TY - JOUR T1 - Loss-of-function mutations in cause a new form of inherited thrombocytopenia. JF - Blood Y1 - 2019 A1 - Marconi, Caterina A1 - Di Buduo, Christian A A1 - LeVine, Kellie A1 - Barozzi, Serena A1 - Faleschini, Michela A1 - Bozzi, Valeria A1 - Palombo, Flavia A1 - McKinstry, Spencer A1 - Lassandro, Giuseppe A1 - Giordano, Paola A1 - Noris, Patrizia A1 - Balduini, Carlo L A1 - Savoia, Anna A1 - Balduini, Alessandra A1 - Pippucci, Tommaso A1 - Seri, Marco A1 - Katsanis, Nicholas A1 - Pecci, Alessandro AB -

Inherited thrombocytopenias (ITs) are a heterogeneous group of disorders characterized by low platelet count that may result in bleeding tendency. Despite progress being made in defining the genetic causes of ITs, nearly 50% of patients with familial thrombocytopenia are affected with forms of unknown origin. Here, through exome sequencing of 2 siblings with autosomal-recessive thrombocytopenia, we identified biallelic loss-of-function variants in This gene encodes for a receptor-like PTP, PTPRJ (or CD148), which is expressed abundantly in platelets and megakaryocytes. Consistent with the predicted effects of the variants, both probands have an almost complete loss of PTPRJ at the messenger RNA and protein levels. To investigate the pathogenic role of PTPRJ deficiency in hematopoiesis in vivo, we carried out CRISPR/Cas9-mediated ablation of (the ortholog of human ) in zebrafish, which induced a significantly decreased number of CD41 thrombocytes in vivo. Moreover, megakaryocytes of our patients showed impaired maturation and profound defects in SDF1-driven migration and formation of proplatelets in vitro. Silencing of in a human megakaryocytic cell line reproduced the functional defects observed in patients' megakaryocytes. The disorder caused by mutations presented as a nonsyndromic thrombocytopenia characterized by spontaneous bleeding, small-sized platelets, and impaired platelet responses to the GPVI agonists collagen and convulxin. These platelet functional defects could be attributed to reduced activation of Src family kinases. Taken together, our data identify a new form of IT and highlight a hitherto unknown fundamental role for PTPRJ in platelet biogenesis.

VL - 133 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30591527?dopt=Abstract ER - TY - JOUR T1 - Clinical and pathogenetic features of ETV6 related thrombocytopenia with predisposition to acute lymphoblastic leukemia. JF - Haematologica Y1 - 2016 A1 - Melazzini, Federica A1 - Palombo, Flavia A1 - Balduini, Alessandra A1 - De Rocco, Daniela A1 - Marconi, Caterina A1 - Noris, Patrizia A1 - Gnan, Chiara A1 - Pippucci, Tommaso A1 - Bozzi, Valeria A1 - Faleschini, Michela A1 - Barozzi, Serena A1 - Doubek, Michael A1 - Di Buduo, Christian A A1 - Stano Kozubik, Katerina A1 - Radova, Lenka A1 - Loffredo, Giuseppe A1 - Pospisilova, Sarka A1 - Alfano, Caterina A1 - Seri, Marco A1 - Balduini, Carlo L A1 - Pecci, Alessandro A1 - Savoia, Anna AB -

ETV6-related thrombocytopenia (ETV6-RT) is an autosomal dominant thrombocytopenia that has been recently identified in a few families and has been suspected to predispose to hematological malignancies. To gain further information on this disorder, we searched for ETV6 mutations in the 130 families with inherited thrombocytopenia of unknown origin from our cohort of 274 consecutive pedigrees with familial thrombocytopenia. We identified 20 ETV6-RT patients from 7 pedigrees. They have 5 different ETV6 variants, including three novel mutations affecting the highly conserved E26 transformation-specific domain. The relative frequency of ETV6-RT resulted 2.6% in the whole case series and 4.6% among the families with known forms of inherited thrombocytopenia. The degree of thrombocytopenia and bleeding tendency of ETV6-RT patients were mild, but 4 subjects developed B-cell acute lymphoblastic leukemia during childhood, resulting in a significantly increased incidence compared to the general population. Clinical and laboratory findings did not identify any peculiar defects that can be used to suspect this disorder by routine diagnostic workup. However, at variance with most inherited thrombocytopenias, platelet size was not enlarged. In vitro studies revealed that patients megakaryocytes have defective maturation and impaired proplatelet formation. Moreover, ETV6-RT platelets have reduced ability to spread on fibrinogen. Since also the dominant thrombocytopenias due to mutations in RUNX1 and ANKRD26 are characterized by normal platelet size and predispose to hematological malignancies, we suggest that mutation screening of ETV6, RUNX1 and ANKRD26 should be performed in all the subjects with autosomal dominant thrombocytopenia and normal platelet size.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/27365488?dopt=Abstract ER -