Vestnik dermatologii i venerologiiVestnik dermatologii i venerologiiВестник дерматологии и венерологии0042-46092313-6294Rossijskoe Obschestvo Dermatovenerologov i Kosmetologov139110.25208/vdv1391REVIEWSОБЗОР ЛИТЕРАТУРЫReview ArticleJunctional epidermolysis bullosa: genotype-phenotype correlationsПограничный буллезный эпидермолиз: клинико-генетические корреляцииhttps://orcid.org/0000-0002-7625-05038771-4990KubanovAlexey A.КубановАлексей Алексеевич
Russian Federation

MD, Dr. Sci. (Med.), Professor, Academician of the Russian Academy of Sciences

д.м.н., профессор, академик РАН

alex@cnikvi.ruhttps://orcid.org/0000-0002-9688-27273385-4723ChikinVadim V.ЧикинВадим Викторович
Russian Federation

MD, Dr. Sci. (Med.)

д.м.н., доцент

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

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

к.м.н., доцент

karamova@cnikvi.ruhttps://orcid.org/0000-0002-6402-09629859-1912MonchakovskayaEkaterina S.МончаковскаяЕкатерина Сергеевна
Russian Federation

Junior Research Associate

младший научный сотрудник

monchakovskaya@cnikvi.ruState Research Center of Dermatovenereology and CosmetologyГосударственный научный центр дерматовенерологии и косметологии221120222701202398617381810202217112022Copyright ©; 2023, Kubanov A.A., Chikin V.V., Karamova A.E., Monchakovskaya E.S.Copyright ©; 2023, Кубанов А.А., Чикин В.В., Карамова А.Э., Мончаковская Е.С.2023Kubanov A.A., Chikin V.V., Karamova A.E., Monchakovskaya E.S.Кубанов А.А., Чикин В.В., Карамова А.Э., Мончаковская Е.С.https://creativecommons.org/licenses/by/4.0https://vestnikdv.ru/jour/article/view/1391

Junctional epidermolysis bullosa most commonly results from mutations in the LAMA3, LAMB3, LAMC2, COL17A1, ITGA6 and ITGB4 genes. Junctional epidermolysis bullosa is characterized by clinical heterogeneity. To date, scientific findings allow to evaluate correlations between the severity of clinical manifestations and genetic defects underlying in the development of the disease. A systematic literature search was performed using PubMed and RSCI, and keywords including “junctional epidermolysis bullosa”, “laminin 332”, “collagen XVII”, “α6β4 integrin”. The review includes description of clinical findings of junctional epidermolysis bullosa, mutation location and types, its’ impact on protein production and functions. To evaluate the impact of gene mutation on protein functions, this review explores the structure and functions of lamina lucida components, including laminin 332, collagen XVII and α6β4 integrin, which are frequently associated with the development of junctional epidermolysis bullosa. The correlation between severe types of junctional epidermolysis bullosa and mutations resulting in premature stop codon generation and complete absence of protein expression has been described. Although, genotype-phenotype correlations should be analyzed carefully due to mechanisms which enable to improve protein expression.

Пограничный буллезный эпидермолиз в большинстве случаев вызывается различными мутациями генов LAMA3, LAMB3, LAMC2, COL17A1, ITGA6 и ITGB4 и характеризуется значительной вариабельностью клинических проявлений. К настоящему времени накоплены данные, позволяющие оценить корреляции между тяжестью болезни и характером генетических нарушений, лежащих в основе ее развития. Проведен анализ публикаций, обнаруженных в базах данных научной литературы PubMed и РИНЦ при поиске по ключевым словам «пограничный буллезный эпидермолиз» (junctional epidermolysis bullosa), «ламинин-332» (laminin 332), «коллаген XVII типа» (collagen XVII), «α6β4 интегрин» (α6β4 integrin). Описаны клинические проявления пограничного врожденного буллезного эпидермолиза, локализация и тип мутации, ее влияние на синтез и функционирование белка. Для оценки влияния мутации гена на функционирование белка рассматривали строение и функции белков светлой пластинки базальной мембраны кожи, с мутациями которых наиболее часто ассоциируется пограничный врожденный буллезный эпидермолиз, — ламинин-332, коллаген XVII типа и α6β4-интегрин. Обнаружено, что при пограничном врожденном буллезном эпидермолизе существует корреляция между носительством мутаций, приводящих к образованию преждевременных стоп-кодонов и отсутствию синтеза белка, и тяжелым течением болезни. Однако необходима осторожность при проведении клинико-генетических корреляций, так как существуют механизмы, позволяющие восстанавливать синтез отсутствующего белка.

