Network                                              Kindlernet         Epidermolysis bullosaMolecular Heterogeneity of Bl...
•  Epidermolysis bullosa (EB): clinical and molecular   heterogeneity, „classical“ types of EB•  EB Center Freiburg: diagn...
Epidermolysis bullosa hereditaria (EB)                   • Clinically and genetically heterogeneous                   grou...
EB classification: 4 main typesmutations in 16 genes cause more than 30 EB subtypes        EB simplex   Junctional EB     ...
Molecular heterogeneity of EBComplexity of epidermal and dermo-epidermal adhesion                                         ...
EB simplex:    75 % of cases caused by keratin 5 or keratin 14 mutations     localized                        Dowling-Mear...
Junctional EB:molecular heterogeneity and spectrum of collagen XVII mutations                                             ...
Junctional EB:molecular heterogeneity and spectrum of laminin-332 mutations  Loss-of-function mutations: lethal junctional...
Dystrophic EB:  spectrum of phenotypes due to collagen VII mutations                                                    re...
Epidermolysis bullosa Center Freiburg                           Department of Dermatology                                 ...
EB Center Freiburg> 700 EB patients with precise diagnostic and known mutations               EB diagnostics and patient v...
Molecular diagnostics of EB    Immunofluorescence mappinglevel of blister formation and defective protein            Mutat...
Early diagnosis of EB in newborn    EB simplex                       junctional EB non Herlitz  good prognosis            ...
Late diagnosis of mild forms of EB                                     14
New and rare EB subtypes•  Novel human disorder with junctional EB, kidney and   lung involvement•  Molecular heterogeneit...
Novel human disorder withjunctional EB, kidney and lung         involvement                                 16
mechanically induced blisters starting at the age of 3 monthssparse hair, nail dystrophy4 months                5 months  ...
Neonatal respiratory distress        day 1                            3 monthsRX                    RX                    ...
• junctional cleavage with laminin-332 at blister base and roof                                         • disorganized lam...
Integrin alpha3 - knockout mice:abnormal kidney and lung organogenesis and skin blistering with            disorganized sk...
Homozygous integrin alpha3 mutation:                          loss of protein expressionIntegrin alpha3 /Nuclei   Integrin...
Integrin alpha3Cell-matrix and cell-cell adhesions Skin                                  Podocyte                  Machuca...
Loss of integrin alpha3:           Anomalies of the basement membranes in skin, kidney and lung                           ...
Control         Patient                                           24          Has et al., N Engl J Med, 2012
Integrin alpha3 mutations:   new disorder with kidney, lung and skin involvementPatients                   Patient 1      ...
Molecular heterogeneity of  lethal acantholytic EB                             26
Lethal acantholytic EB   molecular heterogeneity: desmoplakin or plakoglobin mutationsdesmoplakin mutations               ...
Loss of plakoglobin affects desmosomal proteins                                           Control   Patient               ...
Kindler syndrome    with a particular pattern ofdisseminated revertant mosaicism                                   29
Kindler syndrome - kindlin-1 mutations              progressive phenotype:blistering, poikiloderma, scarring and skin canc...
Disseminated pattern of revertant mosaicism in            Kindler syndrome ?                                              ...
Normal appearing skin represents revertant mosaicism:restoration of kindlin-1 expression; normalisation of skin morphology...
Reversion mechanism:back mutations in nucleotide repeats                                                         33       ...
Molecular heterogeneity of           EB simplex•  25% of patients without keratin 5 or 14   mutations: molecular basis?•  ...
EB simplex-Ogna: an unrecognized disease                                                                       35         ...
EB simplex – Ogna: plectin mutation p.R2000Wreduced or preserved signal with plectin domain specific antibodies           ...
Acral peeling skin syndrome may resemble           localised EB simplex in childrenAcral peeling skin syndrome            ...
38
Acral peeling skin syndrome:superficial blisters due to transglutaminase 5 mutations d                                    ...
Epidermolysis Bullosa diagnostic team        EB Center Freiburg              Dimitra Kiritsi            Manuela Pigors    ...
AcknowledgementsHeidelberg                     Ann ArborIngrid Hausser                 Friedhelm HildebrandtBeate Straub  ...
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Молекулярная гетерогенность пузырчаток: парадигма буллезного эпидермолиза (Molecular Heterogeneity of Blistering Disorders: The Paradigm of Epidermolysis Bullosa)

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Материалы с I Евразийской Конференции по редким заболеваниям и редким лекарствам и III Всероссийской Конференции по редким заболеваниям и редко применяемым медицинским технологиям
«Дорога жизни».
