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CN-LOH in PIGV causes PNH, in a case of ET and nephrotic syndrome
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International audience. Classical paroxysmal nocturnal hemoglobinura (PNH) is an acquired glycosylphosphatidylinositol (GPI) anchor deficiency in a hematopoietic stem cell (HSC) due to mutations in PIGA. However, the reasons for clonal expansion in an acquired loss of function of GPI biosynthesis, is still a matter of debate. Here we describe, how PNH also manifested in a patient with essential thrombocythemia (ET) after a copy number neutral loss-of-heterozygosity (CN-LOH) in PIGV, another gene of the GPI-anchor deficiency.Similar to other proliferative myeloid malignancies, the clonal expansion of the HSC with ET resulted in our case from a de novo mutation in MPL (p.W515L) on chromosome 1 (1p34.2). 16.7 MB upstream of the acquired MPL mutation in cis, the patient carried a heterozygous pathogenic mutation in PIGV (p.R469X, 1p36.11), congenitally. A somatic CN-LOH in the HSC comprised almost the entire p-arm of chromosome 1. Hence, the MPL mutation p.W5151L gained dominance and deteriorated ET and while homozygosity of p.R469X in PIGV resulted in a GPI-anchor deficiency and manifestation of PNH. In addition to ET and PNH, the patient presented with nephrotic syndrome that ceased after treatment with eculizumab and hydroxycarbamide. We determined the origin of kidney injury as a result of podocyte instability due to an increase of non-GPI linked soluble uPAR. In this report we identified PIGV as a novel gene causing PNH and provide insights into the pathomechanism of acquired GPI anchor deficiency and expansion of PNH cells. Furthermore, we discuss the contribution of PNH to kidney injury.
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