junctional epidermolysis bullosagenotype-phenotype correlationslaminin 332collagen XVIIintegrin α6β4пограничный буллезный эпидермолизклинико-генетические корреляцииламинин-332коллаген XVII типаα6β4-интегринHas 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.18921Fine JD, Bruckner-Tuderman L, Eady RAJ, 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.2014.01.903Mariath 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.2020.05.001Has C, Kern JS. Collagen XVII. Dermatol Clin. 2010;28(1):61–66. doi: 10.1016/j.det.2009.10.007Kiritsi D, Has C, Bruckner-Tuderman L. Laminin 332 in junctional epidermolysis bullosa. Cell Adh Migr. 2013;7(1):135–141. doi: 10.4161/cam.22418Lee M, Chen Q, Wang H, Zhang J, Lin Z, Yang Y. ITGB4-associated junctional epidermolysis bullosa without pylori atresia but profound genito-urinary involvement. Acta Derm Venereol. 2015;95(1):112–113. doi: 10.2340/00015555-1888Laimer M, Lanschuetzer CM, Diem A, Bauer JW. Herlitz junctional epidermolysis bullosa. Dermatol Clin. 2010;28(1):55–60. doi: 10.1016/j.det.2009.10.006Ansai O, Shinkuma S, Kabata Y, Katsumi T, Hagiwara R, Tomii K, et al. Amino acid charge and epidermolysis bullosa simplex severity: genotype-phenotype correlations. J Eur Acad Dermatol Venereol. 2020;34(2):e87–e90. doi: 10.1111/jdv.15990Natale MI, Manzur GB, Lusso SB, Cella E, Giovo ME, Andrada R, et al. Analysis of COL7A1 pathogenic variants in a large cohort of dystrophic epidermolysis bullosa patients from Argentina reveals a new genotype-phenotype correlation. Am J Med Genet A. 2022;188(11):3153–3161. doi: 10.1002/ajmg.a.62957Uitto J, Has C, Vahidnezhad H, Youssefian L, Bruckner-Tuderman L. Molecular pathology of the basement membrane zone in heritable blistering diseases: The paradigm of epidermolysis bullosa. Matrix Biol. 2017;57–58:76–85. doi: 10.1016/j.matbio.2016.07.009Turcan I, Pasmooij AMG, Akker PC van den, Lemmink H, Halmos GB, Sinke RJ, et al. Heterozygosity for a novel missense mutation in the ITGB4 gene associated with autosomal dominant epidermolysis bullosa. JAMA Dermatol. 2016;152(5):558–562. doi: 10.1001/jamadermatol.2015.5236Sugawara K, Tsuruta D, Ishii M, Jones JCR, Kobayashi H. Laminin-332 and -511 in skin. Exp Dermatol. 2008;17(6):473–480. doi: 10.1111/j.1600-0625.2008.00721.xHas C, Nyström A, Saeidian AH, Bruckner-Tuderman L, Uitto J. Epidermolysis bullosa: Molecular pathology of connective tissue components in the cutaneous basement membrane zone. Matrix Biol. 2018;71–72:313–329. doi: 10.1016/j.matbio.2018.04.001Aumailley M, Bruckner-Tuderman L, Carter WG, Deutzmann R, Edgar D, Ekblom P, et al. A simplified laminin nomenclature. Matrix Biol. 2005;24(5):326–332. doi: 10.1016/j.matbio.2005.05.006Domogatskaya A, Rodin S, Tryggvason K. Functional diversity of laminins. Annu Rev Cell Dev Biol. 2012;28:523–553. doi: 10.1146/annurev-cellbio-101011-155750Aumailley M. The laminin family. Cell Adh Migr. 2013;7(1):48–55. doi: 10.4161/cam.22826Macdonald PR, Lustig A, Steinmetz MO, Kammerer RA. Laminin chain assembly is regulated by specific coiled-coil interactions. J Struct Biol. 2010;170(2):398–405. doi: 10.1016/j.jsb.2010.02.004Matsui C, Wang CK, Nelson CF, Bauer EA, Hoeffler WK. The assembly of laminin-5 subunits. J Biol Chem. 1995;270(40):23496–23503. doi: 10.1074/jbc.270.40.23496Nomizu M, Utani A, Beck K, Otaka A, Roller PP, Yamada Y. Mechanism of laminin chain assembly into a triple-stranded coiled-coil structure. Biochemistry. 1996;35(9):2885–2893. doi: 10.1021/bi951555nAntonsson P, Kammerer RA, Schulthess T, Hänisch G, Engel J. Stabilization of the alpha-helical coiled-coil domain in laminin by C-terminal disulfide bonds. J Mol Biol. 1995;250(1):74–79. doi: 10.1006/jmbi.1995.0359Utani A, Nomizu M, Timpl R, Roller PP, Yamada Y. Laminin chain assembly. Specific sequences at the C terminus of the long arm are required for the formation of specific double- and triple-stranded coiled-coil structures. J Biol Chem. 1994;269(29):19167–19175.Aumailley M, Smyth N. The role of laminins in basement membrane function. J Anat. 1998;193(1):1–21. doi: 10.1046/j.1469-7580.1998.19310001.xShaw L, Sugden CJ, Hamill KJ. Laminin polymerization and inherited disease: lessons from genetics. Front Genet. 