Vestnik dermatologii i venerologiiVestnik dermatologii i venerologiiВестник дерматологии и венерологии0042-46092313-6294Rossijskoe Obschestvo Dermatovenerologov i Kosmetologov1690910.25208/vdv16909fymwloREVIEWSОБЗОР ЛИТЕРАТУРЫReview ArticleEpidermolysis bullosa simplex: genotype-phenotype correlationsПростой врожденный буллезный эпидермолиз: клинико-генетические корреляцииhttps://orcid.org/0000-0002-9688-27273385-4723ChikinVadim V.ЧикинВадим Викторович
Russian Federation

MD, Dr. Sci. (Med.), Senior Research Associate

д.м.н., старший научный сотрудник

chikin@cnikvi.ruhttps://orcid.org/0000-0003-3805-84893604-6491KaramovaArfenia E.КарамоваАрфеня Эдуардовна
Russian Federation

MD, Cand. Sci. (Med.), Assistant Professor

к.м.н., доцент

karamova@cnikvi.ruState Research Center of Dermatovenereology and CosmetologyГосударственный научный центр дерматовенерологии и косметологии25112025131220251015Vestnik dermatologii i venerologiiВестник дерматологии и венерологии22442105202528102025Copyright ©; 2025, Chikin V.V., Karamova A.E.Copyright ©; 2025, Чикин В.В., Карамова А.Э.2025Chikin V.V., Karamova A.E.Чикин В.В., Карамова А.Э.https://creativecommons.org/licenses/by-nc/4.0https://vestnikdv.ru/jour/article/view/16909

Epidermolysis bullosa simplex (EBS) includes a group of diseases characterized by varying severity, possible damage to visceral organs, and various outcomes ranging from complete regression of the rash to death. The initial clinical manifestations of EBS do not allow for predicting further course of the disease, however clinical and genetic correlations may be used for this purpose. We analyzed the literature from the PubMed and RSCI databases to characterize the clinical and genetic correlations in EBS. The analysis revealed that the most severe course of skin lesions in patients with EBS is associated with mutations in the KRT5 and KRT14 genes which alter the HIP (helix initiation peptide) and HTP (helix termination peptide) motifs in the corresponding proteins as well as the helical regions of keratins 5 and 14. The study also identified factors that can reduce reliability of predicting the course of EBS using clinical and genetic correlations. These include the degree of difference in the physical and chemical properties of the mutant and wild-type amino acids in case of missense mutations as well as the possible influence of other gene variants that may contribute to the clinical presentation of the disease. Detection of PLEC1 gene mutations suggests the possibility of developing muscular dystrophy, KLHL24 cardiomyopathy, CD151 nephropathy and deafness over the course of an EBS patient’s life. Thus, clinical and genetic correlations have been established that can be used to predict the course of EBS, and limitations for their application have been determined.

Простой врожденный буллезный эпидермолиз (ВБЭ) включает в себя группу заболеваний, характеризующихся различной тяжестью течения, возможным поражением внутренних органов и различными исходами — от полного регресса высыпаний до смерти больного. Первоначальные клинические проявления простого ВБЭ не позволяют прогнозировать дальнейшее течение болезни, однако для этого могут быть использованы клинико-генетические корреляции. Проведен анализ литературы из баз данных PubMed и РИНЦ с целью характеристики клинико-генетических корреляций при простом ВБЭ. В результате проведенного анализа установлено, что наиболее тяжелое течение поражения кожи у больных простым ВБЭ ассоциируется с мутациями генов KRT5 и KRT14, изменяющими в соответствующих белках мотивы HIP (пептид инициации спирали) и HTP (пептид завершения спирали), а также спиральные участки кератинов 5 и 14. Отмечены также факторы, способные снижать надежность прогнозирования течения простого ВБЭ с использованием клинико-генетических корреляций. К ним относятся степень различий физико-химических свойств мутантной аминокислоты и аминокислоты дикого типа в случае миссенс-мутаций, а также возможное влияние вариантов других генов, способных участвовать в формировании клинической картины болезни. Выявление мутаций гена PLEC1 указывает на возможность развития с течением жизни у больного простым ВБЭ мышечной дистрофии, KLHL24 — кардиомиопатии, CD151 — нефропатии и глухоты. Таким образом, установлены клинико-генетические корреляции, которые могут быть использованы для прогнозирования течения простого ВБЭ, а также определены ограничения для их применения.

epidermolysis bullosa simplexgenotype-phenotype correlationskeratins 5 and 14plectinexophilin-5простой врожденный буллезный эпидермолизклинико-генетические корреляциикератины 5 и 14плектинэкзофилин-5The manuscript was prepared and published as part of the fulfillment of the Federal State Budgetary Institution "SSCDC" of the Ministry of Health of the Russian Federation No. 056-00005-25-00 "Development of a medicinal product based on somatic cells for the treatment of patients with congenital epidermolysis bullosa" for 2025 and for the planned period of 2026 and 2027.Рукопись подготовлена и опубликована в рамках выполнения государственного задания ФГБУ «ГНЦДК» Минздрава России № 056-00005-25-00 «Разработка лекарственного препарата на основе соматических клеток для лечения больных врожденным буллезным эпидермолизом» на 2025 г. и на плановый период 2026 и 2027 гг.Has C, Bauer JW, Bodemer C, Bolling MC, Bruckner-Tuderman L, Diem A, et al. Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility. Br J Dermatol. 2020;183(4):614–627. doi: 10.1111/bjd.18921Bardhan A, Bruckner-Tuderman L, Chapple IL, Fine JD, Harper N, Has C, et al. Epidermolysis bullosa. Nat Rev Dis Primers. 2020;6(1):78. doi: 10.1038/s41572-020-0210-0Кубанов А.А., Карамова А.Э., Чикин В.В., Богданова Е.В., Мончаковская Е.