TY - JOUR T1 - Loss-of-function mutations in cause a new form of inherited thrombocytopenia. JF - Blood Y1 - 2019 A1 - Marconi, Caterina A1 - Di Buduo, Christian A A1 - LeVine, Kellie A1 - Barozzi, Serena A1 - Faleschini, Michela A1 - Bozzi, Valeria A1 - Palombo, Flavia A1 - McKinstry, Spencer A1 - Lassandro, Giuseppe A1 - Giordano, Paola A1 - Noris, Patrizia A1 - Balduini, Carlo L A1 - Savoia, Anna A1 - Balduini, Alessandra A1 - Pippucci, Tommaso A1 - Seri, Marco A1 - Katsanis, Nicholas A1 - Pecci, Alessandro 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-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' 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.

VL - 133 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30591527?dopt=Abstract ER - TY - JOUR T1 - MYH9-Related Thrombocytopenia: Four Novel Variants Affecting the Tail Domain of the Non-Muscle Myosin Heavy Chain IIA Associated with a Mild Clinical Evolution of the Disorder. JF - Hamostaseologie Y1 - 2019 A1 - Zaninetti, Carlo A1 - De Rocco, Daniela A1 - Giangregorio, Tania A1 - Bozzi, Valeria A1 - Demeter, Judit A1 - Leoni, Pietro A1 - Noris, Patrizia A1 - Ryhänen, Samppa A1 - Barozzi, Serena A1 - Pecci, Alessandro A1 - Savoia, Anna AB -

-related disease (-RD) is an autosomal-dominant thrombocytopenia caused by mutations in the gene for non-muscle myosin heavy chain IIA (NMMHC-IIA). Patients present congenital macrothrombocytopenia and inclusions of NMMHC-IIA in leukocytes, and have a variable risk of developing kidney damage, sensorineural deafness, presenile cataracts and/or liver enzymes abnormalities. The spectrum of mutations found in -RD patients is limited and the incidence and severity of the non-congenital features are predicted by the causative variant. In particular, different alterations of the C-terminal tail domain of NMMHC-IIA associate with remarkably different disease evolution. We report four novel mutations affecting the tail domain of NMMHC-IIA and responsible for -RD in four families. Two variants cause amino acid substitutions in the coiled-coil region of NMMHC-IIA, while the other two are a splicing variant and a single nucleotide deletion both resulting in frameshift alterations of the short non-helical tailpiece. Characterization of phenotypes of affected individuals shows that all of these novel variants are associated with a mild clinical evolution of the disease.

VL - 39 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29996171?dopt=Abstract ER - TY - JOUR T1 - ACTN1 mutations lead to a benign form of platelet macrocytosis not always associated with thrombocytopenia. JF - Br J Haematol Y1 - 2018 A1 - Faleschini, Michela A1 - Melazzini, Federica A1 - Marconi, Caterina A1 - Giangregorio, Tania A1 - Pippucci, Tommaso A1 - Cigalini, Elena A1 - Pecci, Alessandro A1 - Bottega, Roberta A1 - Ramenghi, Ugo A1 - Siitonen, Timo A1 - Seri, Marco A1 - Pastore, Annalisa A1 - Savoia, Anna A1 - Noris, Patrizia AB -

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.

VL - 183 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30351444?dopt=Abstract ER - TY - JOUR T1 - MYH9: Structure, functions and role of non-muscle myosin IIA in human disease. JF - Gene Y1 - 2018 A1 - Pecci, Alessandro A1 - Ma, Xuefei A1 - Savoia, Anna A1 - Adelstein, Robert S KW - Animals KW - Cell Line KW - Deafness KW - Hearing Loss, Sensorineural KW - Humans KW - Mice KW - Molecular Motor Proteins KW - Mutation KW - Myosin Heavy Chains KW - Neoplasms KW - Nonmuscle Myosin Type IIA KW - Phosphorylation KW - Renal Insufficiency, Chronic KW - Thrombocytopenia AB -

The MYH9 gene encodes the heavy chain of non-muscle myosin IIA, a widely expressed cytoplasmic myosin that participates in a variety of processes requiring the generation of intracellular chemomechanical force and translocation of the actin cytoskeleton. Non-muscle myosin IIA functions are regulated by phosphorylation of its 20 kDa light chain, of the heavy chain, and by interactions with other proteins. Variants of MYH9 cause an autosomal-dominant disorder, termed MYH9-related disease, and may be involved in other conditions, such as chronic kidney disease, non-syndromic deafness, and cancer. This review discusses the structure of the MYH9 gene and its protein, as well as the regulation and physiologic functions of non-muscle myosin IIA with particular reference to embryonic development. Moreover, the review focuses on current knowledge about the role of MYH9 variants in human disease.