2021;12:707087. doi: 10.3389/fgene.2021.707087Zimmerman T, Blanco FJ. The coiled-coil structure potential of the laminin LCC domain is very fragmented and does not differentiate between natural and non-detected isoforms. J Biomol Struct Dyn. 2007;24(4):413–420. doi: 10.1080/07391102.2007.10507129Beck K, Dixon TW, Engel J, Parry DA. Ionic interactions in the coiled-coil domain of laminin determine the specificity of chain assembly. J Mol Biol. 1993;231(2):311–323. doi: 10.1006/jmbi.1993.1284Schneider H, Mühle C, Pacho F. Biological function of laminin-5 and pathogenic impact of its deficiency. Eur J Cell Biol. 2007;86(11–12):701–717. doi: 10.1016/j.ejcb.2006.07.004Timpl R, Tisi D, Talts JF, Andac Z, Sasaki T, Hohenester E. Structure and function of laminin LG modules. Matrix Biol. 2000;19(4):309–317. doi: 10.1016/s0945-053x(00)00072-xRousselle P, Beck K. Laminin 332 processing impacts cellular behavior. Cell Adh Migr. 2013;7(1):122–134. doi: 10.4161/cam.23132Tsubota Y, Yasuda C, Kariya Y, Ogawa T, Hirosaki T, Mizushima H, et al. Regulation of biological activity and matrix assembly of laminin-5 by COOH-terminal, LG4-5 domain of alpha3 chain. J Biol Chem. 2005;280(15):14370–14377. doi: 10.1074/jbc.M413051200Baudoin C, Fantin L, Meneguzzi G. Proteolytic processing of the laminin alpha3 G domain mediates assembly of hemidesmosomes but has no role on keratinocyte migration. J Invest Dermatol. 2005;125(5):883–888. doi: 10.1111/j.0022-202X.2005.23881.xChampliaud MF, Lunstrum GP, Rousselle P, Nishiyama T, Keene DR, Burgeson RE. Human amnion contains a novel laminin variant, laminin 7, which like laminin 6, covalently associates with laminin 5 to promote stable epithelial-stromal attachment. J Cell Biol. 1996;132(6):1189–1198. doi: 10.1083/jcb.132.6.1189Van Agtmael T, Bruckner-Tuderman L. Basement membranes and human disease. Cell Tissue Res. 2010;339(1):167–188. doi: 10.1007/s00441-009-0866-yBehrens DT, Villone D, Koch M, Brunner G, Sorokin L, Robenek H, et al. The epidermal basement membrane is a composite of separate laminin- or collagen IV-containing networks connected by aggregated perlecan, but not by nidogens. J Biol Chem. 2012;287(22):18700–18709. doi: 10.1074/jbc.M111.336073Has C, Nyström A. Epidermal basement membrane in health and disease. Curr Top Membr. 2015;76:117–170. doi: 10.1016/bs.ctm.2015.05.003Rousselle P, Keene DR, Ruggiero F, Champliaud MF, Rest M, Burgeson RE. Laminin 5 binds the NC-1 domain of type VII collagen. J Cell Biol. 1997;138(3):719–728. doi: 10.1083/jcb.138.3.719Aumailley M, El Khal A, Knöss N, Tunggal L. Laminin 5 processing and its integration into the ECM. Matrix Biol. 2003;22(1):49–54. doi: 10.1016/s0945-053x(03)00013-1Chen M, Marinkovich MP, Veis A, Cai X, Rao CN, O'Toole EA, et al. Interactions of the amino-terminal noncollagenous (NC1) domain of type VII collagen with extracellular matrix components. A potential role in epidermal-dermal adherence in human skin. J Biol Chem. 1997;272(23):14516–14522. doi: 10.1074/jbc.272.23.14516Ido H, Nakamura A, Kobayashi R, Ito S, Li S, Futaki S, et al. The requirement of the glutamic acid residue at the third position from the carboxyl termini of the laminin gamma chains in integrin binding by laminins. J Biol Chem. 2007;282(15):11144–11154. doi: 10.1074/jbc.M609402200Taniguchi Y, Ido H, Sanzen N, Hayashi M, Sato-Nishiuchi R, Futaki S, et al. The C-terminal region of laminin beta chains modulates the integrin binding affinities of laminins. J Biol Chem. 2009;284(12):7820–7831. doi: 10.1074/jbc.M809332200Marinkovich MP. Tumour microenvironment: laminin 332 in squamous-cell carcinoma. Nat Rev Cancer. 2007;7(5):370–380. doi: 10.1038/nrc2089Yamada M, Sekiguchi K. Molecular Basis of Laminin-Integrin Interactions. Curr Top Membr. 2015;76:197–229. doi: 10.1016/bs.ctm.2015.07.002Ogawa T, Tsubota Y, Hashimoto J, Kariya Y, Miyazaki K. The short arm of laminin gamma2 chain of laminin-5 (laminin-332) binds syndecan-1 and regulates cellular adhesion and migration by suppressing phosphorylation of integrin beta4 chain. Mol Biol Cell. 2007;18(5):1621–1633. doi: 10.1091/mbc.e06-09-0806Van den Bergh F, Giudice GJ. BP180 (type XVII collagen) and its role in cutaneous biology and disease. Adv Dermatol. 2003;19:37–71.Franzke CW, Tasanen K, Schumann H, Bruckner-Tuderman L. Collagenous transmembrane proteins: collagen XVII as a prototype. Matrix Biol. 2003;22(4):299–309. doi: 10.1016/s0945-053x(03)00051-9Gatalica B, Pulkkinen L, Li K, Kuokkanen K, Ryynänen M, McGrath JA, et al. Cloning of the human type XVII collagen gene (COL17A1), and detection of novel mutations in generalized atrophic benign epidermolysis bullosa. Am J Hum Genet. 1997;60(2):352–365.Areida SK, Reinhardt DP, Muller PK, Fietzek PP, Kowitz J, Marinkovich MP, et al. Properties of the collagen type XVII ectodomain. Evidence for n- to c-terminal triple helix folding. J Biol Chem. 2001;276(2):1594–1601. doi: 10.1074/jbc.M008709200Van den Bergh F, Fu CL, Olague-Marchan M, Giudice GJ. The NC16A domain of collagen XVII plays a role in triple helix assembly and stability. Biochem Biophys Res Commun. 