau RS. 2012. EVER proteins, key elements of the natural anti-human papillomavirus barrier, are regulated upon T-cell activation. Public Library of Science One 7(6), 39995. https://doi.org/10.1371/journal.pone.0039995

Lazarczyk M, Pons, C, Mendoza JA, Cassonnet P, Jacob Y, Favre M. 2008. Regulation of cellular zinc balance as a potential mechanism of EVER-mediated protection against pathogenesis by cutaneous oncogenic human papillomaviruses.  Journal of Experimental Medicine 205(1), 35-42. http://dx.doi.org/10.1084/jem.20071311

Leisner TM, Freeman TC, Black JL, Parise LV. 2016. CIB1: a small protein with big ambitions. Federation of American Societies for Experimental Biology 30(8), 2640–2650. http://dx.doi.org/10.1096/fj.201500073R

Li SL, Duo LN, Wang HJ, Dai W, Zhou EY, Xu YN, Zheng LT. 2016. Identification of LCK mutation in a family with atypical epidermodysplasia verruciformis with T‐cell defects and virus‐induced squamous cell carcinoma. British Journal of Dermatology 175(6), 1204-1209. https://doi.org/10.1111/bjd.14679

Liu YQ, Zhang GL, Mo XH, Wang B, Wu F, Chen J, Cai QL. 2017. A novel homozygous DOCK 8 mutation associated with unusual coexistence of gross molluscum contagiosum and epidermodysplasia verruciformis in a DOCK 8 deficiency patient. Journal of the European Academy of Dermatology and Venereology 1(311), 504-505. https://doi.org/10.1111/jdv.14344

Lutzner MA, Blanchet-Bardon C, Orth G. 1984. Clinical observations, virologic studies, and treatment trials in patients with epidermodysplasia verruciformis, a disease induced by specific human papillomaviruses. Journal of Investigative Dermatology 83(1), 18-25. https://doi.org/10.1038/jid.1984.15

McDermott DF, Gammon B, Snijders PJ, Mbata I, Phifer B, Howland Hartley A, Hwang ST. 2009. Autosomal dominant epidermodysplasia verruciformis lacking a known EVER1 or EVER2 mutation. Pediatric dermatology 26(3), 306-310. https://doi.org/10.1111/j.1525-1470.2008.00853.x

Nehme NT, Schmid JP, Debeurme F, André-Schmutz I, Lim A, Nitschke P, de Saint Basile G. 2012. MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival. Blood119(15), 3458–3468. http://dx.doi.org/10.1182/blood-2011-09-378364

Notarangelo LD. 2018. HPV: CIB1 is for EVER and EVER. The Journal of experimental medicine 215(9), 2229–2231. http://dx.doi.org/10.1084/jem.20181207

Ogawa Y, Kinoshita M, Shimada S, Kawamura T. 2018. Zinc and Skin Disorders. Nutrients 10(2), http://dx.doi.org/10.3390/nu10020199

Orth G. 2006. Genetics of epidermodysplasia verruciformis: insights into host defense against papillomaviruses. In Seminars in immunology 18(6), 362-374. https://doi.org/10.1016/j.smim.2006.07.008

Orth G. 2008. Host defenses against human papillomaviruses: lessons from epidermodysplasia verruciformis. In Immunology, Phenotype First: How Mutations Have Established New Principles and Pathways in Immunology. 59-83 Springer, Berlin, Heidelberg.

Otrofanowei E, Akinkugbe A, Ayanlowo O. 2017. Management challenges of epidermodysplasia verruciformis in a resource-limited setting: A retrospective review. Journal of Clinical Sciences 14(4), 162. http://dx.doi.org/10.4103/jcls.jcls_94_16

Platt CD, Fried AJ, Hoyos-Bachiloglu R, Usmani GN, Schmidt B, Whangbo J, Geha RS. 2017. Combined immunodeficiency with EBV positive B cell lymphoma and epidermodysplasia verruciformis due to a novel homozygous mutation in RASGRP1. Clinical immunology 183, 142–144. http://dx.doi.org/101016/j.clim.2017.08.007

Przybyszewska J, Zlotogorski A, Ramot Y. 2017. Re-evaluation of epidermodysplasia verruciformis: reconciling more than 90 years of debate. Journal of the American Academy of Dermatology 76(6), 1161-1175. https://doi.org/10.1016/j.jaad.2016.12.035

Ramoz N, Rueda LA, Bouadjar B, Montoya LS, Orth G, Favre M. 2002. Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis. Nature genetics 32(4), 579. http://dx.doi.org/10.1038/ng1044

Sanal O, Jing H, Ozgur T, Ayvaz D, Strauss-Albee DM, Ersoy-Evans S, Su HC. 2012. Additional diverse findings expand the clinical presentation of DOCK8 deficiency. Journal of clinical immunology 32(4), 698–708. http://dx.doi.org/10.1007/s10875-012-9664-5