VL - 664 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29679756?dopt=Abstract ER - TY - JOUR T1 - A new form of inherited thrombocytopenia due to monoallelic loss of function mutation in the thrombopoietin gene. JF - Br J Haematol Y1 - 2018 A1 - Noris, Patrizia A1 - Marconi, Caterina A1 - De Rocco, Daniela A1 - Melazzini, Federica A1 - Pippucci, Tommaso A1 - Loffredo, Giuseppe A1 - Giangregorio, Tania A1 - Pecci, Alessandro A1 - Seri, Marco A1 - Savoia, Anna VL - 181 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28466964?dopt=Abstract ER - TY - JOUR T1 - Mutations of RUNX1 in families with inherited thrombocytopenia. JF - Am J Hematol Y1 - 2017 A1 - De Rocco, Daniela A1 - Melazzini, Federica A1 - Marconi, Caterina A1 - Pecci, Alessandro A1 - Bottega, Roberta A1 - Gnan, Chiara A1 - Palombo, Flavia A1 - Giordano, Paola A1 - Coccioli, Maria Susanna A1 - Glembotsky, Ana C A1 - Heller, Paula G A1 - Seri, Marco A1 - Savoia, Anna A1 - Noris, Patrizia KW - Adult KW - Blood Platelets KW - Cell Size KW - Child KW - Child, Preschool KW - Core Binding Factor Alpha 2 Subunit KW - Female KW - Frameshift Mutation KW - Genes, Dominant KW - Heterozygote KW - Humans KW - Introns KW - Leukemia, Myeloid, Acute KW - Male KW - Middle Aged KW - Mutation, Missense KW - Protein Domains KW - RNA Splice Sites KW - Sequence Deletion KW - Thrombocythemia, Essential KW - Thrombopoietin KW - Transcriptional Activation KW - Young Adult VL - 92 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28240786?dopt=Abstract ER - TY - JOUR T1 - MYH9 gene mutations associated with bleeding. JF - Platelets Y1 - 2017 A1 - Savoia, Anna A1 - De Rocco, Daniela A1 - Pecci, Alessandro KW - Asymptomatic Diseases KW - Blood Platelets KW - Cell Size KW - Chromosomes, Human, Pair 22 KW - Exons KW - Gene Expression KW - Genetic Association Studies KW - Genotype KW - Hearing Loss, Sensorineural KW - Hemorrhage KW - Humans KW - Molecular Motor Proteins KW - Mutation KW - Myosin Heavy Chains KW - Phenotype KW - Platelet Count KW - Protein Domains KW - Severity of Illness Index KW - Thrombocytopenia VL - 28 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28368695?dopt=Abstract ER - TY - JOUR T1 - Clinical and pathogenetic features of ETV6 related thrombocytopenia with predisposition to acute lymphoblastic leukemia. JF - Haematologica Y1 - 2016 A1 - Melazzini, Federica A1 - Palombo, Flavia A1 - Balduini, Alessandra A1 - De Rocco, Daniela A1 - Marconi, Caterina A1 - Noris, Patrizia A1 - Gnan, Chiara A1 - Pippucci, Tommaso A1 - Bozzi, Valeria A1 - Faleschini, Michela A1 - Barozzi, Serena A1 - Doubek, Michael A1 - Di Buduo, Christian A A1 - Stano Kozubik, Katerina A1 - Radova, Lenka A1 - Loffredo, Giuseppe A1 - Pospisilova, Sarka A1 - Alfano, Caterina A1 - Seri, Marco A1 - Balduini, Carlo L A1 - Pecci, Alessandro A1 - Savoia, Anna AB -

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.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/27365488?dopt=Abstract ER - TY - JOUR T1 - Nonmuscle Myosin Heavy Chain IIA Mutation Predicts Severity and Progression of Sensorineural Hearing Loss in Patients With MYH9-Related Disease. JF - Ear Hear Y1 - 2016 A1 - Verver, Eva J J A1 - Topsakal, Vedat A1 - Kunst, Henricus P M A1 - Huygen, Patrick L M A1 - Heller, Paula G A1 - Pujol-Moix, Núria A1 - Savoia, Anna A1 - Benazzo, Marco A1 - Fierro, Tiziana A1 - Grolman, Wilko A1 - Gresele, Paolo A1 - Pecci, Alessandro AB -

