Paroxysmal nocturnal hemoglobinuria: an acquired X-linked genetic disease with somatic-cell mosaicism

Luzzatto, Lucio

doi:10.1016/j.gde.2006.04.015

Cited by 52 publications

(43 citation statements)

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“…The identification of activating mutations in the gene coding for the tyrosine kinase JAK2 (JAK2-V617F and JAK2 exon 12 mutations) in almost all PV patients and in a large percentage of ET and PMF patients, [2][3][4][5][6][7] led to a series of follow-up studies to investigate their functional consequences. 8 Nevertheless, how a single mutation can contribute to the pathogenesis of three phenotypically distinct disease entities is still largely unclear.…”

Section: Molecular Basis and Clonal Evolution Of Myeloproliferative Nmentioning

confidence: 99%

“…These two proteins, being GPI-linked, are missing from the surface of PNH red cells as a result of a somatic mutation of the X-linked PIG-A gene, that encodes a protein required for an early step of the GPI molecule biosynthesis. 6 (B) In the steady state, PNH erythrocytes suffer from spontaneous (tick-over) complement activation, with consequent intravascular hemolysis through formation of the MAC; exacerbated hemolysis will result from activation of extra complement through the classical pathway. (C) On eculizumab, PNH erythrocytes are protected from hemolysis from the inhibition of C5 cleavage; however, upstream complement activation may lead to C3 opsonization and possible extravascular hemolysis.…”

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confidence: 99%

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Paroxysmal nocturnal hemoglobinuria and eculizumab

Luzzatto¹,

Risitano²,

Notaro³

2010

Haematologica

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Section: Molecular Basis and Clonal Evolution Of Myeloproliferative Nmentioning

confidence: 99%

mentioning

confidence: 99%

Paroxysmal nocturnal hemoglobinuria and eculizumab

Luzzatto¹,

Risitano²,

Notaro³

2010

Haematologica

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“…PNH stem cells that have an acquired PIG-A mutation generate little to no glycosylphosphatidylinositol (GPI) resulting in partial (type II) or complete (type III) deficiency of GPI-linked membrane proteins including the complement regulatory molecules decay-accelerating factor (DAF; CD55) and CD59. 1,2 The in vivo lifespan of PNH III erythrocytes is 6 days or more 3,4 and that of PNH II erythrocytes can be close to that of normal erythrocytes (120 days). 4 Unprotected foreign cells such as rabbit erythrocytes, which lack regulators of the human alternative pathway convertase as well as CD59, lyse in less than 5 minutes when exposed to normal human serum (NHS).…”

Section: Introductionmentioning

confidence: 96%

Factor H–mediated cell surface protection from complement is critical for the survival of PNH erythrocytes

Ferreira

Pangburn

2007

Blood

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IntroductionParoxysmal nocturnal hemoglobinuria (PNH) is an acquired stem-cell disorder of clonal nature. PNH stem cells that have an acquired PIG-A mutation generate little to no glycosylphosphatidylinositol (GPI) resulting in partial (type II) or complete (type III) deficiency of GPI-linked membrane proteins including the complement regulatory molecules decay-accelerating factor (DAF; CD55) and CD59. 1,2 The in vivo lifespan of PNH III erythrocytes is 6 days or more 3,4 and that of PNH II erythrocytes can be close to that of normal erythrocytes (120 days). 4 Unprotected foreign cells such as rabbit erythrocytes, which lack regulators of the human alternative pathway convertase as well as CD59, lyse in less than 5 minutes when exposed to normal human serum (NHS). Unprotected PNH erythrocytes are not, as would be expected, rapidly lysed by complement.Factor H (fH), a serum protein composed of 20 CCP domains, plays a key role in the homeostasis of the complement system on host-cell surfaces and in plasma. It controls activation of the alternative pathway through its 4 N-terminal domains, limiting formation of C3b by acting as a cofactor for factor I in the inactivation of C3b and by accelerating the decay of alternative pathway C3/C5 convertase (C3b,Bb). The sites on CCP domains 19 to 20 are essential for fH-mediated interaction with host cells [5][6][7][8] through the binding of both surface-bound polyanions and C3b, iC3b, or C3d. [9][10][11] We have shown 6 that a recombinant form of these C-terminal domains (rH19-20) competes with full-length fH, inhibiting its binding to C3b and host polyanions on cells. This leads to impaired fH complement-regulatory functions and increased complement activation on host surfaces, without affecting complement control in plasma. 6 Since PNH III cells survive longer than expected for cells that are devoid of GPI-linked membrane-bound regulatory proteins, we examined the contribution of fH to their extended half-life by specifically inhibiting fH-mediated cell surface protection with rH19-20. Patients, materials, and methods Human erythrocytesBlood from 4 patients with PNH and 2 healthy adults was collected by venipuncture and the erythrocytes were frozen at Ϫ80°C by standard methods. 12 All PNH patients had positive acidified serum tests for PNH. 13 The University of Texas Health Science Center institutional review board approved protocols, and written informed consent was obtained from all donors in accordance with the Declaration of Helsinki. All samples used in this study were collected prior to 1986 and have been stored frozen since then. Proteins and buffersC-terminal domains 19 and 20 of human fH (rH19-20) were cloned, expressed in yeast, and purified as described. 14 Human fH was purified from NHS. 15 The following buffers were used: VBS, 5 mM veronal, 145 mM NaCl, 0.02% NaN 3 , pH 7.3; GVB, VBS containing 0.1% gelatin; GVBE, GVB containing 10 mM EDTA (ethylenediaminetetraacetic acid); MgEGTA, 0.1 M MgCl 2 , 0.1 M EGTA (ethyleneglycoltetraacetic acid), pH 7.3. Hemolytic ...

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“…Patients with the acquired deficiency have a clonal red cell population lacking GPI anchored proteins, including CD59 and DAF, and the clinical disorder paroxysmal nocturnal hemoglobinuria (PNH). 189 …”

Section: Decay Accelerating Factor (Cd55) Deficiencymentioning

confidence: 99%