@article {10745, title = {Loss-of-function mutations in cause a new form of inherited thrombocytopenia.}, journal = {Blood}, volume = {133}, year = {2019}, month = {2019 Mar 21}, pages = {1346-1357}, abstract = {

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{\textquoteright} 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.

}, issn = {1528-0020}, doi = {10.1182/blood-2018-07-859496}, author = {Marconi, Caterina and Di Buduo, Christian A and LeVine, Kellie and Barozzi, Serena and Faleschini, Michela and Bozzi, Valeria and Palombo, Flavia and McKinstry, Spencer and Lassandro, Giuseppe and Giordano, Paola and Noris, Patrizia and Balduini, Carlo L and Savoia, Anna and Balduini, Alessandra and Pippucci, Tommaso and Seri, Marco and Katsanis, Nicholas and Pecci, Alessandro} } @article {10748, title = {ACTN1 mutations lead to a benign form of platelet macrocytosis not always associated with thrombocytopenia.}, journal = {Br J Haematol}, volume = {183}, year = {2018}, month = {2018 Oct}, pages = {276-288}, abstract = {

The inherited thrombocytopenias (IT) are a heterogeneous group of diseases resulting from mutations in more than 30 different genes. Among them, ACTN1-related thrombocytopenia (ACTN1-RT; Online Mendelian Inheritance in Man: 615193) is one of the most recently identified forms. It has been described as a mild autosomal dominant macrothrombocytopenia caused by mutations in ACTN1, a gene encoding for one of the two non-muscle isoforms of α-actinin. We recently identified seven new unrelated families with ACTN1-RT caused by different mutations. Two of them are novel missense variants (p.Trp128Cys and p.Pro233Leu), whose pathogenic role has been confirmed by in~vitro studies. Together with the 10 families we have previously described, our cohort of ACTN1-RT now consists of 49 individuals carrying ACTN1 mutations. This is the largest case series ever collected and enabled a critical evaluation of the clinical aspects of the disease. We concluded that ACTN1-RT is the fourth most frequent form of IT worldwide and it is characterized by platelet macrocytosis in all affected subjects and mild thrombocytopenia in less than 80\% of cases. The risk of bleeding, either spontaneous or upon haemostatic challenge, is negligible and there are no other associated defects, either congenital or acquired. Therefore, ACTN1-RT is a benign form of IT, whose diagnosis provides affected individuals and their families with a good prognosis.

}, issn = {1365-2141}, doi = {10.1111/bjh.15531}, author = {Faleschini, Michela and Melazzini, Federica and Marconi, Caterina and Giangregorio, Tania and Pippucci, Tommaso and Cigalini, Elena and Pecci, Alessandro and Bottega, Roberta and Ramenghi, Ugo and Siitonen, Timo and Seri, Marco and Pastore, Annalisa and Savoia, Anna and Noris, Patrizia} } @article {10535, title = {A new form of inherited thrombocytopenia due to monoallelic loss of function mutation in the thrombopoietin gene.}, journal = {Br J Haematol}, volume = {181}, year = {2018}, month = {2018 Jun}, pages = {698-701}, issn = {1365-2141}, doi = {10.1111/bjh.14694}, author = {Noris, Patrizia and Marconi, Caterina and De Rocco, Daniela and Melazzini, Federica and Pippucci, Tommaso and Loffredo, Giuseppe and Giangregorio, Tania and Pecci, Alessandro and Seri, Marco and Savoia, Anna} } @article {10546, title = {Mutations of RUNX1 in families with inherited thrombocytopenia.}, journal = {Am J Hematol}, volume = {92}, year = {2017}, month = {2017 06}, pages = {E86-E88}, keywords = {Adult, Blood Platelets, Cell Size, Child, Child, Preschool, Core Binding Factor Alpha 2 Subunit, Female, Frameshift Mutation, Genes, Dominant, Heterozygote, Humans, Introns, Leukemia, Myeloid, Acute, Male, Middle Aged, Mutation, Missense, Protein Domains, RNA Splice Sites, Sequence Deletion, Thrombocythemia, Essential, Thrombopoietin, Transcriptional Activation, Young Adult}, issn = {1096-8652}, doi = {10.1002/ajh.24703}, author = {De Rocco, Daniela and Melazzini, Federica and Marconi, Caterina and Pecci, Alessandro and Bottega, Roberta and Gnan, Chiara and Palombo, Flavia and Giordano, Paola and Coccioli, Maria Susanna and Glembotsky, Ana C and Heller, Paula G and Seri, Marco and Savoia, Anna and Noris, Patrizia} } @article {8503, title = {Clinical and pathogenetic features of ETV6 related thrombocytopenia with predisposition to acute lymphoblastic leukemia.}, journal = {Haematologica}, year = {2016}, month = {2016 Jun 30}, abstract = {

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.