2006;350(4):1032–1037. doi: 10.1016/j.bbrc.2006.09.147Hurskainen T, Moilanen J, Sormunen R, Franzke CW, Soininen R, Loeffek S, et al. Transmembrane collagen XVII is a novel component of the glomerular filtration barrier. Cell Tissue Res. 2012;348(3):579–588. doi: 10.1007/s00441-012-1368-xSeppänen A, Suuronen T, Hofmann SC, Majamaa K, Alafuzoff I. Distribution of collagen XVII in the human brain. Brain Res. 2007;1158:50–56. doi: 10.1016/j.brainres.2007.04.073Kondo J, Kusachi S, Ninomiya Y, Yoshioka H, Oohashi T, Doi M, et al. Expression of type XVII collagen alpha 1 chain mRNA in the mouse heart. Jpn Heart J. 1998;39(2):211–220. doi: 10.1536/ihj.39.211Asaka T, Akiyama M, Domon T, Nishie W, Natsuga K, Fujita Y, et al. Type XVII collagen is a key player in tooth enamel formation. Am J Pathol. 2009;174(1):91–100. doi: 10.2353/ajpath.2009.080573Koster 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_9Hopkinson 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.11.1.277Koster 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(2):387–399. doi: 10.1242/jcs.00241Tasanen K, Tunggal L, Chometon G, Bruckner-Tuderman L, Aumailley M. Keratinocytes from patients lacking collagen XVII display a migratory phenotype. Am J Pathol. 2004;164(6):2027–2038. doi: 10.1016/S0002-9440(10)63762-5Tamura RN, Rozzo C, Starr L, Chambers J, Reichardt LF, Cooper HM, et al. Epithelial integrin alpha 6 beta 4: complete primary structure of alpha 6 and variant forms of beta 4. J Cell Biol. 1990;111(4):1593–1604. doi: 10.1083/jcb.111.4.1593Hogervorst F, Kuikman I, Borne AE von dem, Sonnenberg A. Cloning and sequence analysis of beta-4 cDNA: an integrin subunit that contains a unique 118 kd cytoplasmic domain. EMBO J. 1990;9(3):765–770. doi: 10.1002/j.1460-2075.1990.tb08171.xPereda JM de, 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.2009.48Schaapveld RQ, Borradori L, Geerts D, Leusden MR van, Kuikman I, Nievers MG, et al. Hemidesmosome formation is initiated by the beta4 integrin subunit, requires complex formation of beta4 and HD1/plectin, and involves a direct interaction between beta4 and the bullous pemphigoid antigen 180. J Cell Biol. 1998;142(1):271–284. doi: 10.1083/jcb.142.1.271Chung HJ, Uitto J. Epidermolysis bullosa with pyloric atresia. Dermatol Clin. 2010;28(1):43–54. doi: 10.1016/j.det.2009.10.005Dellambra E, Prislei S, Salvati AL, Madeddu ML, Golisano O, Siviero E, et al. Gene correction of integrin beta4-dependent pyloric atresia-junctional epidermolysis bullosa keratinocytes establishes a role for beta4 tyrosines 1422 and 1440 in hemidesmosome assembly. J Biol Chem. 2001;276(44):41336–41342. doi: 10.1074/jbc.M103139200Nievers MG, Schaapveld RQ, Oomen LC, Fontao L, Geerts D, Sonnenberg A. Ligand-independent role of the beta 4 integrin subunit in the formation of hemidesmosomes. J Cell Sci. 1998;111(12):1659–1672. doi: 10.1242/jcs.111.12.1659Niessen CM, Hulsman EH, Oomen LC, Kuikman I, Sonnenberg A. A minimal region on the integrin beta4 subunit that is critical to its localization in hemidesmosomes regulates the distribution of HD1/plectin in COS-7 cells. J Cell Sci. 1997;110(15):1705–1716. doi: 10.1242/jcs.110.15.1705Mainiero F, Pepe A, Wary KK, Spinardi L, Mohammadi M, Schlessinger J, et al. Signal transduction by the alpha 6 beta 4 integrin: distinct beta 4 subunit sites mediate recruitment of Shc/Grb2 and association with the cytoskeleton of hemidesmosomes. EMBO J. 1995;14(18):4470–4481. doi: 10.1002/j.1460-2075.1995.tb00126.xHogervorst F, Kuikman I, Borne AE von dem, Sonnenberg A. Cloning and sequence analysis of beta-4 cDNA: an integrin subunit that contains a unique 118 kd cytoplasmic domain. EMBO J. 1990;9(3):765–770. doi: 10.1002/j.1460-2075.1990.tb08171.xTuckwell DS, Humphries MJ. A structure prediction for the ligand-binding region of the integrin beta subunit: evidence for the presence of a von Willebrand factor A domain. FEBS Lett. 1997;400(3):297–303. doi: 10.1016/s0014-5793(96)01368-3Colombatti A, Bonaldo P. The superfamily of proteins with von Willebrand factor type A-like domains: one theme common to components of extracellular matrix, hemostasis, cellular adhesion, and defense mechanisms. Blood. 1991;77(11):2305–2315.Luo BH, Carman CV, Springer TA. Structural basis of integrin regulation and signaling. Annu Rev Immunol. 2007;25:619–647. doi: 10.1146/annurev.immunol.25.022106.141618Fu G, Wang W, Luo BH. Overview: structural biology of integrins. Methods Mol Biol. 2012;757:81–99. doi: 10.1007/978-1-61779-166-6_7Huang C, Springer TA. Folding of the beta-propeller domain of the integrin alphaL subunit is independent of the I domain and dependent on the beta2 subunit. Proc Natl Acad Sci U S A. 1997;94(7):3162–3167. doi: 10.1073/pnas.94.7.3162Lu C, Oxvig C, Springer TA. The structure of the beta-propeller domain and C-terminal region of the integrin alphaM subunit. Dependence on beta subunit association and prediction of domains. J Biol Chem. 1998;273(24):15138–15147. doi: 10.1074/jbc.273.24.15138Kamata T, Tieu KK, Irie A, Springer TA, Takada Y. Amino acid residues in the alpha IIb subunit that are critical for ligand binding to integrin alpha IIbbeta 3 are clustered in the beta-propeller model. J Biol Chem. 2001;276(47):44275–44283. doi: 10.1074/jbc.M107021200Masunaga T, Ogawa J, Akiyama M, Nishikawa T, Shimizu H, Ishiko A. Compound heterozygosity for novel splice site mutations of ITGA6 in lethal junctional epidermolysis bullosa with pyloric atresia. J Dermatol. 