Empfohlen
Empfohlen
Weitere ähnliche Inhalte
Ähnlich wie Молекулярная гетерогенность пузырчаток: парадигма буллезного эпидермолиза (Molecular Heterogeneity of Blistering Disorders: The Paradigm of Epidermolysis Bullosa)
Ähnlich wie Молекулярная гетерогенность пузырчаток: парадигма буллезного эпидермолиза (Molecular Heterogeneity of Blistering Disorders: The Paradigm of Epidermolysis Bullosa) (20)
Kürzlich hochgeladen
Kürzlich hochgeladen (20)
Молекулярная гетерогенность пузырчаток: парадигма буллезного эпидермолиза (Molecular Heterogeneity of Blistering Disorders: The Paradigm of Epidermolysis Bullosa)
- 1. Network Kindlernet Epidermolysis bullosa Molecular Heterogeneity of Blistering Disorders: the Paradigm of Epidermolysis bullosa Cristina Has Department of Dermatology University of Freiburg, Germany Moskow 22.06.2012 1
- 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. 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. EB classification: 4 main types mutations 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. Molecular heterogeneity of EB Complexity of epidermal and dermo-epidermal adhesion 5
- 6. EB simplex: 75 % of cases caused by keratin 5 or keratin 14 mutations localized Dowling-Meara Dowling-Meara daughter mother Dowling-Meara Dowling-Meara generalized mottled pigmentation recessive 6 Has, Bruckner-Tuderman and Uitto, Rimoin‘s Principles and Practice of Medical Genetics
- 7. Junctional EB: molecular heterogeneity and spectrum of collagen XVII mutations 7 Has and Bruckner-Tuderman, in press
- 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. Dystrophic EB: spectrum of phenotypes due to collagen VII mutations recessive dystrophic EB loss-of-function mutations dominant dystrophic EB gylcine substitutions In frame deletions 9 Has, Bruckner-Tuderman and Uitto, Rimoin‘s Principles and Practice of Medical Genetics
- 10. Epidermolysis bullosa Center Freiburg Department of Dermatology EB team Physicians Lab team Coordination Social work Nursing Documentation 10
- 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. Molecular diagnostics of EB Immunofluorescence mapping level of blister formation and defective protein Mutation analysis precise molecular defect 12
- 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. Late diagnosis of mild forms of EB 14
- 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. Novel human disorder with junctional EB, kidney and lung involvement 16
- 17. mechanically induced blisters starting at the age of 3 months sparse hair, nail dystrophy 4 months 5 months 17 Has et al., N Engl J Med, 2012
- 18. Neonatal respiratory distress day 1 3 months RX 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. • junctional cleavage with laminin-332 at blister base and roof • disorganized laminin-332 Control Patient Laminin-332 /Nuclei 19 Has et al., N Engl J Med, 2012
- 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. Homozygous integrin alpha3 mutation: loss of protein expression Integrin 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. Integrin alpha3 Cell-matrix and cell-cell adhesions Skin Podocyte Machuca E et al. Hum. Mol. Genet. 2009;18:R185-R194 22
- 23. Loss of integrin alpha3: Anomalies of the basement membranes in skin, kidney and lung - Collagen IV staining - Skin Kidney Lung Control Patient 23 Has et al., N Engl J Med, 2012
- 24. Control Patient 24 Has et al., N Engl J Med, 2012
- 25. Integrin alpha3 mutations: new disorder with kidney, lung and skin involvement Patients Patient 1 Patient 2 Patient 3 ITGA3 mutations c.1173_1174del c.1538-1G>A c.1883G>C p.Pro392ValfsX2 p.Arg628Pro Origin Southern Italy Gaza Pakistan Clinical features Kidney Congenital nephrotic Congenital nephrotic Congenital nephrotic syndrome syndrome syndrome Peritoneal dialysis Peritoneal dialysis Peritoneal dialysis Lung Respiratory distress, Respiratory distress, Respiratory distress, oxygen-dependent, oxygen-dependent oxygen-dependent, aspiration pneumonia, aspiration pneumonia, recurrent respiratory recurrent respiratory infections infections Skin Blisters, nail dystrophy Persistent erosions on Blisters, nail dystrophy the buttocks Demise 7 ½ months 4 months 19 months 25 Has et al., N Engl J Med, 2012
- 26. Molecular heterogeneity of lethal acantholytic EB 26
- 27. Lethal acantholytic EB molecular heterogeneity: desmoplakin or plakoglobin mutations desmoplakin mutations plakoglobin mutations Jonkman et al, AmJ Hum Genet 2005 Pigors et al, Hum Mol Genet 2011 Bolling et al, J Invest Dermatol 2010 JUP Junction Plakoglobin c.1615 C>T; p.Q539X 27
- 28. Loss of plakoglobin affects desmosomal proteins Control Patient Plakoglobin Control Patient Control Patient Desmoplakin E-cadherin Desmoglein 3 a catenin 28 Pigors et al, Hum Mol Genet 2011
- 29. Kindler syndrome with a particular pattern of disseminated revertant mosaicism 29
- 30. Kindler syndrome - kindlin-1 mutations progressive phenotype: blistering, poikiloderma, scarring and skin cancer 30 Has et al, Hum Mut 2011
- 31. Disseminated pattern of revertant mosaicism in Kindler syndrome ? 31 Kiritsi et al, J Clin Invest 2012
- 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. Reversion mechanism: back mutations in nucleotide repeats 33 Kiritsi et al, J Clin Invest 2012
- 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. EB simplex-Ogna: an unrecognized disease 35 Kiritsi et al, J Invest Dermatol in press
- 36. EB simplex – Ogna: plectin mutation p.R2000W reduced or preserved signal with plectin domain specific antibodies Plectin 10F6 GP21 Control Patient 36 Kiritsi et al, J Invest Dermatol in press
- 37. Acral peeling skin syndrome may resemble localised EB simplex in children Acral peeling skin syndrome EB simplex TGM5: p.G113C KRT14: p.L143P 2y 2y 37 Kiritsi et al, J Invest Dermatol 2010
- 38. 38
- 39. Acral peeling skin syndrome: superficial blisters due to transglutaminase 5 mutations d 39 Pigors et al, J Invest Dermatol 2012
- 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-Tuderman Thank you for your attention! 40
- 41. Acknowledgements Heidelberg Ann Arbor Ingrid Hausser Friedhelm Hildebrandt Beate Straub Virginia Vega-Warner Tel Aviv Zürich Benjamin Dekel Giuseppina Sparta Lisa Weibel London Alexander Moeller Detlef Boeckenhauer Guido Laube Aoife Waters 41