A new form of inherited thrombocytopenia caused by loss-of-function mutations in <em>PTPRJ</em>

Caterina Marconi, Christian A. Di Buduo, Kellie LeVine, Serena Barozzi, Michela Faleschini, Valeria Bozzi, Flavia Palombo, Spencer McKinstry, Giuseppe Lassandro, Paola Giordano, Patrizia Noris, Carlo L. Balduini, Anna Savoia, Alessandra Balduini, Tommaso Pippucci, Marco Seri, Nicholas Katsanis, Alessandro Pecci

Research output: Contribution to journalArticle

Abstract

Loss of the tyrosine phosphatase PTPRJ due to biallelic null mutations in its gene causes autosomal-recessive thrombocytopenia.Thrombocytopenia is characterized by small platelets and platelet dysfunction, and derives from multiple defects of megakaryocyte biology. 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 two siblings with autosomal recessive thrombocytopenia, we identified two biallelic loss-of-function variants in PTPRJ. This gene encodes for a receptor-like protein tyrosine phosphatase, PTPRJ (or CD148), expressed abundantly in platelets and megakaryocytes. Consistent with the predicted effects of the variants, both probands have an almost complete loss of PTPRJ both at the level of mRNA and protein. To investigate the pathogenic role of PTPRJ deficiency in hematopoiesis in vivo, we carried out CRISPR/Cas9-mediated ablation of ptprja (the ortholog of human PTPRJ) 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 PTPRJ in a human megakaryocytic cell line reproduced the functional defects observed in patients' megakaryocytes. The disorder caused by PTPRJ mutations presented as a non-syndromic 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 of PTPRJ in platelet biogenesis.
Original languageEnglish
Pages (from-to)blood-2018-07-859496
JournalBlood
DOIs
Publication statusPublished - Jan 1 2018

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Thrombocytopenia
Blood Platelets
Mutation
Megakaryocytes
Class 3 Receptor-Like Protein Tyrosine Phosphatases
Receptor-Like Protein Tyrosine Phosphatases
Clustered Regularly Interspaced Short Palindromic Repeats
Hemorrhage
Exome
src-Family Kinases
Hematopoiesis
Zebrafish
Platelet Count
Genes
Tyrosine
Siblings
Collagen
Cell Line
Messenger RNA
Proteins

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A new form of inherited thrombocytopenia caused by loss-of-function mutations in <em>PTPRJ</em> / Marconi, Caterina; Di Buduo, Christian A.; LeVine, Kellie; Barozzi, Serena; Faleschini, Michela; Bozzi, Valeria; Palombo, Flavia; McKinstry, Spencer; Lassandro, Giuseppe; Giordano, Paola; Noris, Patrizia; Balduini, Carlo L.; Savoia, Anna; Balduini, Alessandra; Pippucci, Tommaso; Seri, Marco; Katsanis, Nicholas; Pecci, Alessandro.

In: Blood, 01.01.2018, p. blood-2018-07-859496.