21-23 июня 2012 года в гостиничном комплексе «Измайлово»

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Молекулярная гетерогенность пузырчаток: парадигма буллезного эпидермолиза (Molecular Heterogeneity of Blistering Disorders: The Paradigm of Epidermolysis Bullosa)

  1. 1. Network Kindlernet Epidermolysis bullosaMolecular Heterogeneity of Blistering Disorders: the Paradigm of Epidermolysis bullosa Cristina Has Department of Dermatology University of Freiburg, Germany Moskow 22.06.2012 1
  2. 2. •  Epidermolysis bullosa (EB): clinical and molecular heterogeneity, „classical“ types of EB•  EB Center Freiburg: diagnostic and patient care•  New and rare EB subtypes 2
  3. 3. Epidermolysis bullosa hereditaria (EB) • Clinically and genetically heterogeneous group of genodermatoses characterized by mucocutaneous blistering and chronic epithelial fragility • Intraepidermal or dermo-epidermal tissue separation 3
  4. 4. EB classification: 4 main typesmutations in 16 genes cause more than 30 EB subtypes EB simplex Junctional EB Dystrophic EB Kindler syndrome 4 Has and Bruckner-Tuderman, J Invest Dermatol in press
  5. 5. Molecular heterogeneity of EBComplexity of epidermal and dermo-epidermal adhesion 5
  6. 6. EB simplex: 75 % of cases caused by keratin 5 or keratin 14 mutations localized Dowling-Meara Dowling-Meara daughter motherDowling-Meara Dowling-Meara generalized mottled pigmentation recessive 6 Has, Bruckner-Tuderman and Uitto, Rimoin‘s Principles and Practice of Medical Genetics
  7. 7. Junctional EB:molecular heterogeneity and spectrum of collagen XVII mutations 7 Has and Bruckner-Tuderman, in press
  8. 8. Junctional EB:molecular heterogeneity and spectrum of laminin-332 mutations Loss-of-function mutations: lethal junctional EB Herlitz Missense or / and splicing mutations: junctional EB non-Herlitz 8 Has, Bruckner-Tuderman and Uitto, Rimoin‘s Principles and Practice of Medical Genetics
  9. 9. Dystrophic EB: spectrum of phenotypes due to collagen VII mutations recessive dystrophic EB loss-of-function mutationsdominant dystrophic EB gylcine substitutions In frame deletions 9 Has, Bruckner-Tuderman and Uitto, Rimoin‘s Principles and Practice of Medical Genetics
  10. 10. Epidermolysis bullosa Center Freiburg Department of Dermatology EB team Physicians Lab teamCoordination Social work Nursing Documentation 10
  11. 11. EB Center Freiburg> 700 EB patients with precise diagnostic and known mutations EB diagnostics and patient visits 2004 - 2011 225 200 175 150 125 100 75 50 25 0 04 05 06 07 08 09 10 11 20 20 20 20 20 20 20 20 Mutation analyses Immunofluorescence mappings Patient visits 11
  12. 12. Molecular diagnostics of EB Immunofluorescence mappinglevel of blister formation and defective protein Mutation analysis precise molecular defect 12
  13. 13. Early diagnosis of EB in newborn EB simplex junctional EB non Herlitz good prognosis good prognosis junctional EB Herlitz severe recessive dystrophic EB lethal severe prognosis 13 Has, Bruckner-Tuderman and Uitto, Rimoin‘s Principles and Practice of Medical Genetics
  14. 14. Late diagnosis of mild forms of EB 14
  15. 15. New and rare EB subtypes•  Novel human disorder with junctional EB, kidney and lung involvement•  Molecular heterogeneity of lethal acantholytic EB•  Kindler syndrome: disseminated pattern of revertant mosaicism•  Molecular heterogeneity of EB simplex: EB simplex-Ogna and acral peeling skin syndrome 15
  16. 16. Novel human disorder withjunctional EB, kidney and lung involvement 16
  17. 17. mechanically induced blisters starting at the age of 3 monthssparse hair, nail dystrophy4 months 5 months 17 Has et al., N Engl J Med, 2012
  18. 18. Neonatal respiratory distress day 1 3 monthsRX RX HRCT Congenital nephrotic syndrome – peritoneal dialysis day 14 Control Patient Kidney H&E Mutations excluded in NPHS2, WT1, CFTR und ABCA3 18 Has et al., N Engl J Med, 2012
  19. 19. • junctional cleavage with laminin-332 at blister base and roof • disorganized laminin-332 Control PatientLaminin-332 /Nuclei 19 Has et al., N Engl J Med, 2012
  20. 20. Integrin alpha3 - knockout mice:abnormal kidney and lung organogenesis and skin blistering with disorganized skin basement membrane Wildtyp Integrin alpha3 KO Laminin-332 Wildtyp Integrin alpha3 KO Integrin alpha3 KO Kreidberg et al., Development 1996 DiPersio et al., J Cell Biol 1997 20