Sharafian S, Ziaee V, Shahrooei M, Ahadi M, Parvaneh N. 2019. A Novel STK4 Mutation Presenting with Juvenile Idiopathic Arthritis and Epidermodysplasia Verruciformis. Journal of clinical immunology 39(1), 11-14. https://doi.org/10.1007/s10875-018-05868

Shiow LR, Roadcap DW, Paris K, Watson SR, Grigorova IL, Lebet T, Cyster JG. 2008. The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency. Nature immunology 9(11), 1307–1315. http://dx.doi.org/10.1038/ni.1662

Sichero L, Rollison DE, Amorrortu RP, Tommasino M. 2019. Beta human papillomavirus and associated diseases. Acta cytologica 63(2), 100-108. https://doi.org/10.1159/000492659

Sorte HS, Osnes LT, Fevang B, Aukrust P, Erichsen HC, Backe PH, Muzny DM. 2016. A potential founder variant in CARMIL2/RLTPR in three Norwegian families with warts, molluscum contagiosum, and T‐cell dysfunction. Molecular genetics & genomic medicine 4(6), 604-616. https://doi.org/10.1002/mgg3.237

Stepensky P, Rensing-Ehl A, Gather R, Revel-Vilk S, Fischer U, Nabhani S, Firat E. 2015. Early-onset Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency. Blood 125(5), 753-761. https://doi.org/10.1182/blood-2014-08-593202

Stray-Pedersen A, Jouanguy E, Crequer A, Bertuch AA, Brown BS, Jhangiani SN, Metry D. 2014. Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy. Journal of clinical immunology 34(7), 871-890. http://dx.doi.org/10.1007/s10875-014-0074-8

Swati S, Sowjanya K, Lakuma R, Sunaina SA, Srividya G, Rohitha V. 2017. Epidermodysplasia Verruciformis-A Genetic Disorder. Systematic Reviews in Pharmacy 8(1), 71. http://dx.doi.org/10.5530/srp.2017.1.12

Tahiat A, Badran YR, Chou J, Cangemi B, Lefranc G, Labgaa ZM, Gharnaout M. 2017. Epidermodysplasia verruciformis as a manifestation of ARTEMIS deficiency in a young adult. Journal of Allergy and Clinical Immunology 139(1), 372-375. https://doi.org/10.1016/j.jaci.2016.07.024

Uddin KF, Amin MR, Majumder SN, Aleem MA, Rahaman MA, Dity NJ, Scherer S. 2018. An ANKRD26 nonsense somatic mutation in a female with epidermodysplasia verruciformis (Tree Man Syndrome). Clinical case reports 6(8), 1426–1430. http://dx.doi.org/10.1002/ccr3.1595.

Vahidnezhad H, Youssefian L, Saeidian AH, Mansoori B, Jazayeri A, Azizpour A, Casanova JL. 2019. A CIB1 Splice-Site Founder Mutation in Families with Typical Epidermodysplasia Verruciformis. The Journal of investigative dermatology 139(5), 1195. https://doi.org/10.1016/j.jid.2018.07.010

Youssefian L, Vahidnezhad H, Mahmoudi H, Saeidian AH, Daneshpazhooh M, Hesari KK, Jouanguy E. 2019a. Epidermodysplasia Verruciformis: Genetic Heterogeneity and EVER1 and EVER2 Mutations Revealed by Genome-Wide Analysis. Journal of Investigative Dermatology 139(1), 241-244. https://doi.org/10.1016/j.jid.2018.07.010

Youssefian L, Vahidnezhad H, Mahmoudi H, Saeidian A, Aghazadeh N, Sotoudeh S, Uitto J. 2017. Homozygous mutation in ITK associated with monogenic inborn errors of immunity underlies susceptibility to human papilloma virus infections (epidermodysplasia verruciformis). Journal of Investigative Dermatology 137(5), 110. https://doi.org/10.1016/j.jid.2017.02.661

Youssefian L, Vahidnezhad H, Yousefi M, Saeidian AH, Azizpour A, Touat A, Mansoori B. 2019b. Inherited interleukin 2-inducible T-cell (ITK) kinase deficiency in siblings with epidermodysplasia verruciformis and Hodgkin lymphoma. Clinical Infectious Diseases 68(11), 1938-1941. https://doi.org/10.1093/cid/ciy942

Zampetti A, Giurdanella F, Manco S, Linder D, Gnarra M, Guerriero G, Feliciani C. 2013. Acquired epidermodysplasia verruciformis: a comprehensive review and a proposal for treatment. Dermatologic Surgery 39(7), 974-980. https://doi.org/10.1111/dsu.121.35