2017;44(2):160–166. doi: 10.1111/1346-8138.13575Vaz SO, Dâmaso C, Liu L, Ozoemena L, Mota-Vieira L. Severe phenotype of junctional epidermolysis bullosa generalised intermediate type caused by homozygous COL17A1:c.505C>T (p.Arg169*) mutation. Eur J Dermatol. 2018;28(3):412–413. doi: 10.1684/ejd.2018.3279Dang N, Klingberg S, Rubin AI, Edwards M, Borelli S, Relic J, et al. Differential expression of pyloric atresia in junctional epidermolysis bullosa with ITGB4 mutations suggests that pyloric atresia is due to factors other than the mutations and not predictive of a poor outcome: three novel mutations and a review of the literature. Acta Derm Venereol. 2008;88(5):438–448. doi: 10.2340/00015555-0484Schumann H, Kiritsi D, Pigors M, Hausser I, Kohlhase J, Peters J, et al. Phenotypic spectrum of epidermolysis bullosa associated with  integrin mutations. Br J Dermatol. 2013;169(1):115–124. doi: 10.1111/bjd.12317Hammersen J, Has C, Naumann-Bartsch N, Stachel D, Kiritsi D, Söder S, et al. Genotype, clinical course, and therapeutic decision making in 76 infants with severe generalized junctional epidermolysis bullosa. J Invest Dermatol. 2016;136(11):2150–2157. doi: 10.1016/j.jid.2016.06.609Pulkkinen L, Rouan F, Bruckner-Tuderman L, Wallerstein R, Garzon M, Brown T, et al. Novel ITGB4 mutations in lethal and nonlethal variants of epidermolysis bullosa with pyloric atresia: missense versus nonsense. Am J Hum Genet. 1998;63(5):1376–1387. doi: 10.1086/302116Mühle C, Jiang QJ, Charlesworth A, Bruckner-Tuderman L, Meneguzzi G, Schneider H. Novel and recurrent mutations in the laminin-5 genes causing lethal junctional epidermolysis bullosa: molecular basis and clinical course of Herlitz disease. Hum Genet. 2005;116(1-2):33–42. doi: 10.1007/s00439-004-1210-yVidal F, Baudoin C, Miquel C, Galliano MF, Christiano AM, Uitto J, et al. Cloning of the laminin alpha 3 chain gene (LAMA3) and identification of a homozygous deletion in a patient with Herlitz junctional epidermolysis bullosa. Genomics. 1995;30(2):273–280. doi: 10.1006/geno.1995.9877Vailly J, Pulkkinen L, Miquel C, Christiano AM, Gerecke D, Burgeson RE, et al. Identification of a homozygous one-basepair deletion in exon 14 of the LAMB3 gene in a patient with Herlitz junctional epidermolysis bullosa and prenatal diagnosis in a family at risk for recurrence. J Invest Dermatol. 1995;104(4):462–466. doi: 10.1111/1523-1747.ep12605898Takizawa Y, Shimizu H, Pulkkinen L, Suzumori K, Kakinuma H, Uitto J, et al. Combination of a novel frameshift mutation (1929delCA) and a recurrent nonsense mutation (W610X) of the LAMB3 gene in a Japanese patient with Herlitz junctional epidermolysis bullosa, and their application for prenatal testing. J Invest Dermatol. 1998;111(6):1239–1241. doi: 10.1038/sj.jid.5600370Takizawa Y, Pulkkinen L, Shimizu H, Lin L, Hagiwara S, Nishikawa T, et al. Maternal uniparental meroisodisomy in the LAMB3 region of chromosome 1 results in lethal junctional epidermolysis bullosa. J Invest Dermatol. 1998;110(5):828–831. doi: 10.1046/j.1523-1747.1998.00186.xTakizawa Y, Shimizu H, Pulkkinen L, Nonaka S, Kubo T, Kado Y, et al. Novel premature termination codon mutations in the laminin gamma2-chain gene (LAMC2) in Herlitz junctional epidermolysis bullosa. J Invest Dermatol. 1998;111(6):1233–1234. doi: 10.1046/j.1523-1747.1998.00438.xPosteraro P, De Luca N, Meneguzzi G, El Hachem M, Angelo C, Gobello T, et al. Laminin-5 mutational analysis in an Italian cohort of patients with junctional epidermolysis bullosa. J Invest Dermatol. 2004;123(4):639–648. doi: 10.1111/j.0022-202X.2004.23302.xCastori M, Floriddia G, De Luca N, Pascucci M, Ghirri P, Boccaletti V, et al. Herlitz junctional epidermolysis bullosa: laminin-5 mutational profile and carrier frequency in the Italian population. Br J Dermatol. 2008;158(1):38–44. doi: 10.1111/j.1365-2133.2007.08208.xMizushima H, Takamura H, Miyagi Y, Kikkawa Y, Yamanaka N, Yasumitsu H, et al. Identification of integrin-dependent and -independent cell adhesion domains in COOH-terminal globular region of laminin-5 alpha 3 chain. Cell Growth Differ. 