С. Эпидемиология и состояние оказания медицинской помощи больным врожденным буллезным эпидермолизом в Российской Федерации. Вестник РАМН. 2018;73(6):420–430. [Kubanov AA, Karamova AE, Chikin VV, Bogdanova EV, Monchakovskaya ES. Epidemiology and Providing of Healthcare for Patients with Inherited Epidermolysis Bullosa in the Russian Federation. Annals of the Russian Academy of Medical Sciences. 2018;73(6):420–430. (In Russ.)] doi: 10.15690/vramn980Baardman R, Yenamandra VK, Duipmans JC, Pasmooij AMG, Jonkman MF, van den Akker PC, et al. Novel insights into the epidemiology of epidermolysis bullosa (EB) from the Dutch EB Registry: EB more common than previously assumed? J Eur Acad Dermatol Venereol. 2021;35(4):995–1006. doi: 10.1111/jdv.17012Fine JD. Epidemiology of Inherited Epidermolysis Bullosa Based on Incidence and Prevalence Estimates From the National Epidermolysis Bullosa Registry. JAMA Dermatol. 2016;152 (11):1231–1238. doi: 10.1001/jamadermatol.2016.2473Mariath LM, Santin JT, Schuler-Faccini L, Kiszewski AE. Inherited epidermolysis bullosa: update on the clinical and genetic aspects. An Bras Dermatol. 2020;95(5):551–569. doi: 10.1016/j.abd.2020.05.001Coulombe PA, Kerns ML, Fuchs E. Epidermolysis bullosa simplex: a paradigm for disorders of tissue fragility. J Clin Invest. 2009;119(7):1784–1793. doi: 10.1172/JCI38177Bolling MC, Lemmink HH, Jansen GH, Jonkman MF. Mutations in KRT5 and KRT14 cause epidermolysis bullosa simplex in 75% of the patients. Br J Dermatol. 2011;164(3):637–644. doi: 10.1111/j.1365-2133.2010.10146.xRugg EL, Horn HM, Smith FJ, Wilson NJ, Hill AJ, Magee GJ, et al. Epidermolysis bullosa simplex in Scotland caused by a spectrum of keratin mutations. J Invest Dermatol. 2007;127(3):574–580. doi: 10.1038/sj.jid.5700571Wertheim-Tysarowska K, Ołdak M, Giza A, Kutkowska-Kaźmierczak A, Sota J, Przybylska D, et al. Novel sporadic and recurrent mutations in KRT5 and KRT14 genes in Polish epidermolysis bullosa simplex patients: further insights into epidemiology and genotype-phenotype correlation. J Appl Genet. 2016;57(2):175–181. doi: 10.1007/s13353-015-0310-9Bolling MC, Jongbloed JD, Boven LG, Diercks GF, Smith FJ, Irwin McLean WH, et al. Plectin mutations underlie epidermolysis bullosa simplex in 8% of patients. J Invest Dermatol. 2014;134(1):273–276. doi: 10.1038/jid.2013.277Has C, Fischer J. Inherited epidermolysis bullosa: New diagnostics and new clinical phenotypes. Exp Dermatol. 2019;28(10):1146–1152. doi: 10.1111/exd.13668So JY, Fulchand S, Wong CY, Li S, Nazaroff J, Gorell ES, et al. A global, cross-sectional survey of patient-reported outcomes, disease burden, and quality of life in epidermolysis bullosa simplex. Orphanet J Rare Dis. 2022;17(1):270. doi: 10.1186/s13023-022-02433-3Jerábková B, Marek J, Bucková H, Kopecková L, Veselý K, Valícková J, et al. Keratin mutations in patients with epidermolysis bullosa simplex: correlations between phenotype severity and disturbance of intermediate filament molecular structure. Br J Dermatol. 2010;162(5):1004–1013. doi: 10.1111/j.1365-2133.2009.09626.xSathishkumar D, Orrin E, Terron-Kwiatkowski A, Browne F, Martinez AE, Mellerio JE, et al. The p.Glu477Lys mutation in keratin 5 is strongly associated with mortality in generalized severe epidermolysis bullosa simplex. J Invest Dermatol. 2016;136(3):719–721. doi: 10.1016/j.jid.2015.11.024Fine JD, Johnson LB, Weiner M, Suchindran C. Cause-specific risks of childhood death in inherited epidermolysis bullosa. J Pediatr. 2008;152(2):276–280. doi: 10.1016/j.jpeds.2007.06.039Uitto J, Atanasova VS, Jiang Q, South AP. Precision medicine for heritable skin diseases — The paradigm of epidermolysis bullosa. J Investig Dermatol Symp Proc. 2018;19(2):S74–S76. doi: 10.1016/j.jisp.2018.09.004Horn HM, Tidman MJ. The clinical spectrum of epidermolysis bullosa simplex. Br J Dermatol. 2000;142(3):468–472. doi: 10.1046/j.1365-2133.2000.03358.xGanani D, Malovitski K, Sarig O, Gat A, Sprecher E, Samuelov L. Epidermolysis bullosa simplex due to bi-allelic DST mutations: Case series and review of the literature. Pediatr Dermatol. 2021;38(2):436–441. doi: 10.1111/pde.14477Karamatic Crew V, Burton N, Kagan A, Green CA, Levene C, Flinter F, et al. CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin. Blood. 2004;104(8):2217–2223. doi: 10.1182/blood-2004-04-1512Vahidnezhad H, Youssefian L, Saeidian AH, Mahmoudi H, Touati A, Abiri M, et al. Recessive mutation in tetraspanin CD151 causes Kindler syndrome-like epidermolysis bullosa with multi-systemic manifestations including nephropathy. Matrix Biol. 2018;66:22–33. doi: 10.1016/j.matbio.2017.11.003Dunn C, Ambur A, Foss M, Nathoo R. Expanding the spectrum of epidermolysis bullosa simplex: Syndromic epidermolysis bullosa simplex with nephropathy and epilepsy secondary to CD151 tetraspanin defect-a case report and review of the literature. JAAD Case Rep. 2022;23:136–140. doi: 10.1016/j.jdcr.2022.03.012Liu L, Dopping-Hepenstal PJ, Lovell PA, Michael M, Horn H, Fong K, et al. Autosomal recessive epidermolysis bullosa simplex due to loss of BPAG1-e expression. J Invest Dermatol. 2012;132(3Pt 1):742–744. doi: 10.1038/jid.2011.379He Y, Leppert J, Steinke H, Has C. Homozygous nonsense mutation and additional deletion of an amino acid in BPAG1e causing mild localized epidermolysis bullosa simplex. Acta Derm Venereol. 2017;97(5):657–659. doi: 10.2340/00015555-2618Fine JD, Bruckner-Tuderman L, Eady RA, Bauer EA, Bauer JW, Has C, et al. Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification. J Am Acad Dermatol. 2014;70(6):1103–1126. doi: 10.1016/j.jaad.2014.01.903Almokali K, Alshalawi H, Aldriwesh MG, Alotibi RS. Nephrotic syndrome: Pretibial epidermolysis bullosa in a patient with CD151 tetraspanin defect: A case report. Int J Health Sci (Qassim). 2024;18(1):35–40.McGrath JA, Ishida-Yamamoto A, Tidman MJ, Heagerty AH, Schofield OM, Eady RA. Epidermolysis bullosa simplex (Dowling–Meara). A clinicopathological review. Br J Dermatol. 1992;126(5):421–430. doi: 10.1111/j.1365-2133.1992.tb11813.xArin MJ. The molecular basis of human keratin disorders. Hum Genet. 