}, issn = {1592-8721}, doi = {10.3324/haematol.2016.147496}, author = {Melazzini, Federica and Palombo, Flavia and Balduini, Alessandra and De Rocco, Daniela and Marconi, Caterina and Noris, Patrizia and Gnan, Chiara and Pippucci, Tommaso and Bozzi, Valeria and Faleschini, Michela and Barozzi, Serena and Doubek, Michael and Di Buduo, Christian A and Stano Kozubik, Katerina and Radova, Lenka and Loffredo, Giuseppe and Pospisilova, Sarka and Alfano, Caterina and Seri, Marco and Balduini, Carlo L and Pecci, Alessandro and Savoia, Anna} } @article {3633, title = {ACTN1-related thrombocytopenia: identification of novel families for phenotypic characterization.}, journal = {Blood}, volume = {125}, year = {2015}, month = {2015 Jan 29}, pages = {869-72}, abstract = {

Inherited thrombocytopenias (ITs) are a heterogeneous group of syndromic and nonsyndromic diseases caused by mutations affecting different genes. Alterations of ACTN1, the gene encoding for α-actinin 1, have recently been identified in a few families as being responsible for a mild form of IT (ACTN1-related thrombocytopenia; ACTN1-RT). To better characterize this disease, we screened ACTN1 in 128 probands and found 10 (8 novel) missense heterozygous variants in 11 families. Combining bioinformatics, segregation, and functional studies, we demonstrated that all but 1 amino acid substitution had deleterious effects. The clinical and laboratory findings of 31 affected individuals confirmed that ACTN1-RT is a mild macrothrombocytopenia with low risk for bleeding. Low reticulated platelet counts and only slightly increased serum thrombopoietin levels indicated that the latest phases of megakaryopoiesis were affected. Given its relatively high frequency in our cohort (4.2\%), ACTN1-RT has to be taken into consideration in the differential diagnosis of ITs.

}, keywords = {Actinin, Adolescent, Adult, Aged, Aged, 80 and over, Blood Platelets, Case-Control Studies, Child, Child, Preschool, Female, Gene Expression, Genotype, Heterozygote, Humans, Male, Middle Aged, Mutation, Missense, Pedigree, Phenotype, Platelet Count, Severity of Illness Index, Thrombocytopenia, Thrombopoiesis, Thrombopoietin}, issn = {1528-0020}, doi = {10.1182/blood-2014-08-594531}, author = {Bottega, Roberta and Marconi, Caterina and Faleschini, Michela and Baj, Gabriele and Cagioni, Claudia and Pecci, Alessandro and Pippucci, Tommaso and Ramenghi, Ugo and Pardini, Simonetta and Ngu, Loretta and Baronci, Carlo and Kunishima, Shinji and Balduini, Carlo L and Seri, Marco and Savoia, Anna and Noris, Patrizia} } @article {3554, title = {Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia.}, journal = {Haematologica}, volume = {99}, year = {2014}, month = {2014 Aug}, pages = {1387-94}, abstract = {

Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy and the course of pregnancy did not differ from that of healthy subjects in terms of miscarriages, fetal bleeding and pre-term births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but 2 of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8\% to 14.2\% depending on the definition of abnormal blood loss, suggesting that the risk of abnormal blood loss was increased with respect to the general population. However, no mother died or had to undergo hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery below 50 {\texttimes} 10(9)/L.

}, keywords = {Adult, Female, Humans, Infant, Newborn, Pregnancy, Pregnancy Complications, Hematologic, Retrospective Studies, Thrombocytopenia, Young Adult}, issn = {1592-8721}, doi = {10.3324/haematol.2014.105924}, author = {Noris, Patrizia and Schlegel, Nicole and Klersy, Catherine and Heller, Paula G and Civaschi, Elisa and Pujol-Moix, N{\'u}ria and Fabris, Fabrizio and Favier, R{\'e}mi and Gresele, Paolo and Latger-Cannard, V{\'e}ronique and Cuker, Adam and Nurden, Paquita and Greinacher, Andreas and Cattaneo, Marco and De Candia, Erica and Pecci, Alessandro and Hurtaud-Roux, Marie-Fran{\c c}oise and Glembotsky, Ana C and Mu{\~n}iz-Diaz, Eduardo and Randi, Maria Luigia and Trillot, Nathalie and Bury, Loredana and Lecompte, Thomas and Marconi, Caterina and Savoia, Anna and Balduini, Carlo L and Bayart, Sophie and Bauters, Anne and Benabdallah-Guedira, Sch{\'e}h{\'e}razade and Boehlen, Fran{\c c}oise and Borg, Jeanne-Yvonne and Bottega, Roberta and Bussel, James and De Rocco, Daniela and de Maistre, Emmanuel and Faleschini, Michela and Falcinelli, Emanuela and Ferrari, Silvia and Ferster, Alina and Fierro, Tiziana and Fleury, Dominique and Fontana, Pierre and James, Chlo{\'e} and Lanza, Francois and Le Cam Duchez, V{\'e}ronique and Loffredo, Giuseppe and Magini, Pamela and Martin-Coignard, Dominique and Menard, Fanny and Mercier, Sandra and Mezzasoma, Annamaria and Minuz, Pietro and Nichele, Ilaria and Notarangelo, Lucia D and Pippucci, Tommaso and Podda, Gian Marco and Pouymayou, Catherine and Rigouzzo, Agnes and Royer, Bruno and Sie, Pierre and Siguret, Virginie and Trichet, Catherine and Tucci, Alessandra and Saposnik, B{\'e}atrice and Veneri, Dino} } @article {1736, title = {Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families.}, journal = {Blood}, volume = {117}, year = {2011}, month = {2011 Jun 16}, pages = {6673-80}, abstract = {