1997;8(9):979–987.Nielsen PK, Gho YS, Hoffman MP, Watanabe H, Makino M, Nomizu M, et al. Identification of a major heparin and cell binding site in the LG4 module of the laminin alpha 5 chain. J Biol Chem. 2000;275(19):14517–14523. doi: 10.1074/jbc.275.19.14517Ruzzi L, Gagnoux-Palacios L, Pinola M, Belli S, Meneguzzi G, D'Alessio M, et al. A homozygous mutation in the integrin alpha6 gene in junctional epidermolysis bullosa with pyloric atresia. J Clin Invest. 1997;99(12):2826–2831. doi: 10.1172/JCI119474Aho S, Uitto J. Direct interaction between the intracellular domains of bullous pemphigoid antigen 2 (BP180) and beta 4 integrin, hemidesmosomal components of basal keratinocytes. Biochem Biophys Res Commun. 1998;243(3):694–699. doi: 10.1006/bbrc.1998.8162Spinardi L, Einheber S, Cullen T, Milner TA, Giancotti FG. A recombinant tail-less integrin beta 4 subunit disrupts hemidesmosomes but does not suppress alpha 6 beta 4-mediated cell adhesion to laminins. J Cell Biol. 1995;129(2):473–487. doi: 10.1083/jcb.129.2.473Culbertson MR. RNA surveillance. Unforeseen consequences for gene expression, inherited genetic disorders and cancer. Trends Genet. 1999;15(2):74–80. doi: 10.1016/s0168-9525(98)01658-8Urlaub G, Mitchell PJ, Ciudad CJ, Chasin LA. Nonsense mutations in the dihydrofolate reductase gene affect RNA processing. Mol Cell Biol. 1989;9(7):2868–2880. doi: 10.1128/mcb.9.7.2868-2880.1989Cui Y, Hagan KW, Zhang S, Peltz SW. Identification and characterization of genes that are required for the accelerated degradation of mRNAs containing a premature translational termination codon. Genes Dev. 1995;9(4):423–436. doi: 10.1101/gad.9.4.423McIntosh I, Hamosh A, Dietz HC. Nonsense mutations and diminished mRNA levels. Nat Genet. 1993;4(3):219. doi: 10.1038/ng0793-219Kivirikko S, McGrath JA, Baudoin C, Aberdam D, Ciatti S, Dunnill MG, et al. A homozygous nonsense mutation in the alpha 3 chain gene of laminin 5 (LAMA3) in lethal (Herlitz) junctional epidermolysis bullosa. Hum Mol Genet. 1995;4(5):959–962. doi: 10.1093/hmg/4.5.959Nakano A, Pulkkinen L, Murrell D, Rico J, Lucky AW, Garzon M, et al. Epidermolysis bullosa with congenital pyloric atresia: novel mutations in the beta 4 integrin gene (ITGB4) and genotype/phenotype correlations. Pediatr Res. 2001;49(5):618–626. doi: 10.1203/00006450-200105000-00003Pulkkinen L, Kurtz K, Xu Y, Bruckner-Tuderman L, Uitto J. Genomic organization of the integrin beta 4 gene (ITGB4): a homozygous splice-site mutation in a patient with junctional epidermolysis bullosa associated with pyloric atresia. Lab Invest. 1997;76(6): 823–833.Ellis C, Eason C, Snyder A, Siegel M, Pai GS, Ryan E, et al. Novel missense p.R252L mutation of ITGB4 compounded with known 3793+1G>A mutation associated with nonlethal epidermolysis bullosa-pyloric atresia with obstructive uropathy. JAAD Case Rep. 2021;11:63–68. doi: 10.1016/j.jdcr.2021.03.016Peters BP, Hartle RJ, Krzesicki RF, Kroll TG, Perini F, Balun JE, et al. The biosynthesis, processing, and secretion of laminin by human choriocarcinoma cells. J Biol Chem. 1985;260(27):14732–14742.Allegra M, Gagnoux-Palacios L, Gache Y, Roques S, Lestringant G, Ortonne JP, et al. Rapid decay of alpha6 integrin caused by a mis-sense mutation in the propeller domain results in severe junctional epidermolysis bullosa with pyloric atresia. J Invest Dermatol. 2003;121(6):1336–1343. doi: 10.1111/j.1523-1747.2003.12625.xVarki R, Sadowski S, Pfendner E, Uitto J. Epidermolysis bullosa. I. Molecular genetics of the junctional and hemidesmosomal variants. J Med Genet. 2006;43(8):641–652. doi: 10.1136/jmg.2005.039685Pulkkinen L, Uitto J. Heterozygosity for premature termination codon mutations in LAMB3 in siblings with non-lethal junctional epidermolysis bullosa. J Invest Dermatol. 1998;111(6):1244–1246. doi: 10.1046/j.1523-1747.1998.00399.xGache Y, Allegra M, Bodemer C, Pisani-Spadafora A, Prost Y de, Ortonne JP, et al. Genetic bases of severe junctional epidermolysis bullosa presenting spontaneous amelioration with aging. Hum Mol Genet. 2001;10(21):2453–2461. doi: 10.1093/hmg/10.21.2453McGrath JA, Ashton GH, Mellerio JE, Salas-Alanis JC, Swensson O, McMillan JR, et al. Moderation of phenotypic severity in dystrophic and junctional forms of epidermolysis bullosa through in-frame skipping of exons containing non-sense or frameshift mutations. J Invest Dermatol. 1999;113(3):314–321. doi: 10.1046/j.1523-1747.1999.00709.xSwensson O, Christophers E. Generalized atrophic benign epidermolysis bullosa in 2 siblings complicated by multiple squamous cell carcinomas. Arch Dermatol. 1998;134(2):199–203. doi: 10.1001/archderm.134.2.199Chavanas S, Gache Y, Vailly J, Kanitakis J, Pulkkinen L, Uitto J, et al. Splicing modulation of integrin beta4 pre-mRNA carrying a branch point mutation underlies epidermolysis bullosa with pyloric atresia undergoing spontaneous amelioration with ageing. Hum Mol Genet. 