2009;125(4):355–373. doi: 10.1007/s00439-009-0646-5Mithwani AA, Hashmi A, Adil S. Epidermolysis bullosa and congenital pyloric atresia. BMJ Case Rep. 2013;2013:bcr2013201207. doi: 10.1136/bcr-2013-201207Parelkar SV, Kapadnis SP, Sanghvi BV, Joshi PB, Mundada D, Shetty S, et al. Pyloric atresia — three cases and review of literature. Afr J Paediatr Surg. 2014;11(4):362–365. doi: 10.4103/0189-6725.143178Natsuga K. Plectin-related skin diseases. J Dermatol Sci. 2015;77(3):139–145. doi: 10.1016/j.jdermsci.2014.11.005Sawamura D, Goto M, Sakai K, Nakamura H, McMillan JR, Akiyama M, et al. Possible involvement of exon 31 alternative splicing in phenotype and severity of epidermolysis bullosa caused by mutations in PLEC1. J Invest Dermatol. 2007;127(6):1537–1540. doi: 10.1038/sj.jid.5700707Charlesworth A, Chiaverini C, Chevrant-Breton J, DelRio M, Diociaiuti A, Dupuis RP, et al. Epidermolysis bullosa simplex with PLEC mutations: new phenotypes and new mutations. Br J Dermatol. 2013;168(4):808–814. doi: 10.1111/bjd.12202Pfendner E, Uitto J. Plectin gene mutations can cause epidermolysis bullosa with pyloric atresia. J Invest Dermatol. 2005;124(1):111–115. doi: 10.1111/j.0022-202X.2004.23564.xTurcan I, Pasmooij AM, Gostyński A, van den Akker PC, Lemmink HH, Diercks GF, et al. Epidermolysis bullosa simplex caused by distal truncation of BPAG1-e: An intermediate generalized phenotype with prurigo papules. J Invest Dermatol. 2017;137(10):2227–2230. doi: 10.1016/j.jid.2017.04.041Diociaiuti A, Pisaneschi E, Rossi S, Condorelli AG, Carnevale C, Zambruno G, et al. Autosomal recessive epidermolysis bullosa simplex due to EXPH5 mutation: neonatal diagnosis of the first Italian case and literature review. J Eur Acad Dermatol Venereol. 2020;34(11):e694–e697. doi: 10.1111/jdv.16372McGrath JA, Stone KL, Begum R, Simpson MA, Dopping-Hepenstal PJ, Liu L, et al. Germline mutation in EXPH5 implicates the Rab27B effector protein Slac2-b in inherited skin fragility. Am J Hum Genet. 2012;91(6):1115–1121. doi: 10.1016/j.ajhg.2012.10.012Lee JY, Liu L, Hsu CK, Aristodemou S, Ozoemena L, Ogboli M, et al. Mutations in KLHL24 add to the molecular heterogeneity of epidermolysis bullosa simplex. J Invest Dermatol. 2017;137(6):1378–1380. doi: 10.1016/j.jid.2017.01.004Mariath LM, Santin JT, Frantz JA, Doriqui MJ, Schuler-Faccini L, Kiszewski AE. Genotype-phenotype correlations on epidermolysis bullosa with congenital absence of skin: A comprehensive review. Clin Genet. 2021;99(1):29–41. doi: 10.1111/cge.13792He Y, Maier K, Leppert J, Hausser I, Schwieger-Briel A, Weibel L, et al. Monoallelic mutations in the translation initiation codon of KLHL24 cause skin fragility. Am J Hum Genet. 2016;99(6):1395–1404. doi: 10.1016/j.ajhg.2016.11.005Lin Z, Li S, Feng C, Yang S, Wang H, Ma D, et al. Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility. Nat Genet. 2016;48(12):1508–1516. doi: 10.1038/ng.3701El Hachem M, Barresi S, Diociaiuti A, Boldrini R, Condorelli AG, Capoluongo E, et al. Phenotypic features of epidermolysis bullosa simplex due to KLHL24 mutations in 3 Italian cases. Acta Derm Venereol. 2019;99(2):238–239. doi: 10.2340/00015555-3046Yenamandra VK, van den Akker PC, Lemmink HH, Jan SZ, Diercks GFH, Vermeer M, et al. Cardiomyopathy in patients with epidermolysis bullosa simplex with mutations in KLHL24. Br J Dermatol. 2018;179(5):1181–1183. doi: 10.1111/bjd.16797Schwieger-Briel A, Fuentes I, Castiglia D, Barbato A, Greutmann M, Leppert J, et al. Epidermolysis bullosa simplex with KLHL24 mutations is associated with dilated cardiomyopathy. J Invest Dermatol. 2019;139(1):244–249. doi: 10.1016/j.jid.2018.07.022Alkhalifah A, Chiaverini C, Charlesworth A, Has C, Lacour JP. Burnlike scars: A sign suggestive of KLHL24-related epidermolysis bullosa simplex. Pediatr Dermatol. 2018;35(3):e193–e195. doi: 10.1111/pde.13443Bolling MC, Jonkman MF. KLHL24: Beyond skin fragility. J Invest Dermatol. 2019;139(1):22–24. doi: 10.1016/j.jid.2018.08.010Burke MA, Cook SA, Seidman JG, Seidman CE. Clinical and mechanistic insights into the genetics of cardiomyopathy. J Am Coll Cardiol. 2016;68(25):2871–2886. doi: 10.1016/j.jacc.2016.08.079Kyrova J, Kopeckova L, Buckova H, Mrazova L, Vesely K, Hermanova M, et al. Epidermolysis bullosa simplex with muscular dystrophy. Review of the literature and a case report. J Dermatol Case Rep. 2016;10(3):39–48. doi: 10.3315/jdcr.2016.1231Gache Y, Chavanas S, Lacour JP, Wiche G, Owaribe K, Meneguzzi G, et al. Defective expression of plectin/HD1 in epidermolysis bullosa simplex with muscular dystrophy. J Clin Invest. 1996;97(10):2289–2298. doi: 10.1172/JCI118671Fischer T, Gedde-Dahl T Jr. Epidermolysis bullosa simplex and mottled pigmentation: a new dominant syndrome. I. Clinical and histological features. Clin Genet. 1979;15(3):228–238. doi: 10.1111/j.1399-0004.1979.tb00972.xWesterhof W, Dingemans KP. Generalized mottled pigmentation with postnatal skin blistering in three generations. J Am Acad Dermatol. 2004;50(5Suppl):S65–69. doi: 10.1016/j.jaad.2003.07.015Bruckner-Tuderman L, Vogel A, Rüegger S, Odermatt B, Tönz O, Schnyder UW. Epidermolysis bullosa simplex with mottled pigmentation. J Am Acad Dermatol. 1989;21(2Pt 2):425–432. doi: 10.1016/s0190-9622(89)80052-0Echeverría-García B, Vicente A, Hernández Á, Mascaró JM, Colmenero I, Terrón A, et al. Epidermolysis bullosa simplex with mottled pigmentation: a family report and review. Pediatr Dermatol. 2013;30(6):e125–31. doi: 10.1111/j.1525-1470.2012.01748.xCombemale P, Kanitakis J. Epidermolysis bullosa simplex with mottled pigmentation. Case report and review of the literature. Dermatology. 1994;189(2):173–178. doi: 10.1159/000246826Coleman R, Harper JI, Lake BD. Epidermolysis bullosa simplex with mottled pigmentation. Br J Dermatol. 