Research output: Contribution to journalArticle

Marconi, C, Di Buduo, CA, LeVine, K, Barozzi, S, Faleschini, M, Bozzi, V, Palombo, F, McKinstry, S, Lassandro, G, Giordano, P, Noris, P, Balduini, CL, Savoia, A, Balduini, A, Pippucci, T, Seri, M, Katsanis, N & Pecci, A 2018, 'A new form of inherited thrombocytopenia caused by loss-of-function mutations in <em>PTPRJ</em>', Blood, pp. blood-2018-07-859496. https://doi.org/10.1182/blood-2018-07-859496
Marconi, Caterina ; Di Buduo, Christian A. ; LeVine, Kellie ; Barozzi, Serena ; Faleschini, Michela ; Bozzi, Valeria ; Palombo, Flavia ; McKinstry, Spencer ; Lassandro, Giuseppe ; Giordano, Paola ; Noris, Patrizia ; Balduini, Carlo L. ; Savoia, Anna ; Balduini, Alessandra ; Pippucci, Tommaso ; Seri, Marco ; Katsanis, Nicholas ; Pecci, Alessandro. / A new form of inherited thrombocytopenia caused by loss-of-function mutations in <em>PTPRJ</em>. In: Blood. 2018 ; pp. blood-2018-07-859496.
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abstract = "Loss of the tyrosine phosphatase PTPRJ due to biallelic null mutations in its gene causes autosomal-recessive thrombocytopenia.Thrombocytopenia is characterized by small platelets and platelet dysfunction, and derives from multiple defects of megakaryocyte biology. 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 two siblings with autosomal recessive thrombocytopenia, we identified two biallelic loss-of-function variants in PTPRJ. This gene encodes for a receptor-like protein tyrosine phosphatase, PTPRJ (or CD148), expressed abundantly in platelets and megakaryocytes. Consistent with the predicted effects of the variants, both probands have an almost complete loss of PTPRJ both at the level of mRNA and protein. To investigate the pathogenic role of PTPRJ deficiency in hematopoiesis in vivo, we carried out CRISPR/Cas9-mediated ablation of ptprja (the ortholog of human PTPRJ) 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 PTPRJ in a human megakaryocytic cell line reproduced the functional defects observed in patients' megakaryocytes. The disorder caused by PTPRJ mutations presented as a non-syndromic 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 of PTPRJ in platelet biogenesis.",
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T1 - A new form of inherited thrombocytopenia caused by loss-of-function mutations in PTPRJ

AU - Marconi, Caterina

AU - Di Buduo, Christian A.

AU - LeVine, Kellie

AU - Barozzi, Serena

AU - Faleschini, Michela

AU - Bozzi, Valeria

AU - Palombo, Flavia

AU - McKinstry, Spencer

AU - Lassandro, Giuseppe

AU - Giordano, Paola

AU - Noris, Patrizia

AU - Balduini, Carlo L.

AU - Savoia, Anna

AU - Balduini, Alessandra

AU - Pippucci, Tommaso

AU - Seri, Marco

AU - Katsanis, Nicholas

AU - Pecci, Alessandro

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Loss of the tyrosine phosphatase PTPRJ due to biallelic null mutations in its gene causes autosomal-recessive thrombocytopenia.Thrombocytopenia is characterized by small platelets and platelet dysfunction, and derives from multiple defects of megakaryocyte biology. 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 two siblings with autosomal recessive thrombocytopenia, we identified two biallelic loss-of-function variants in PTPRJ. This gene encodes for a receptor-like protein tyrosine phosphatase, PTPRJ (or CD148), expressed abundantly in platelets and megakaryocytes. Consistent with the predicted effects of the variants, both probands have an almost complete loss of PTPRJ both at the level of mRNA and protein. To investigate the pathogenic role of PTPRJ deficiency in hematopoiesis in vivo, we carried out CRISPR/Cas9-mediated ablation of ptprja (the ortholog of human PTPRJ) 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 PTPRJ in a human megakaryocytic cell line reproduced the functional defects observed in patients' megakaryocytes. The disorder caused by PTPRJ mutations presented as a non-syndromic 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 of PTPRJ in platelet biogenesis.

AB - Loss of the tyrosine phosphatase PTPRJ due to biallelic null mutations in its gene causes autosomal-recessive thrombocytopenia.Thrombocytopenia is characterized by small platelets and platelet dysfunction, and derives from multiple defects of megakaryocyte biology. 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 two siblings with autosomal recessive thrombocytopenia, we identified two biallelic loss-of-function variants in PTPRJ. This gene encodes for a receptor-like protein tyrosine phosphatase, PTPRJ (or CD148), expressed abundantly in platelets and megakaryocytes. Consistent with the predicted effects of the variants, both probands have an almost complete loss of PTPRJ both at the level of mRNA and protein. To investigate the pathogenic role of PTPRJ deficiency in hematopoiesis in vivo, we carried out CRISPR/Cas9-mediated ablation of ptprja (the ortholog of human PTPRJ) 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 PTPRJ in a human megakaryocytic cell line reproduced the functional defects observed in patients' megakaryocytes. The disorder caused by PTPRJ mutations presented as a non-syndromic 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 of PTPRJ in platelet biogenesis.

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DO - 10.1182/blood-2018-07-859496

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SN - 0006-4971

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