1999;8(11):2097–2105. doi: 10.1093/hmg/8.11.2097McGrath JA, Pulkkinen L, Christiano AM, Leigh IM, Eady RA, Uitto J. Altered laminin 5 expression due to mutations in the gene encoding the beta 3 chain (LAMB3) in generalized atrophic benign epidermolysis bullosa. J Invest Dermatol. 1995;104(4):467–474. doi: 10.1111/1523-1747.ep12605904McGarth JA, Christiano AM, Pulkkinen L, Eady RA, Uitto J. Compound heterozygosity for nonsense ans missense mutations in the LAMB3 gene in nonlethal junctional epidermolysis bullosa. J Invest Dermatol. 1996;106(5):1157–1159. doi: 10.1111/1523-1747.ep12340210Wu Y, Li G, Zhu X. A novel homozygous point mutation in the COL17A1 gene in a Chinese family with generalized atrophic benign epidermolysis bullosa. J Dermatol Sci. 2002;28(3):181–186. doi: 10.1016/s0923-1811(01)00163-3McGrath JA, Gatalica B, Li K, Dunnill MG, McMillan JR, Christiano AM, et al. Compound heterozygosity for a dominant glycine substitution and a recessive internal duplication mutation in the type XVII collagen gene results in junctional epidermolysis bullosa and abnormal dentition. Am J Pathol. 1996;148(6):1787–1796.Castiglia D, Posteraro P, Spirito F, Pinola M, Angelo C, Puddu P, et al. Novel mutations in the LAMC2 gene in non-Herlitz junctional epidermolysis bullosa: effects on laminin-5 assembly, secretion, and deposition. J Invest Dermatol. 2001;117(3):731–739. doi: 10.1046/j.0022-202x.2001.01453.xGagnoux-Palacios L, Allegra M, Spirito F, Pommeret O, Romero C, Ortonne JP, et al. The short arm of the laminin gamma2 chain plays a pivotal role in the incorporation of laminin 5 into the extracellular matrix and in cell adhesion. J Cell Biol. 2001;153(4):835–850. doi: 10.1083/jcb.153.4.835Leusden MR van, Pas HH, Gedde-Dahl T Jr, Sonnenberg A, Jonkman MF. Truncated typeXVII collagen expression in a patient with non-herlitz junctional epidermolysis bullosa caused by a homozygous splice-site mutation. Lab Invest. 2001;81(6):887–894. doi: 10.1038/labinvest.3780297Whittock NV, Sher C, Gold I, Libman V, Reish O. A founder COL17A1 splice site mutation leading to generalized atrophic benign epidermolysis bullosa in an extended inbred Palestinian family from Israel. Genet Med. 2003;5(6):435–439. doi: 10.1097/01.gim.0000096494.61125.d8Pulkkinen L, Marinkovich MP, Tran HT, Lin L, Herron GS, Uitto J. Compound heterozygosity for novel splice site mutations in the BPAG2/COL17A1 gene underlies generalized atrophic benign epidermolysis bullosa. J Invest Dermatol. 1999;113(6):1114–1118. doi: 10.1046/j.1523-1747.1999.00793.xSchumann H, Hammami-Hauasli N, Pulkkinen L, Mauviel A, Küster W, Lüthi U, et al. Three novel homozygous point mutations and a new polymorphism in the COL17A1 gene: relation to biological and clinical phenotypes of junctional epidermolysis bullosa. Am J Hum Genet. 1997;60(6):1344–1353. doi: 10.1086/515463Pasmooij AMG, Pas HH, Deviaene FCL, Nijenhuis M, Jonkman MF. Multiple correcting COL17A1 mutations in patients with revertant mosaicism of epidermolysis bullosa. Am J Hum Genet. 2005;77(5):727–740. doi: 10.1086/497344Jonkman MF, Scheffer H, Stulp R, Pas HH, Nijenhuis M, Heeres K, et al. Revertant mosaicism in epidermolysis bullosa caused by mitotic gene conversion. Cell. 1997;88(4):543–551. doi: 10.1016/s0092-8674(00)81894-2Pulkkinen L, Christiano AM, Airenne T, Haakana H, Tryggvason K, Uitto J. Mutations in the gamma 2 chain gene (LAMC2) of kalinin/laminin 5 in the junctional forms of epidermolysis bullosa. Nat Genet. 1994;6(3):293–297. doi: 10.1038/ng0394-293Inoue M, Tamai K, Shimizu H, Owaribe K, Nakama T, Hashimoto T, et al. A homozygous missense mutation in the cytoplasmic tail of beta4 integrin, G931D, that disrupts hemidesmosome assembly and underlies Non-Herlitz junctional epidermolysis bullosa without pyloric atresia? J Invest Dermatol. 2000;114(5):1061–1064. doi: 10.1046/j.1523-1747.2000.00960-3.xYu Y, Wang Z, Mi Z, Sun L, Fu X, Yu G, et al. Epidermolysis bullosa in Chinese patients: Genetic analysis and mutation landscape in 57 pedigrees and sporadic cases. Acta Derm Venereol. 2021;101(7):adv00503. doi: 10.2340/00015555-3843Scaturro M, Posteraro P, Mastrogiacomo A, Zaccaria ML, De Luca N, Mazzanti C, et al. A missense mutation (G1506E) in the adhesion G domain of laminin-5 causes mild junctional epidermolysis bullosa. Biochem Biophys Res Commun. 2003;309(1):96–103. doi: 10.1016/s0006-291x(03)01533-xPosteraro P, Sorvillo S, Gagnoux-Palacios L, Angelo C, Paradisi M, Meneguzzi G, et al. Compound heterozygosity for an out-of-frame deletion and a splice site mutation in the LAMB3 gene causes nonlethal junctional epidermolysis bullosa. Biochem Biophys Res Commun. 