1993;128(6):679–685. doi: 10.1111/j.1365-2133.1993.tb00265.xHoriguchi Y, Sawamura D, Mori R, Nakamura H, Takahashi K, Shimizu H. Clinical heterogeneity of 1649delG mutation in the tail domain of keratin 5: a Japanese family with epidermolysis bullosa simplex with mottled pigmentation. J Invest Dermatol. 2005;125(1):83–85. doi: 10.1111/j.0022-202X.2005.23790.xAndres C, Chen W, Hofmann H, Ring J, Schnopp C. Epidermolysis bullosa simplex with mottled pigmentation: a case report. Int J Dermatol. 2009;48(7):753–754. doi: 10.1111/j.1365-4632.2009.03846.xHarel A, Bergman R, Indelman M, Sprecher E. Epidermolysis bullosa simplex with mottled pigmentation resulting from a recurrent mutation in KRT14. J Invest Dermatol. 2006;126(7):1654–1657. doi: 10.1038/sj.jid.5700296Uttam J, Hutton E, Coulombe PA, Anton-Lamprecht I, Yu QC, Gedde-Dahl T Jr, et al. The genetic basis of epidermolysis bullosa simplex with mottled pigmentation. Proc Natl Acad Sci U S A. 1996;93(17):9079–9084. doi: 10.1073/pnas.93.17.9079Irvine AD, Rugg EL, Lane EB, Hoare S, Peret C, Hughes AE, et al. Molecular confirmation of the unique phenotype of epidermolysis bullosa simplex with mottled pigmentation. Br J Dermatol. 2001;144(1):40–45. doi: 10.1046/j.1365-2133.2001.03950.xHamada T, Ishii N, Kawano Y, Takahashi Y, Inoue M, Yasumoto S, et al. The P25L mutation in the KRT5 gene in a Japanese family with epidermolysis bullosa simplex with mottled pigmentation. Br J Dermatol. 2004;150(3):609–611. doi: 10.1046/j.1365-2133.2004.05820.xPascucci M, Posteraro P, Pedicelli C, Provini A, Auricchio L, Paradisi M, et al. Epidermolysis bullosa simplex with mottled pigmentation due to de novo P25L mutation in keratin 5 in an Italian patient. Eur J Dermatol. 2006;16(6):620–622.Irvine AD, McKenna KE, Jenkinson H, Hughes AE. A mutation in the V1 domain of keratin 5 causes epidermolysis bullosa simplex with mottled pigmentation. J Invest Dermatol. 1997;108(5):809–810. doi: 10.1111/1523-1747.ep12292263Tang HY, Du WD, Cui Y, Fan X, Quan C, Fang QY, et al. One novel and two recurrent mutations in the keratin 5 gene identified in Chinese patients with epidermolysis bullosa simplex. Clin Exp Dermatol. 2009;34(8):e957–961. doi: 10.1111/j.1365-2230.2009.03703.xMoog U, de Die-Smulders CE, Scheffer H, van der Vlies P, Henquet CJ, Jonkman MF. Epidermolysis bullosa simplex with mottled pigmentation: clinical aspects and confirmation of the P24L mutation in the KRT5 gene in further patients. Am J Med Genet. 1999;86(4):376–379. doi: 10.1002/(sici)1096-8628(19991008)86:4<376::aid-ajmg12>3.0.co;2-wYasukawa K, Sawamura D, Akiyama M, Motoda N, Shimizu H. Keratotic lesions in epidermolysis bullosa simplex with mottled pigmentation. J Am Acad Dermatol. 2005;52(1):172–173. doi: 10.1016/j.jaad.2004.07.046Shurman D, Losi-Sasaki J, Grimwood R, Kivirikko S, Tichy E, Uitto J, et al. Epidermolysis bullosa simplex with mottled pigmentation: mutation analysis in the first reported Hispanic pedigree with the largest single generation of affected individuals to date. Eur J Dermatol. 2006;16(2):132–135.Kumagai Y, Umegaki-Arao N, Sasaki T, Nakamura Y, Takahashi H, Ashida A, et al. Distinct phenotype of epidermolysis bullosa simplex with infantile migratory circinate erythema due to frameshift mutations in the V2 domain of KRT5. J Eur Acad Dermatol Venereol. 2017;31(5):e241–e243. doi: 10.1111/jdv.14005Yalici-Armagan B, Kabacam S, Taskiran ZE, Gököz Ö, Utine GE, Ersoy-Evans S. A novel mutation of keratin 5 in epidermolysis bullosa simplex with migratory circinate erythema. Pediatr Dermatol. 2020;37(2):358–361. doi: 10.1111/pde.14087Lee SE, Choi JY, Kim SE, Kim SC. A novel deletion mutation in the 2B domain of KRT5 in epidermolysis bullosa simplex with childhood-onset migratory circinate erythema. Eur J Dermatol. 2018;28(1):123–125. doi: 10.1684/ejd.2017.3190Winter L, Wiche G. The many faces of plectin and plectinopathies: pathology and mechanisms. Acta Neuropathol. 2013;125(1):77–93. doi: 10.1007/s00401-012-1026-0Leung CL, Zheng M, Prater SM, Liem RK. The BPAG1 locus: Alternative splicing produces multiple isoforms with distinct cytoskeletal linker domains, including predominant isoforms in neurons and muscles. J Cell Biol. 2001;154(4):691–697. doi: 10.1083/jcb.200012098Walko G, Castañón MJ, Wiche G. Molecular architecture and function of the hemidesmosome. Cell Tissue Res. 2015;360(3):529–544. doi: 10.1007/s00441-015-2216-6Leung CL, Liem RK, Parry DA, Green KJ. The plakin family. J Cell Sci. 2001;114(Pt 19):3409–3410. doi: 10.1242/jcs.114.19.3409Koster J, Geerts D, Favre B, Borradori L, Sonnenberg A. Analysis of the interactions between BP180, BP230, plectin and the integrin alpha6beta4 important for hemidesmosome assembly. J Cell Sci. 2003;116(Pt 2):387–399. doi: 10.1242/jcs.00241Moll R, Divo M, Langbein L. The human keratins: biology and pathology. Histochem Cell Biol. 2008;129(6):705–733. doi: 10.1007/s00418-008-0435-6Chamcheu JC, Siddiqui IA, Syed DN, Adhami VM, Liovic M, Mukhtar H. Keratin gene mutations in disorders of human skin and its appendages. Arch Biochem Biophys. 2011;508(2):123–137. doi: 10.1016/j.abb.2010.12.019Herrmann H, Aebi U. Intermediate filaments: Structure and assembly. Cold Spring Harb Perspect Biol. 2016;8(11):a018242. doi: 10.1101/cshperspect.a018242Liovic M, Stojan J, Bowden PE, Gibbs D, Vahlquist A, Lane EB, et al. A novel keratin 5 mutation (K5V186L) in a family with EBS-K: a conservative substitution can lead to development of different disease phenotypes. J Invest Dermatol. 2001;116(6):964–969. doi: 10.1046/j.1523-1747.2001.01334.xYasukawa K, Sawamura D, McMillan JR, Nakamura H, Shimizu H. Dominant and recessive compound heterozygous mutations in epidermolysis bullosa simplex demonstrate the role of the stutter region in keratin intermediate filament assembly. J Biol Chem. 2002;277(26):23670–23674. doi: 10.1074/jbc.M200974200Jankowski M, Wertheim-Tysarowska K, Jakubowski R, Sota J, Nowak W, Czajkowski R. Novel KRT14 mutation causing epidermolysis bullosa simplex with variable phenotype. Exp Dermatol. 