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

Autor:	Marconi C; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy., Di Buduo CA; Department of Molecular Medicine, University of Pavia, Pavia, Italy.; Biotechnology Research Laboratories, IRCCS Policlinico San Matteo Foundation, Pavia, Italy., LeVine K; Center for Human Disease Modeling, Duke University, Durham, NC., Barozzi S; Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, Pavia, Italy., Faleschini M; Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy., Bozzi V; Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, Pavia, Italy., Palombo F; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy., McKinstry S; Center for Human Disease Modeling, Duke University, Durham, NC., Lassandro G; Department of Biomedical Science and Human Oncology, Pediatric Unit, University 'Aldo Moro,' Bari, Italy., Giordano P; Department of Biomedical Science and Human Oncology, Pediatric Unit, University 'Aldo Moro,' Bari, Italy., Noris P; Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, Pavia, Italy., Balduini CL; Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, Pavia, Italy.; Ferrata-Storti Foundation, Pavia, Italy., Savoia A; Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy.; Department of Medical Sciences, University of Trieste, Trieste, Italy; and., Balduini A; Department of Molecular Medicine, University of Pavia, Pavia, Italy.; Biotechnology Research Laboratories, IRCCS Policlinico San Matteo Foundation, Pavia, Italy.; Department of Biomedical Engineering, Tufts University, Medford, MA., Pippucci T; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy., Seri M; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy., Katsanis N; Center for Human Disease Modeling, Duke University, Durham, NC., Pecci A; Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, Pavia, Italy.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2019 Mar 21; Vol. 133 (12), pp. 1346-1357. Date of Electronic Publication: 2018 Dec 27.
DOI:	10.1182/blood-2018-07-859496
Abstrakt:	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. (© 2019 by The American Society of Hematology.)
Databáze:	MEDLINE
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