1998;243(3):758–764. doi: 10.1006/bbrc.1998.8180Mellerio JE, Pulkkinen L, McMillan JR, Lake BD, Horn HM, Tidman MJ, et al. Pyloric atresia-junctional epidermolysis bullosa syndrome: mutations in the integrin beta4 gene (ITGB4) in two unrelated patients with mild disease. Br J Dermatol. 1998;139(5):862–871. doi: 10.1046/j.1365-2133.1998.02515.xTasanen K, Floeth M, Schumann H, Bruckner-Tuderman L. Hemizygosity for a glycine substitution in collagen XVII: unfolding and degradation of the ectodomain. J Invest Dermatol. 2000;115(2):207–212. doi: 10.1046/j.1523-1747.2000.00049.xYuen WY, Pas HH, Sinke RJ, Jonkman MF. Junctional epidermolysis bullosa of late onset explained by mutations in COL17A1. Br J Dermatol. 2011;164(6):1280–1284. doi: 10.1111/j.1365-2133.2011.10359.xVanotti S, Chiaverini C, Charlesworth A, Bonnet N, Berbis P, Meneguzzi G, et al. Late-onset skin fragility in childhood: a case of junctional epidermolysis bullosa of late onset caused by a missense mutation in COL17A1. Br J Dermatol. 2013;169(3):714–715. doi: 10.1111/bjd.12353Väisänen L, Has C, Franzke C, Hurskainen T, Tuomi ML, Bruckner-Tuderman L, et al. Molecular mechanisms of junctional epidermolysis bullosa: Col 15 domain mutations decrease the thermal stability of collagen XVII. J Invest Dermatol. 2005;125(6):1112–1118. doi: 10.1111/j.0022-202X.2005.23943.xTasanen K, Eble JA, Aumailley M, Schumann H, Baetge J, Tu H, et al. Collagen XVII is destabilized by a glycine substitution mutation in the cell adhesion domain Col15. J Biol Chem. 2000;275(5):3093–3099. doi: 10.1074/jbc.275.5.3093Huilaja L, Hurskainen T, Autio-Harmainen H, Sormunen R, Tu H, Hofmann SC, et al. Glycine substitution mutations cause intracellular accumulation of collagen XVII and affect its post-translational modifications. J Invest Dermatol. 2009;129(9):2302–2306. doi: 10.1038/jid.2009.22Pulkkinen L, Jonkman MF, McGrath JA, Kuijpers A, Paller AS, Uitto J. LAMB3 mutations in generalized atrophic benign epidermolysis bullosa: consequences at the mRNA and protein levels. Lab Invest. 1998;78(7):859–867.Hou PC, Natsuga K, Tu WT, Huang HY, Chen B, Chen LY, et al. Complexity of transcriptional and translational interference of laminin-332 subunits in junctional epidermolysis bullosa with LAMB3 mutations. Acta Derm Venereol. 2021;101(8):adv00522. doi: 10.2340/00015555-3874Mazzanti 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.xPasmooij AMG, Zalen S van, Nijenhuis AM, Kloosterhuis AJ, Zuiderveen J, Jonkman MF, et al. A very mild form of non-Herlitz junctional epidermolysis bullosa: BP180 rescue by outsplicing of mutated exon 30 coding for the COL15 domain. Exp Dermatol. 2004;13(2):125–128. doi: 10.1111/j.0906-6705.2004.00141.xDietz HC, Kendzior RJ Jr. Maintenance of an open reading frame as an additional level of scrutiny during splice site selection. Nat Genet. 1994;8(2):183–188. doi: 10.1038/ng1094-183Kiritsi D, Kern JS, Schumann H, Kohlhase J, Has C, Bruckner-Tuderman L. Molecular mechanisms of phenotypic variability in junctional epidermolysis bullosa. J Med Genet. 2011;48(7):450–457. doi: 10.1136/jmg.2010.086751Franzke CW, Has C, Schulte C, Huilaja L, Tasanen K, Aumailley M, et al. C-terminal truncation impairs glycosylation of transmembrane collagen XVII and leads to intracellular accumulation. J Biol Chem. 2006;281(40):30260–30268. doi: 10.1074/jbc.M604464200Коталевская Ю.Ю., Марычева Н.М. Трудности дифференциальной диагностики подтипов пограничного типа буллезного эпидермолиза: описание двух клинических наблюдений. Альманах клинической медицины. 2019;47(1):83–93 [Kotalevskaya YuYu, Marycheva NM. Challenges of the differential diagnosis between the subtypes of the junctional epidermolysis bullosa: presentation of two clinical cases. Al'manah klinicheskoj mediciny. 2019;47(1):83–93. (In Russ.)] doi: 10.18786/2072-0505-2019-47-009Kubanov AA, Karamova AE, Chikin VV, Monchakovskaya ES, Nefedova MA. Efficacy of intradermal allogeneic fibroblast injections in junctional epidermolysis bullosa. Russian Open Medical Journal. 2022;11(3):e0315. doi: 10.15275/rusomj.2022.0315Кубанов 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 Российской академии медицинских наук. 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. Vestnik Rossijskoj akademii medicinskih nauk. 2018;73(6):420–430. (In Russ.)] doi: 10.15690/vramn980Гаджимурадова К.М., Иванова М.А., Гаджимурадов М.Н., Алиева С.Н. Клинические и эпидемиологические особенности врожденного буллезного эпидермолиза в Республике Дагестан. Лечащий Врач. 2022;2(25):54–63. [Gadzhimuradova KM, Ivanova MA, Gadzhimuradov MN, Alieva SN. Clinical and epidemiological features of congenital epidermolysis bullosa in the Republic of Dagestan. Lechashhij Vrach. 2022;2(25)54–63. (In Russ.)] doi: 10.51793/OS.2022.25.2.009