2014;23(9):684–687. doi: 10.1111/exd.12478Leung CL, Green KJ, Liem RK. Plakins: a family of versatile cytolinker proteins. Trends Cell Biol. 2002;12(1):37–45. doi: 10.1016/s0962-8924(01)02180-8Eldirany SA, Lomakin IB, Ho M, Bunick CG. Recent insight into intermediate filament structure. Curr Opin Cell Biol. 2021;68:132–143. doi: 10.1016/j.ceb.2020.10.001Omary MB, Ku NO, Tao GZ, Toivola DM, Liao J. “Heads and tails” of intermediate filament phosphorylation: multiple sites and functional insights. Trends Biochem Sci. 2006;31(7):383–394. doi: 10.1016/j.tibs.2006.05.008Wu KC, Bryan JT, Morasso MI, Jang SI, Lee JH, Yang JM, et al. Coiled-coil trigger motifs in the 1B and 2B rod domain segments are required for the stability of keratin intermediate filaments. Mol Biol Cell. 2000;11(10):3539–3358. doi: 10.1091/mbc.11.10.3539Banerjee S, Wu Q, Yu P, Qi M, Li C. In silico analysis of all point mutations on the 2B domain of K5/K14 causing epidermolysis bullosa simplex: a genotype-phenotype correlation. Mol Biosyst. 2014;10(10):2567–2577. doi: 10.1039/c4mb00138aLee CH, Kim MS, Chung BM, Leahy DJ, Coulombe PA. Structural basis for heteromeric assembly and perinuclear organization of keratin filaments. Nat Struct Mol Biol. 2012;19(7):707–715. doi: 10.1038/nsmb.2330Müller FB, Küster W, Wodecki K, Almeida H Jr, Bruckner-Tuderman L, Krieg T, et al. Novel and recurrent mutations in keratin KRT5 and KRT14 genes in epidermolysis bullosa simplex: implications for disease phenotype and keratin filament assembly. Hum Mutat. 2006;27(7):719–720. doi: 10.1002/humu.9437Fuchs E, Weber K. Intermediate filaments: structure, dynamics, function, and disease. Annu Rev Biochem. 1994;63:345–382. doi: 10.1146/annurev.bi.63.070194.002021Planko L, Böhse K, Höhfeld J, Betz RC, Hanneken S, Eigelshoven S, et al. Identification of a keratin-associated protein with a putative role in vesicle transport. Eur J Cell Biol. 2007;86(11–12):827–839. doi: 10.1016/j.ejcb.2007.02.004Coulombe PA, Lee CH. Defining keratin protein function in skin epithelia: epidermolysis bullosa simplex and its aftermath. J Invest Dermatol. 2012;132(3Pt 2):763–775. doi: 10.1038/jid.2011.450Has C, Schumann H, Leppert J, He Y, Hartmann B, Hausser I, et al. Monoallelic Large Intragenic KRT5 Deletions Account for Genetically Unsolved Cases of Epidermolysis Bullosa Simplex. J Invest Dermatol. 2017;137(10):2231–2234. doi: 10.1016/j.jid.2017.05.016Titeux M, Mazereeuw-Hautier J, Hadj-Rabia S, Prost C, Tonasso L, Fraitag S, et al. Three severe cases of EBS Dowling-Meara caused by missense and frameshift mutations in the keratin 14 gene. J Invest Dermatol. 2006;126(4):773–776. doi: 10.1038/sj.jid.5700154Arin MJ, Grimberg G, Schumann H, De Almeida H Jr, Chang YR, Tadini G, et al. Identification of novel and known KRT5 and KRT14 mutations in 53 patients with epidermolysis bullosa simplex: correlation between genotype and phenotype. Br J Dermatol. 2010;162(6):1365–1369. doi: 10.1111/j.1365-2133.2010.09657.xSzeverenyi I, Cassidy AJ, Chung CW, Lee BT, Common JE, Ogg SC, et al. The Human Intermediate Filament Database: comprehensive information on a gene family involved in many human diseases. Hum Mutat. 2008;29(3):351–360. doi: 10.1002/humu.20652Steinert PM. Structure, function, and dynamics of keratin intermediate filaments. J Invest Dermatol. 1993;100(6):729–734. doi: 10.1111/1523-1747.ep12475665Steinert PM, Marekov LN, Fraser RD, Parry DA. Keratin intermediate filament structure. Crosslinking studies yield quantitative information on molecular dimensions and mechanism of assembly. J Mol Biol. 1993;230(2):436–452. doi: 10.1006/jmbi.1993.1161Shinkuma S, Nishie W, Jacyk WK, Natsuga K, Ujiie H, Nakamura H, et al. A novel keratin 5 mutation in an African family with epidermolysis bullosa simplex indicates the importance of the amino acid located at the boundary site between the H1 and coil 1A domains. Acta Derm Venereol. 2013;93(5):585–587. doi: 10.2340/00015555-1538Ołdak M, Szczecińska W, Przybylska D, Maksym RB, Podgórska M, Woźniak K, et al. Gene dosage effect of p.Glu170Lys mutation in the KRT5 gene in a Polish family with epidermolysis bullosa simplex. J Dermatol Sci. 2011;61(1):64–67. doi: 10.1016/j.jdermsci.2010.11.002Cummins RE, Klingberg S, Wesley J, Rogers M, Zhao Y, Murrell DF. Keratin 14 point mutations at codon 119 of helix 1A resulting in different epidermolysis bullosa simplex phenotypes. J Invest Dermatol. 2001;117(5):1103–1107. doi: 10.1046/j.0022-202x.2001.01508.xNatsuga K, Nishie W, Smith BJ, Shinkuma S, Smith TA, Parry DA, et al. Consequences of two different amino-acid substitutions at the same codon in KRT14 indicate definitive roles of structural distortion in epidermolysis bullosa simplex pathogenesis. J Invest Dermatol. 2011;131(9):1869–1876. doi: 10.1038/jid.2011.143Lalor L, Titeux M, Palisson F, Fuentes I, Yubero MJ, Tasanen K, et al. Epidermolysis bullosa simplex-generalized severe type due to keratin 5 p.Glu477Lys mutation: Genotype-phenotype correlation and in silico modeling analysis. Pediatr Dermatol. 2019;36(1):132–138. doi: 10.1111/pde.13722Stephens K, Ehrlich P, Weaver M, Le R, Spencer A, Sybert VP. Primers for exon-specific amplification of the KRT5 gene: identification of novel and recurrent mutations in epidermolysis bullosa simplex patients. J Invest Dermatol. 1997;108(3):349–353. doi: 10.1111/1523-1747.ep12286486Letai A, Coulombe PA, Fuchs E. Do the ends justify the mean? Proline mutations at the ends of the keratin coiled-coil rod segment are more disruptive than internal mutations. J Cell Biol. 1992;116(5):1181–1195. doi: 10.1083/jcb.116.5.1181Hamada T, Kawano Y, Szczecinska W, Wozniak K, Yasumoto S, Kowalewski C, et al. Novel keratin 5 and 14 gene mutations in patients with epidermolysis bullosa simplex from Poland. Arch Dermatol Res. 2005;296(12):577–579. doi: 10.1007/s00403-005-0560-1Smith TA, Steinert PM, Parry DA. Modeling effects of mutations in coiled-coil structures: case study using epidermolysis bullosa simplex mutations in segment 1a of K5/K14 intermediate filaments. Proteins. 