  21. 21. Homozygous integrin alpha3 mutation: loss of protein expressionIntegrin alpha3 /Nuclei Integrin alpha3 – gene - exon 8 Integrin alpha3 / Nuclei Skin Control Kidney Lung Control Control Patient Patient Patient c.1173_1174del p.Pro392ValfsX2 21 Has et al., N Engl J Med, 2012
  22. 22. Integrin alpha3Cell-matrix and cell-cell adhesions Skin Podocyte Machuca E et al. Hum. Mol. Genet. 2009;18:R185-R194 22
  23. 23. Loss of integrin alpha3: Anomalies of the basement membranes in skin, kidney and lung - Collagen IV staining - Skin Kidney LungControl Patient 23 Has et al., N Engl J Med, 2012
  24. 24. Control Patient 24 Has et al., N Engl J Med, 2012
  25. 25. Integrin alpha3 mutations: new disorder with kidney, lung and skin involvementPatients Patient 1 Patient 2 Patient 3ITGA3 mutations c.1173_1174del c.1538-1G>A c.1883G>C p.Pro392ValfsX2 p.Arg628ProOrigin Southern Italy Gaza PakistanClinical featuresKidney Congenital nephrotic Congenital nephrotic Congenital nephrotic syndrome syndrome syndrome Peritoneal dialysis Peritoneal dialysis Peritoneal dialysisLung Respiratory distress, Respiratory distress, Respiratory distress, oxygen-dependent, oxygen-dependent oxygen-dependent, aspiration pneumonia, aspiration pneumonia, recurrent respiratory recurrent respiratory infections infectionsSkin Blisters, nail dystrophy Persistent erosions on Blisters, nail dystrophy the buttocksDemise 7 ½ months 4 months 19 months 25 Has et al., N Engl J Med, 2012
  26. 26. Molecular heterogeneity of lethal acantholytic EB 26
  27. 27. Lethal acantholytic EB molecular heterogeneity: desmoplakin or plakoglobin mutationsdesmoplakin mutations plakoglobin mutationsJonkman et al, AmJ Hum Genet 2005 Pigors et al, Hum Mol Genet 2011Bolling et al, J Invest Dermatol 2010 JUP Junction Plakoglobin c.1615 C>T; p.Q539X 27
  28. 28. Loss of plakoglobin affects desmosomal proteins Control Patient Plakoglobin Control Patient Control Patient Desmoplakin E-cadherinDesmoglein 3 a catenin 28 Pigors et al, Hum Mol Genet 2011
  29. 29. Kindler syndrome with a particular pattern ofdisseminated revertant mosaicism 29
  30. 30. Kindler syndrome - kindlin-1 mutations progressive phenotype:blistering, poikiloderma, scarring and skin cancer 30 Has et al, Hum Mut 2011
  31. 31. Disseminated pattern of revertant mosaicism in Kindler syndrome ? 31 Kiritsi et al, J Clin Invest 2012
  32. 32. Normal appearing skin represents revertant mosaicism:restoration of kindlin-1 expression; normalisation of skin morphology, proliferation and dermo-epidermal junction 32 Kiritsi et al, J Clin Invest 2012
  33. 33. Reversion mechanism:back mutations in nucleotide repeats 33 Kiritsi et al, J Clin Invest 2012
  34. 34. Molecular heterogeneity of EB simplex•  25% of patients without keratin 5 or 14 mutations: molecular basis?•  EB simplex-Ogna an unrecognized rare disease•  Acral peeling skin syndrome diagnosed as EB simplex in children 34
  35. 35. EB simplex-Ogna: an unrecognized disease 35 Kiritsi et al, J Invest Dermatol in press
  36. 36. EB simplex – Ogna: plectin mutation p.R2000Wreduced or preserved signal with plectin domain specific antibodies Plectin 10F6 GP21 Control Patient 36 Kiritsi et al, J Invest Dermatol in press
  37. 37. Acral peeling skin syndrome may resemble localised EB simplex in childrenAcral peeling skin syndrome EB simplex TGM5: p.G113C KRT14: p.L143P2y 2y 37 Kiritsi et al, J Invest Dermatol 2010
  38. 38. 38
  39. 39. Acral peeling skin syndrome:superficial blisters due to transglutaminase 5 mutations d 39 Pigors et al, J Invest Dermatol 2012
  40. 40. Epidermolysis Bullosa diagnostic team EB Center Freiburg Dimitra Kiritsi Manuela Pigors Franziska Schauer Yinghong He Gabriele Grüninger Vera Morand Margit Schubert Käthe Thoma Prof. Leena Bruckner-TudermanThank you for your attention! 40
  41. 41. AcknowledgementsHeidelberg Ann ArborIngrid Hausser Friedhelm HildebrandtBeate Straub Virginia Vega-Warner Tel AvivZürich Benjamin DekelGiuseppina SpartaLisa Weibel LondonAlexander Moeller Detlef BoeckenhauerGuido Laube Aoife Waters 41

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