@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 {7700, title = {Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 May}, pages = {535-8}, abstract = {

Some familial platelet disorders are associated with predisposition to leukemia, myelodysplastic syndrome (MDS) or dyserythropoietic anemia. We identified a family with autosomal dominant thrombocytopenia, high erythrocyte mean corpuscular volume (MCV) and two occurrences of B cell-precursor acute lymphoblastic leukemia (ALL). Whole-exome sequencing identified a heterozygous single-nucleotide change in ETV6 (ets variant 6), c.641C>T, encoding a p.Pro214Leu substitution in the central domain, segregating with thrombocytopenia and elevated MCV. A screen of 23 families with similar phenotypes identified 2 with ETV6 mutations. One family also had a mutation encoding p.Pro214Leu and one individual with ALL. The other family had a c.1252A>G transition producing a p.Arg418Gly substitution in the DNA-binding domain, with alternative splicing and exon skipping. Functional characterization of these mutations showed aberrant cellular localization of mutant and endogenous ETV6, decreased transcriptional repression and altered megakaryocyte maturation. Our findings underscore a key role for ETV6 in platelet formation and leukemia predisposition.

}, keywords = {Adult, Child, Preschool, DNA Mutational Analysis, Erythrocytes, Abnormal, Exome, Female, Genetic Association Studies, Genetic Predisposition to Disease, Germ-Line Mutation, HEK293 Cells, Hematologic Diseases, Humans, Male, Mutation, Missense, Pedigree, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Proto-Oncogene Proteins c-ets, Repressor Proteins, Thrombocytopenia}, issn = {1546-1718}, doi = {10.1038/ng.3253}, author = {Noetzli, Leila and Lo, Richard W and Lee-Sherick, Alisa B and Callaghan, Michael and Noris, Patrizia and Savoia, Anna and Rajpurkar, Madhvi and Jones, Kenneth and Gowan, Katherine and Balduini, Carlo L and Pecci, Alessandro and Gnan, Chiara and De Rocco, Daniela and Doubek, Michael and Li, Ling and Lu, Lily and Leung, Richard and Landolt-Marticorena, Carolina and Hunger, Stephen and Heller, Paula and Gutierrez-Hartmann, Arthur and Xiayuan, Liang and Pluthero, Fred G and Rowley, Jesse W and Weyrich, Andrew S and Kahr, Walter H A and Porter, Christopher C and Di Paola, Jorge} } @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} }