2004;55(4):1043–1052. doi: 10.1002/prot.20089Bowden PE, Knight AG, Liovic M. A novel mutation (p.Thr198Ser) in the 1A helix of keratin 5 causes the localized variant of epidermolysis bullosa simplex. Exp Dermatol. 2009;18(7):650–652. doi: 10.1111/j.1600-0625.2008.00820.xGlász-Bóna A, Medvecz M, Sajó R, Lepesi-Benko R, Tulassay Z, Katona M, et al. Easy method for keratin 14 gene amplification to exclude pseudogene sequences: new keratin 5 and 14 mutations in epidermolysis bullosa simplex. J Invest Dermatol. 2009;129(1):229–231. doi: 10.1038/jid.2008.223Liovic M, Bowden PE, Marks R, Komel R. A mutation (N177S) in the structurally conserved helix initiation peptide motif of keratin 5 causes a mild EBS phenotype. Exp Dermatol. 2004;13(5):332–334. doi: 10.1111/j.0906-6705.2004.00171.xGeisler N, Kaufmann E, Weber K. Proteinchemical characterization of three structurally distinct domains along the protofilament unit of desmin 10 nm filaments. Cell. 1982;30(1):277–286. doi: 10.1016/0092-8674(82)90033-2Wilson AK, Coulombe PA, Fuchs E. The roles of K5 and K14 head, tail, and R/K L L E G E domains in keratin filament assembly in vitro. J Cell Biol. 1992;119(2):401–414. doi: 10.1083/jcb.119.2.401Kouklis PD, Hutton E, Fuchs E. Making a connection: direct binding between keratin intermediate filaments and desmosomal proteins. J Cell Biol. 1994;127(4):1049–1060. doi: 10.1083/jcb.127.4.1049Geller L, Kristal L, Morel KD. Epidermolysis bullosa simplex with mottled pigmentation due to a rare keratin 5 mutation: cutaneous findings in infancy. Pediatr Dermatol. 2013;30(5):631–632. doi: 10.1111/pde.12206Gu LH, Kim SC, Ichiki Y, Park J, Nagai M, Kitajima Y. A usual frameshift and delayed termination codon mutation in keratin 5 causes a novel type of epidermolysis bullosa simplex with migratory circinate erythema. J Invest Dermatol. 2003;121(3):482–485. doi: 10.1046/j.1523-1747.2003.12424.xGu LH, Coulombe PA. Defining the properties of the nonhelical tail domain in type II keratin 5: insight from a bullous disease-causing mutation. Mol Biol Cell. 2005;16(3):1427–1438. doi: 10.1091/mbc.e04-06-0498Turcan I, Pasmooij AM, Van den Akker PC, Lemmink H, Sinke RJ, Jonkman MF. Association of epidermolysis bullosa simplex with mottled pigmentation and EXPH5 mutations. JAMA Dermatol. 2016;152(10):1137–1141. doi: 10.1001/jamadermatol.2016.2268Castiglia D, El Hachem M, Diociaiuti A, Carbone T, De Luca N, Pascucci M, et al. T-lymphocytes are directly involved in the clinical expression of migratory circinate erythema in epidermolysis bullosa simplex patients. Acta Derm Venereol. 2014;94(3):307–311. doi: 10.2340/00015555-1691Minakawa S, Nakano H, Nakajima K, Matsuzaki Y, Takiyoshi N, Akasaka E, et al. Mutational analysis on 16 Japanese population cases with epidermolysis bullosa simplex. J Dermatol Sci. 2013;72(3):330–332. doi: 10.1016/j.jdermsci.2013.08.001Wiche G. Role of plectin in cytoskeleton organization and dynamics. J Cell Sci. 1998;111 (Pt 17):2477–2486. doi: 10.1242/jcs.111.17.2477Geerts D, Fontao L, Nievers MG, Schaapveld RQ, Purkis PE, Wheeler GN, et al. Binding of integrin alpha6beta4 to plectin prevents plectin association with F-actin but does not interfere with intermediate filament binding. J Cell Biol. 1999;147(2):417–434. doi: 10.1083/jcb.147.2.417Koster J, van Wilpe S, Kuikman I, Litjens SH, Sonnenberg A. Role of binding of plectin to the integrin beta4 subunit in the assembly of hemidesmosomes. Mol Biol Cell. 2004;15(3):1211–1223. doi: 10.1091/mbc.e03-09-0697Bouameur JE, Favre B, Fontao L, Lingasamy P, Begré N, Borradori L. Interaction of plectin with keratins 5 and 14: dependence on several plectin domains and keratin quaternary structure. J Invest Dermatol. 2014;134(11):2776–2783. doi: 10.1038/jid.2014.255Tsilafakis K, Mavroidis M. Are the head and tail domains of intermediate filaments really unstructured regions? Genes (Basel). 2024;15(5):633. doi: 10.3390/genes15050633Te Molder L, Hoekman L, Kreft M, Bleijerveld O, Sonnenberg A. Comparative interactomics analysis reveals potential regulators of α6β4 distribution in keratinocytes. Biol Open. 2020;9(8):bio054155. doi: 10.1242/bio.054155Castañón MJ, Walko G, Winter L, Wiche G. Plectin-intermediate filament partnership in skin, skeletal muscle, and peripheral nerve. Histochem Cell Biol. 2013;140(1):33–53. doi: 10.1007/s00418-013-1102-0Rezniczek GA, de Pereda JM, Reipert S, Wiche G. Linking integrin alpha6beta4-based cell adhesion to the intermediate filament cytoskeleton: direct interaction between the beta4 subunit and plectin at multiple molecular sites. J Cell Biol. 1998;141(1):209–225. doi: 10.1083/jcb.141.1.209de Pereda JM, Lillo MP, Sonnenberg A. Structural basis of the interaction between integrin alpha6beta4 and plectin at the hemidesmosomes. EMBO J. 2009;28(8):1180–1190. doi: 10.1038/emboj.2009.48Koster J, Borradori L, Sonnenberg A. Hemidesmosomes: molecular organization and their importance for cell adhesion and disease. Handb Exp Pharmacol. 2004;165:243–280. doi: 10.1007/978-3-540-68170-0_9Kiritsi D, Tsakiris L, Schauer F. Plectin in skin fragility disorders. Cells. 2021;10(10):2738. doi: 10.3390/cells10102738Kiritsi D, Pigors M, Tantcheva-Poor I, Wessel C, Arin MJ, Kohlhase J, et al. Epidermolysis bullosa simplex ogna revisited. J Invest Dermatol. 2013;133(1):270–273. doi: 10.1038/jid.2012.248Walko G, Vukasinovic N, Gross K, Fischer I, Sibitz S, Fuchs P, et al. Targeted proteolysis of plectin isoform 1a accounts for hemidesmosome dysfunction in mice mimicking the dominant skin blistering disease EBS-Ogna. PLoS Genet. 