OBJECTIVES: MYH9-related disease (MYH9-RD) is an autosomal- dominant disorder deriving from mutations in MYH9, the gene for the nonmuscle myosin heavy chain (NMMHC)-IIA. MYH9-RD has a complex phenotype including congenital features, such as thrombocytopenia, and noncongenital manifestations, namely sensorineural hearing loss (SNHL), nephropathy, cataract, and liver abnormalities. The disease is caused by a limited number of mutations affecting different regions of the NMMHC-IIA protein. SNHL is the most frequent noncongenital manifestation of MYH9-RD. However, only scarce and anecdotal information is currently available about the clinical and audiometric features of SNHL of MYH9-RD subjects. The objective of this study was to investigate the severity and propensity for progression of SNHL in a large series of MYH9-RD patients in relation to the causative NMMHC-IIA mutations.

DESIGN: This study included the consecutive patients diagnosed with MYH9-RD between July 2007 and March 2012 at four participating institutions. A total of 115 audiograms were analyzed from 63 patients belonging to 45 unrelated families with different NMMHC-IIA mutations. Cross-sectional analyses of audiograms were performed. Regression analysis was performed, and age-related typical audiograms (ARTAs) were derived to characterize the type of SNHL associated with different mutations.

RESULTS: Severity of SNHL appeared to depend on the specific NMMHC-IIA mutation. Patients carrying substitutions at the residue R702 located in the short functional SH1 helix had the most severe degree of SNHL, whereas patients with the p.E1841K substitution in the coiled-coil region or mutations at the nonhelical tailpiece presented a mild degree of SNHL even at advanced age. The authors also disclosed the effects of different amino acid changes at the same residue: for instance, individuals with the p.R702C mutation had more severe SNHL than those with the p.R702H mutation, and the p.R1165L substitution was associated with a higher degree of hearing loss than the p.R1165C. In general, mild SNHL was associated with a fairly flat audiogram configuration, whereas severe SNHL correlated with downsloping configurations. ARTA plots showed that the most progressive type of SNHL was associated with the p.R702C, the p.R702H, and the p.R1165L substitutions, whereas the p.R1165C mutation correlated with a milder, nonprogressive type of SNHL than the p.R1165L. ARTA for the p.E1841K mutation demonstrated a mild degree of SNHL with only mild progression, whereas the ARTA for the mutations at the nonhelical tailpiece did not show any substantial progression.

CONCLUSIONS: These data provide useful tools to predict the progression and the expected degree of severity of SNHL in individual MYH9-RD patients, which is especially relevant in young patients. Consequences in clinical practice are important not only for appropriate patient counseling but also for development of customized, genotype-driven clinical management. The authors recently reported that cochlear implantation has a good outcome in MYH9-RD patients; thus, stricter follow-up and earlier intervention are recommended for patients with unfavorable genotypes.

VL - 37 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26226608?dopt=Abstract ER - TY - JOUR T1 - ACTN1-related thrombocytopenia: identification of novel families for phenotypic characterization. JF - Blood Y1 - 2015 A1 - Bottega, Roberta A1 - Marconi, Caterina A1 - Faleschini, Michela A1 - Baj, Gabriele A1 - Cagioni, Claudia A1 - Pecci, Alessandro A1 - Pippucci, Tommaso A1 - Ramenghi, Ugo A1 - Pardini, Simonetta A1 - Ngu, Loretta A1 - Baronci, Carlo A1 - Kunishima, Shinji A1 - Balduini, Carlo L A1 - Seri, Marco A1 - Savoia, Anna A1 - Noris, Patrizia KW - Actinin KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Blood Platelets KW - Case-Control Studies KW - Child KW - Child, Preschool KW - Female KW - Gene Expression KW - Genotype KW - Heterozygote KW - Humans KW - Male KW - Middle Aged KW - Mutation, Missense KW - Pedigree KW - Phenotype KW - Platelet Count KW - Severity of Illness Index KW - Thrombocytopenia KW - Thrombopoiesis KW - Thrombopoietin AB -

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.