Until recently, thrombocytopenia 2 (THC2) was considered an exceedingly rare form of autosomal dominant thrombocytopenia and only 2 families were known. However, we recently identified mutations in the 5{\textquoteright}-untranslated region of the ANKRD26 gene in 9 THC2 families. Here we report on 12 additional pedigrees with ANKRD26 mutations, 6 of which are new. Because THC2 affected 21 of the 210 families in our database, it has to be considered one of the less rare forms of inherited thrombocytopenia. Analysis of all 21 families with ANKRD26 mutations identified to date revealed that thrombocytopenia and bleeding tendency were usually mild. Nearly all patients had no platelet macrocytosis, and this characteristic distinguishes THC2 from most other forms of inherited thrombocytopenia. In the majority of cases, platelets were deficient in glycoprotein Ia and α-granules, whereas in vitro platelet aggregation was normal. Bone marrow examination and serum thrombopoietin levels suggested that thrombocytopenia was derived from dysmegakaryopoiesis. Unexplained high values of hemoglobin and leukocytes were observed in a few cases. An unexpected finding that warrants further investigation was a high incidence of acute leukemia. Given the scarcity of distinctive characteristics, the ANKRD26-related thrombocytopenia has to be taken into consideration in the differential diagnosis of isolated thrombocytopenias.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Ankyrin Repeat, Child, Cohort Studies, Family, Female, Gene Frequency, Humans, Inheritance Patterns, Male, Middle Aged, Mutation, Pedigree, Thrombocytopenia, Transcription Factors, Young Adult}, issn = {1528-0020}, doi = {10.1182/blood-2011-02-336537}, author = {Noris, Patrizia and Perrotta, Silverio and Seri, Marco and Pecci, Alessandro and Gnan, Chiara and Loffredo, Giuseppe and Pujol-Moix, N{\'u}ria and Zecca, Marco and Scognamiglio, Francesca and De Rocco, Daniela and Punzo, Francesca and Melazzini, Federica and Scianguetta, Saverio and Casale, Maddalena and Marconi, Caterina and Pippucci, Tommaso and Amendola, Giovanni and Notarangelo, Lucia D and Klersy, Catherine and Civaschi, Elisa and Balduini, Carlo L and Savoia, Anna} } @article {1688, title = {Mutations in the 5{\textquoteright} UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2.}, journal = {Am J Hum Genet}, volume = {88}, year = {2011}, month = {2011 Jan 7}, pages = {115-20}, abstract = {

THC2, an autosomal-dominant thrombocytopenia described so far in only two families, has been ascribed to mutations in MASTL or ACBD5. Here, we show that ANKRD26, another gene within the THC2 locus, and neither MASTL nor ACBD5, is mutated in eight unrelated families. ANKRD26 was also found to be mutated in the family previously reported to have an ACBD5 mutation. We identified six different ANKRD26 mutations, which were clustered in a highly conserved 19~bp sequence located in the 5{\textquoteright} untranslated region. Mutations were not detected in 500 controls and are absent from the 1000 Genomes database. Available data from an animal model and Dr.~Watson{\textquoteright}s genome give evidence against haploinsufficiency as the pathogenetic mechanism for ANKRD26-mediated thrombocytopenia. The luciferase reporter assay suggests that these 5{\textquoteright} UTR mutations might enhance ANKRD26 expression. ANKRD26 is the ancestor of a family of primate-specific genes termed POTE, which have been recently identified as a family of proapoptotic proteins. Dysregulation of apoptosis might therefore be the pathogenetic mechanism, as demonstrated for another thrombocytopenia, THC4. Further investigation is needed to provide evidence supporting this hypothesis.

}, keywords = {Ankyrin Repeat, Base Sequence, Chromosome Breakage, Chromosome Disorders, Conserved Sequence, Female, Genes, Dominant, Genetic Loci, Haploinsufficiency, Humans, Male, Molecular Sequence Data, Mutation, Pedigree, Thrombocytopenia}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2010.12.006}, author = {Pippucci, Tommaso and Savoia, Anna and Perrotta, Silverio and Pujol-Moix, N{\'u}ria and Noris, Patrizia and Castegnaro, Giovanni and Pecci, Alessandro and Gnan, Chiara and Punzo, Francesca and Marconi, Caterina and Gherardi, Samuele and Loffredo, Giuseppe and De Rocco, Daniela and Scianguetta, Saverio and Barozzi, Serena and Magini, Pamela and Bozzi, Valeria and Dezzani, Luca and Di Stazio, Mariateresa and Ferraro, Marcella and Perini, Giovanni and Seri, Marco and Balduini, Carlo L} }