2011;7(12):e1002396. doi: 10.1371/journal.pgen.1002396Takahashi Y, Rouan F, Uitto J, Ishida-Yamamoto A, Iizuka H, Owaribe K, et al. Plectin deficient epidermolysis bullosa simplex with 27-year-history of muscular dystrophy. J Dermatol Sci. 2005;37(2):87–93. doi: 10.1016/j.jdermsci.2004.11.003Selcen D, Juel VC, Hobson-Webb LD, Smith EC, Stickler DE, Bite AV, et al. Myasthenic syndrome caused by plectinopathy. Neurology. 2011;76(4):327–336. doi: 10.1212/WNL.0b013e31820882bdNatsuga K, Nishie W, Akiyama M, Nakamura H, Shinkuma S, McMillan JR, et al. Plectin expression patterns determine two distinct subtypes of epidermolysis bullosa simplex. Hum Mutat. 2010;31(3):308–316. doi: 10.1002/humu.21189Bolling MC, Pas HH, de Visser M, Aronica E, Pfendner EG, van den Berg MP, et al. PLEC1 mutations underlie adult-onset dilated cardiomyopathy in epidermolysis bullosa simplex with muscular dystrophy. J Invest Dermatol. 2010;130(4):1178–1181. doi: 10.1038/jid.2009.390Chiavérini C, Charlesworth A, Meneguzzi G, Lacour JP, Ortonne JP. Epidermolysis bullosa simplex with muscular dystrophy. Dermatol Clin. 2010;28(2):245–255. doi: 10.1016/j.det.2010.01.001Natsuga K, Nishie W, Shinkuma S, Arita K, Nakamura H, Ohyama M, et al. Plectin deficiency leads to both muscular dystrophy and pyloric atresia in epidermolysis bullosa simplex. Hum Mutat. 2010;31(10):E1687–E1698. doi: 10.1002/humu.21330Ali A, Hu L, Zhao F, Qiu W, Wang P, Ma X, et al. BPAG1, a distinctive role in skin and neurological diseases. Semin Cell Dev Biol. 2017;69:34–39. doi: 10.1016/j.semcdb.2017.06.005Künzli K, Favre B, Chofflon M, Borradori L. One gene but different proteins and diseases: the complexity of dystonin and bullous pemphigoid antigen 1. Exp Dermatol. 2016;25(1):10–16. doi: 10.1111/exd.12877Groves RW, Liu L, Dopping-Hepenstal PJ, Markus HS, Lovell PA, Ozoemena L, et al. A homozygous nonsense mutation within the dystonin gene coding for the coiled-coil domain of the epithelial isoform of BPAG1 underlies a new subtype of autosomal recessive epidermolysis bullosa simplex. J Invest Dermatol. 2010;130(6):1551–1557. doi: 10.1038/jid.2010.1Ruhrberg C, Watt FM. The plakin family: versatile organizers of cytoskeletal architecture. Curr Opin Genet Dev. 1997;7(3):392–397. doi: 10.1016/s0959-437x(97)80154-2Choi HJ, Park-Snyder S, Pascoe LT, Green KJ, Weis WI. Structures of two intermediate filament-binding fragments of desmoplakin reveal a unique repeat motif structure. Nat Struct Biol. 2002;9(8):612–620. doi: 10.1038/nsb818Ortega E, Buey RM, Sonnenberg A, de Pereda JM. The structure of the plakin domain of plectin reveals a non-canonical SH3 domain interacting with its fourth spectrin repeat. J Biol Chem. 2011;286(14):12429–12438. doi: 10.1074/jbc.M110.197467Jefferson JJ, Ciatto C, Shapiro L, Liem RK. Structural analysis of the plakin domain of bullous pemphigoid antigen1 (BPAG1) suggests that plakins are members of the spectrin superfamily. J Mol Biol. 2007;366(1):244–257. doi: 10.1016/j.jmb.2006.11.036Fontao L, Favre B, Riou S, Geerts D, Jaunin F, Saurat JH, et al. Interaction of the bullous pemphigoid antigen 1 (BP230) and desmoplakin with intermediate filaments is mediated by distinct sequences within their COOH terminus. Mol Biol Cell. 2003;14(5):1978–1992. doi: 10.1091/mbc.e02-08-0548Borradori L, Chavanas S, Schaapveld RQ, Gagnoux-Palacios L, Calafat J, Meneguzzi G, et al. Role of the bullous pemphigoid antigen 180 (BP180) in the assembly of hemidesmosomes and cell adhesion — reexpression of BP180 in generalized atrophic benign epidermolysis bullosa keratinocytes. Exp Cell Res. 1998;239(2):463–476. doi: 10.1006/excr.1997.3923Borradori L, Sonnenberg A. Structure and function of hemidesmosomes: more than simple adhesion complexes. J Invest Dermatol. 1999;112(4):411–418. doi: 10.1046/j.1523-1747.1999.00546.xHopkinson SB, Jones JC. The N terminus of the transmembrane protein BP180 interacts with the N-terminal domain of BP230, thereby mediating keratin cytoskeleton anchorage to the cell surface at the site of the hemidesmosome. Mol Biol Cell. 2000;11(1):277–286. doi: 10.1091/mbc.11.1.277Favre B, Fontao L, Koster J, Shafaatian R, Jaunin F, Saurat JH, et al. The hemidesmosomal protein bullous pemphigoid antigen 1 and the integrin beta 4 subunit bind to ERBIN. Molecular cloning of multiple alternative splice variants of ERBIN and analysis of their tissue expression. J Biol Chem. 2001;276(35):32427–32436. doi: 10.1074/jbc.M011005200Takeichi T, Nanda A, Liu L, Aristodemou S, McMillan JR, Sugiura K, et al. Founder mutation in dystonin-e underlying autosomal recessive epidermolysis bullosa simplex in Kuwait. Br J Dermatol. 2015;172(2):527–531. doi: 10.1111/bjd.13294Al Towijry M, Alanazi AM, Eldesoky F, Alharthi YH, Albalawi IA. Epidermolysis bullosa simplex with dystonin gene mutation: First reported case in Saudi Arabia. Cureus. 2023;15(8):e43206. doi: 10.7759/cureus.43206Cappuccio G, Pinelli M, Torella A, Alagia M, Auricchio R, Staiano A, et al. Expanding the phenotype of DST-related disorder: A case report suggesting a genotype/phenotype correlation. Am J Med Genet A. 2017;173(10):2743–2746. doi: 10.1002/ajmg.a.38367Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010;12(1):19–30; sup pp 1–13. doi: 10.1038/ncb2000McGrath JA. Recently identified forms of epidermolysis bullosa. Ann Dermatol. 2015;27(6):658–666. doi: 10.5021/ad.2015.27.6.658Monteleon CL, Lee IY, Ridky TW. Exophilin-5 supports lysosome-mediated trafficking required for epidermal differentiation. J Invest Dermatol. 2019;139(10):2219–2222.e6. doi: 10.1016/j.jid.2019.04.014Liu L, Mellerio JE, Martinez AE, McMillan JR, Aristodemou S, Parsons M, et al. Mutations in EXPH5 result in autosomal recessive inherited skin fragility. Br J Dermatol. 2014;170(1):196–199. doi: 10.1111/bjd.12723Pigors M, Schwieger-Briel A, Leppert J, Kiritsi D, Kohlhase J, Bruckner-Tuderman L, et al. Molecular heterogeneity of epidermolysis bullosa simplex: contribution of EXPH5 mutations. J Invest Dermatol. 