VL - 125 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25361813?dopt=Abstract ER - TY - JOUR T1 - Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. JF - Nat Genet Y1 - 2015 A1 - Noetzli, Leila A1 - Lo, Richard W A1 - Lee-Sherick, Alisa B A1 - Callaghan, Michael A1 - Noris, Patrizia A1 - Savoia, Anna A1 - Rajpurkar, Madhvi A1 - Jones, Kenneth A1 - Gowan, Katherine A1 - Balduini, Carlo L A1 - Pecci, Alessandro A1 - Gnan, Chiara A1 - De Rocco, Daniela A1 - Doubek, Michael A1 - Li, Ling A1 - Lu, Lily A1 - Leung, Richard A1 - Landolt-Marticorena, Carolina A1 - Hunger, Stephen A1 - Heller, Paula A1 - Gutierrez-Hartmann, Arthur A1 - Xiayuan, Liang A1 - Pluthero, Fred G A1 - Rowley, Jesse W A1 - Weyrich, Andrew S A1 - Kahr, Walter H A A1 - Porter, Christopher C A1 - Di Paola, Jorge KW - Adult KW - Child, Preschool KW - DNA Mutational Analysis KW - Erythrocytes, Abnormal KW - Exome KW - Female KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Germ-Line Mutation KW - HEK293 Cells KW - Hematologic Diseases KW - Humans KW - Male KW - Mutation, Missense KW - Pedigree KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma KW - Proto-Oncogene Proteins c-ets KW - Repressor Proteins KW - Thrombocytopenia AB -

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.

VL - 47 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25807284?dopt=Abstract ER - TY - JOUR T1 - Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. JF - Haematologica Y1 - 2014 A1 - Noris, Patrizia A1 - Schlegel, Nicole A1 - Klersy, Catherine A1 - Heller, Paula G A1 - Civaschi, Elisa A1 - Pujol-Moix, Núria A1 - Fabris, Fabrizio A1 - Favier, Rémi A1 - Gresele, Paolo A1 - Latger-Cannard, Véronique A1 - Cuker, Adam A1 - Nurden, Paquita A1 - Greinacher, Andreas A1 - Cattaneo, Marco A1 - De Candia, Erica A1 - Pecci, Alessandro A1 - Hurtaud-Roux, Marie-Françoise A1 - Glembotsky, Ana C A1 - Muñiz-Diaz, Eduardo A1 - Randi, Maria Luigia A1 - Trillot, Nathalie A1 - Bury, Loredana A1 - Lecompte, Thomas A1 - Marconi, Caterina A1 - Savoia, Anna A1 - Balduini, Carlo L A1 - Bayart, Sophie A1 - Bauters, Anne A1 - Benabdallah-Guedira, Schéhérazade A1 - Boehlen, Françoise A1 - Borg, Jeanne-Yvonne A1 - Bottega, Roberta A1 - Bussel, James A1 - De Rocco, Daniela A1 - de Maistre, Emmanuel A1 - Faleschini, Michela A1 - Falcinelli, Emanuela A1 - Ferrari, Silvia A1 - Ferster, Alina A1 - Fierro, Tiziana A1 - Fleury, Dominique A1 - Fontana, Pierre A1 - James, Chloé A1 - Lanza, Francois A1 - Le Cam Duchez, Véronique A1 - Loffredo, Giuseppe A1 - Magini, Pamela A1 - Martin-Coignard, Dominique A1 - Menard, Fanny A1 - Mercier, Sandra A1 - Mezzasoma, Annamaria A1 - Minuz, Pietro A1 - Nichele, Ilaria A1 - Notarangelo, Lucia D A1 - Pippucci, Tommaso A1 - Podda, Gian Marco A1 - Pouymayou, Catherine A1 - Rigouzzo, Agnes A1 - Royer, Bruno A1 - Sie, Pierre A1 - Siguret, Virginie A1 - Trichet, Catherine A1 - Tucci, Alessandra A1 - Saposnik, Béatrice A1 - Veneri, Dino KW - Adult KW - Female KW - Humans KW - Infant, Newborn KW - Pregnancy KW - Pregnancy Complications, Hematologic KW - Retrospective Studies KW - Thrombocytopenia KW - Young Adult AB -

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 × 10(9)/L.

