Loss-of-function mutations in PTPRJ cause a new form of inherited thrombocytopenia

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 in megakaryocyte biology.Publisher's Note: There is a Blood Commentary on this article in this issue.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 PTPRJ. 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 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 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.
Original languageUndefined/Unknown
Pages (from-to)1346-1357
Number of pages12
JournalBlood
Volume133
Issue number12
DOIs
Publication statusPublished - 2019

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Loss-of-function mutations in PTPRJ cause a new form of inherited thrombocytopenia. / 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, Vol. 133, No. 12, 2019, p. 1346-1357.

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 2019, 'Loss-of-function mutations in PTPRJ cause a new form of inherited thrombocytopenia', Blood, vol. 133, no. 12, pp. 1346-1357. 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. / Loss-of-function mutations in PTPRJ cause a new form of inherited thrombocytopenia. In: Blood. 2019 ; Vol. 133, No. 12. pp. 1346-1357.
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title = "Loss-of-function mutations in PTPRJ cause a new form of inherited thrombocytopenia",
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 in megakaryocyte biology.Publisher's Note: There is a Blood Commentary on this article in this issue.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 PTPRJ. 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 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 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.",
author = "Caterina Marconi and {Di Buduo}, {Christian A.} and Kellie LeVine and Serena Barozzi and Michela Faleschini and Valeria Bozzi and Flavia Palombo and Spencer McKinstry and Giuseppe Lassandro and Paola Giordano and Patrizia Noris and Balduini, {Carlo L.} and Anna Savoia and Alessandra Balduini and Tommaso Pippucci and Marco Seri and Nicholas Katsanis and Alessandro Pecci",
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TY - JOUR

T1 - Loss-of-function mutations in PTPRJ cause a new form of inherited thrombocytopenia

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 - 2019

Y1 - 2019

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 in megakaryocyte biology.Publisher's Note: There is a Blood Commentary on this article in this issue.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 PTPRJ. 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 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 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.

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 in megakaryocyte biology.Publisher's Note: There is a Blood Commentary on this article in this issue.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 PTPRJ. 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 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 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.

U2 - 10.1182/blood-2018-07-859496

DO - 10.1182/blood-2018-07-859496

M3 - Articolo

VL - 133

SP - 1346

EP - 1357

JO - Blood

JF - Blood

SN - 0006-4971

IS - 12

ER -