2014;134(3):842–845. doi: 10.1038/jid.2013.373Rashidghamat E, Ozoemena L, Liu L, McGrath JA, Martinez AE, Mellerio JE. Mutations in EXPH5 underlie a rare subtype of autosomal recessive epidermolysis bullosa simplex. Br J Dermatol. 2016;174(2):452–453. doi: 10.1111/bjd.14047Vahidnezhad H, Youssefian L, Saeidian AH, Touati A, Sotoudeh S, Jazayeri A, et al. Next generation sequencing identifies double homozygous mutations in two distinct genes (EXPH5 and COL17A1) in a patient with concomitant simplex and junctional epidermolysis bullosa. Hum Mutat. 2018;39(10):1349–1354. doi: 10.1002/humu.23592Vermeer MC, Al-Shinnag M, Silljé HH, Gaytan AE, Murrell DF, McGaughran J, et al. A translation re-initiation variant in KLHL24 also causes epidermolysis bullosa simplex and dilated cardiomyopathy via intermediate filament degradation. Br J Dermatol. 2022;187(6):1045–1048. doi: 10.1111/bjd.21832Hedberg-Oldfors C, Abramsson A, Osborn DPS, Danielsson O, Fazlinezhad A, Nilipour Y, et al. Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24. Hum Mol Genet. 2019;28(11):1919–1929. doi: 10.1093/hmg/ddz032Vermeer MC, Bolling MC, Bliley JM, Arevalo Gomez KF, Pavez-Giani MG, Kramer D, et al. Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues. J Clin Invest. 2021;131(17):e140615. doi: 10.1172/JCI140615Has C. The “Kelch” surprise: KLHL24, a new player in the pathogenesis of skin fragility. J Invest Dermatol. 2017;137(6):1211–1212. doi: 10.1016/j.jid.2017.02.011Kotalevskaya YY, Stepanov VA. Syndromic epidermolysis bullosa simplex subtype due to mutations in the KLHL24 gene: series of case reports in Russian families. Front Med (Lausanne). 2024;11:1418239. doi: 10.3389/fmed.2024.1418239Xu X, Zhao J, Wang C, Qu X, Ran M, Ye F, et al. Case Report: De novo KLHL24 gene pathogenic variants in Chinese twin boys with epidermolysis bullosa simplex. Front Genet. 2021;12:729628. doi: 10.3389/fgene.2021.729628Fitter S, Tetaz TJ, Berndt MC, Ashman LK. Molecular cloning of cDNA encoding a novel platelet-endothelial cell tetra-span antigen, PETA-3. Blood. 1995;86(4):1348–1355.Hasegawa H, Kishimoto K, Yanagisawa K, Terasaki H, Shimadzu M, Fujita S. Assignment of SFA-1 (PETA-3), a member of the transmembrane 4 superfamily, to human chromosome 11p15.5 by fluorescence in situ hybridization. Genomics. 1997;40(1):193–196. doi: 10.1006/geno.1996.4563Whittock NV, McLean WH. Genomic organization, amplification, fine mapping, and intragenic polymorphisms of the human hemidesmosomal tetraspanin CD151 gene. Biochem Biophys Res Commun. 2001;281(2):425–430. doi: 10.1006/bbrc.2001.4384Ashman LK. CD151. J Biol Regul Homeost Agents. 2002;16(3):223–226.Sterk LM, Geuijen CA, Oomen LC, Calafat J, Janssen H, Sonnenberg A. The tetraspan molecule CD151, a novel constituent of hemidesmosomes, associates with the integrin alpha6beta4 and may regulate the spatial organization of hemidesmosomes. J Cell Biol. 2000;149(4):969–982. doi: 10.1083/jcb.149.4.969Berditchevski F, Gilbert E, Griffiths MR, Fitter S, Ashman L, Jenner SJ. Analysis of the CD151-alpha3beta1 integrin and CD151-tetraspanin interactions by mutagenesis. J Biol Chem. 2001;276(44):41165–41174. doi: 10.1074/jbc.M104041200Naylor RW, Watson E, Williamson S, Preston R, Davenport JB, Thornton N, et al. Basement membrane defects in CD151-associated glomerular disease. Pediatr Nephrol. 2022;37(12):3105–3115. doi: 10.1007/s00467-022-05447-yRahmani N, Talebi S, Hoseini R, Asghari Kollahi N, Shojaei A. New report of a different clinical presentation of CD151 splicing mutation (c.351+2T>C): Could TSPAN11 be considered as a potential modifier gene for CD151? Mol Syndromol. 2022;13(3):212–220. doi: 10.1159/000519633Brogna S, Wen J. Nonsense-mediated mRNA decay (NMD) mechanisms. Nat Struct Mol Biol. 2009;16(2):107–113. doi: 10.1038/nsmb.1550Kagan A, Feld S, Chemke J, Bar-Khayim Y. Occurrence of hereditary nephritis, pretibial epidermolysis bullosa and beta-thalassemia minor in two siblings with end-stage renal disease. Nephron. 1988;49(4):331–332. doi: 10.1159/000185086Shemanko CS, Mellerio JE, Tidman MJ, Lane EB, Eady RA. Severe palmo-plantar hyperkeratosis in Dowling-Meara epidermolysis bullosa simplex caused by a mutation in the keratin 14 gene (KRT14). J Invest Dermatol. 1998;111(5):893–895. doi: 10.1046/j.1523-1747.1998.00388.xHut PH, v d Vlies P, Jonkman MF, Verlind E, Shimizu H, Buys CH, Scheffer H. Exempting homologous pseudogene sequences from polymerase chain reaction amplification allows genomic keratin 14 hotspot mutation analysis. J Invest Dermatol. 2000;114(4):616–619. doi: 10.1046/j.1523-1747.2000.00928.xKang TW, Lee JS, Kim SE, Oh SW, Kim SC. Novel and recurrent mutations in Keratin 5 and 14 in Korean patients with epidermolysis bullosa simplex. J Dermatol Sci. 2010;57(2):90–94. doi: 10.1016/j.jdermsci.2009.12.002Mazzanti C, Gobello T, Posteraro P, Paradisi M, Meneguzzi G, Chinni L, et al. 180-kDa bullous pemphigoid antigen defective generalized atrophic benign epidermolysis bullosa: report of four cases with an unusually mild phenotype. Br J Dermatol. 1998;138(5):859–866. doi: 10.1046/j.1365-2133.1998.02226.xRuzzi L, Pas H, Posteraro P, Mazzanti C, Didona B, Owaribe K, et al. A homozygous nonsense mutation in type XVII collagen gene (COL17A1) uncovers an alternatively spliced mRNA accounting for an unusually mild form of non-Herlitz junctional epidermolysis bullosa. J Invest Dermatol. 2001;116(1):182–187. doi: 10.1046/j.1523-1747.2001.00229.xTiteux M, Pendaries V, Tonasso L, Décha A, Bodemer C, Hovnanian A. A frequent functional SNP in the MMP1 promoter is associated with higher disease severity in recessive dystrophic epidermolysis bullosa. Hum Mutat. 2008;29(2):267–276. doi: 10.1002/humu.20647Bateman JF, Boot-Handford RP, Lamandé SR. Genetic diseases of connective tissues: cellular and extracellular effects of ECM mutations. Nat Rev Genet. 2009;10(3):173–183. doi: 10.1038/nrg2520