Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 1346-1357 |
| Number of pages | 12 |
| Journal | Blood |
| Volume | 133 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 2019 |
Fingerprint
Keywords
- collagen
- convulxin
- messenger RNA
- protein tyrosine kinase
- adolescent
- Article
- autosomal recessive disorder
- case report
- cell migration
- child
- clinical article
- CRISPR-CAS9 system
- embryo
- female
- gene
- genetic variation
- hematopoiesis
- human
- human cell
- in vivo study
- loss of function mutation
- male
- megakaryocyte
- nonhuman
- phenotype
- predictive value
- priority journal
- ptprj gene
- school child
- thrombocyte
- thrombocytopenia
- whole exome sequencing
- zebra fish
Cite this
Loss-of-function mutations in PTPRJ cause a new form of inherited thrombocytopenia. / Marconi, C.; DI Buduo, C.A.; LeVine, K.; Barozzi, S.; Faleschini, M.; Bozzi, V.; Palombo, F.; McKinstry, S.; Lassandro, G.; Giordano, P.; Noris, P.; Balduini, C.L.; Savoia, A.; Balduini, A.; Pippucci, T.; Seri, M.; Katsanis, N.; Pecci, A.
In: Blood, Vol. 133, No. 12, 2019, p. 1346-1357.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Loss-of-function mutations in PTPRJ cause a new form of inherited thrombocytopenia
AU - Marconi, C.
AU - DI Buduo, C.A.
AU - LeVine, K.
AU - Barozzi, S.
AU - Faleschini, M.
AU - Bozzi, V.
AU - Palombo, F.
AU - McKinstry, S.
AU - Lassandro, G.
AU - Giordano, P.
AU - Noris, P.
AU - Balduini, C.L.
AU - Savoia, A.
AU - Balduini, A.
AU - Pippucci, T.
AU - Seri, M.
AU - Katsanis, N.
AU - Pecci, A.
N1 - Cited By :2 Export Date: 10 October 2019 CODEN: BLOOA Correspondence Address: Seri, M.; Department of Medical and Surgical Sciences, University of Bologna, Via Massarenti 9, Italy; email: marco.seri@unibo.it Chemicals/CAS: collagen, 9007-34-5; convulxin, 37206-04-5; protein tyrosine kinase, 80449-02-1 Funding details: Duke University Funding details: Università di Bologna Funding details: Tufts University Funding details: Fondazione IRCCS Policlinico San Matteo Funding details: 7Department Funding details: Fondazione Cariplo, 2013-0717 Funding text 1: 1Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; 2Department of Molecular Medicine, University of Pavia, Pavia, Italy; 3Biotechnology Research Laboratories, IRCCS Policlinico San Matteo Foundation, Pavia, Italy; 4Center for Human Disease Modeling, Duke University, Durham, NC; 5Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, Pavia, Italy; 6Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy; 7Department of Biomedical Science and Human Oncology, Pediatric Unit, University “Aldo Moro,” Bari, Italy; 8Ferrata-Storti Foundation, Pavia, Italy; 9Department of Medical Sciences, University of Trieste, Trieste, Italy; and 10Department of Biomedical Engineering, Tufts University, Medford, MA Funding text 2: This work was supported by grants from the IRCCS Policlinico San Matteo Foundation, the IRCCS Burlo Garofolo, and the Cariplo Foundation (Italy; grant 2013-0717). 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PY - 2019
Y1 - 2019
N2 - 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-offunction 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. © 2019 by The American Society of Hematology.
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-offunction 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. © 2019 by The American Society of Hematology.
KW - collagen
KW - convulxin
KW - messenger RNA
KW - protein tyrosine kinase
KW - adolescent
KW - Article
KW - autosomal recessive disorder
KW - case report
KW - cell migration
KW - child
KW - clinical article
KW - CRISPR-CAS9 system
KW - embryo
KW - female
KW - gene
KW - genetic variation
KW - hematopoiesis
KW - human
KW - human cell
KW - in vivo study
KW - loss of function mutation
KW - male
KW - megakaryocyte
KW - nonhuman
KW - phenotype
KW - predictive value
KW - priority journal
KW - ptprj gene
KW - school child
KW - thrombocyte
KW - thrombocytopenia
KW - whole exome sequencing
KW - zebra fish
U2 - 10.1182/blood-2018-07-859496
DO - 10.1182/blood-2018-07-859496
M3 - Article
VL - 133
SP - 1346
EP - 1357
JO - Blood
JF - Blood
SN - 0006-4971
IS - 12
ER -