VL - 99 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24763399?dopt=Abstract ER - TY - JOUR T1 - Mutations of cytochrome c identified in patients with thrombocytopenia THC4 affect both apoptosis and cellular bioenergetics. JF - Biochim Biophys Acta Y1 - 2014 A1 - De Rocco, Daniela A1 - Cerqua, Cristina A1 - Goffrini, Paola A1 - Russo, Giovanna A1 - Pastore, Annalisa A1 - Meloni, Francesca A1 - Nicchia, Elena A1 - Moraes, Carlos T A1 - Pecci, Alessandro A1 - Salviati, Leonardo A1 - Savoia, Anna KW - Amino Acid Sequence KW - Animals KW - Apoptosis KW - Base Sequence KW - Cells, Cultured KW - Child, Preschool KW - Cytochromes c KW - DNA Mutational Analysis KW - Embryo, Mammalian KW - Energy Metabolism KW - Family Health KW - Female KW - Fibroblasts KW - Humans KW - Lung KW - Male KW - Mice KW - Molecular Sequence Data KW - Mutation, Missense KW - Oxygen Consumption KW - Pedigree KW - Saccharomyces cerevisiae KW - Sequence Homology, Amino Acid KW - Thrombocytopenia AB -

Inherited thrombocytopenias are heterogeneous diseases caused by at least 20 genes playing different role in the processes of megakaryopoiesis and platelet production. Some forms, such as thrombocytopenia 4 (THC4), are very rare and not well characterized. THC4 is an autosomal dominant mild thrombocytopenia described in only one large family from New Zealand and due to a mutation (G41S) of the somatic isoform of the cytochrome c (CYCS) gene. We report a novel CYCS mutation (Y48H) in patients from an Italian family. Similar to individuals carrying G41S, they have platelets of normal size and morphology, which are only partially reduced in number, but no prolonged bleeding episodes. In order to determine the pathogenetic consequences of Y48H, we studied the effects of the two CYCS mutations in yeast and mouse cellular models. In both cases, we found reduction of respiratory level and increased apoptotic rate, supporting the pathogenetic role of CYCS in thrombocytopenia.

VL - 1842 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24326104?dopt=Abstract ER - TY - JOUR T1 - MYH9-related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations. JF - Hum Mutat Y1 - 2014 A1 - Pecci, Alessandro A1 - Klersy, Catherine A1 - Gresele, Paolo A1 - Lee, Kieran J D A1 - De Rocco, Daniela A1 - Bozzi, Valeria A1 - Russo, Giovanna A1 - Heller, Paula G A1 - Loffredo, Giuseppe A1 - Ballmaier, Matthias A1 - Fabris, Fabrizio A1 - Beggiato, Eloise A1 - Kahr, Walter H A A1 - Pujol-Moix, Núria A1 - Platokouki, Helen A1 - Van Geet, Christel A1 - Noris, Patrizia A1 - Yerram, Preethi A1 - Hermans, Cedric A1 - Gerber, Bernhard A1 - Economou, Marina A1 - De Groot, Marco A1 - Zieger, Barbara A1 - De Candia, Erica A1 - Fraticelli, Vincenzo A1 - Kersseboom, Rogier A1 - Piccoli, Giorgina B A1 - Zimmermann, Stefanie A1 - Fierro, Tiziana A1 - Glembotsky, Ana C A1 - Vianello, Fabrizio A1 - Zaninetti, Carlo A1 - Nicchia, Elena A1 - Güthner, Christiane A1 - Baronci, Carlo A1 - Seri, Marco A1 - Knight, Peter J A1 - Balduini, Carlo L A1 - Savoia, Anna KW - Adult KW - Age of Onset KW - Amino Acid Substitution KW - Cataract KW - Female KW - Genetic Association Studies KW - Genotype KW - Hearing Loss, Sensorineural KW - Humans KW - Italy KW - Linear Models KW - Male KW - Molecular Motor Proteins KW - Mutation KW - Myosin Heavy Chains KW - Phenotype KW - Risk Factors KW - Thrombocytopenia AB -

MYH9-related disease (MYH9-RD) is a rare autosomal-dominant disorder caused by mutations in the gene for nonmuscle myosin heavy chain IIA (NMMHC-IIA). MYH9-RD is characterized by a considerable variability in clinical evolution: patients present at birth with only thrombocytopenia, but some of them subsequently develop sensorineural deafness, cataract, and/or nephropathy often leading to end-stage renal disease (ESRD). We searched for genotype-phenotype correlations in the largest series of consecutive MYH9-RD patients collected so far (255 cases from 121 families). Association of genotypes with noncongenital features was assessed by a generalized linear regression model. The analysis defined disease evolution associated to seven different MYH9 genotypes that are responsible for 85% of MYH9-RD cases. Mutations hitting residue R702 demonstrated a complete penetrance for early-onset ESRD and deafness. The p.D1424H substitution associated with high risk of developing all the noncongenital manifestations of disease. Mutations hitting a distinct hydrophobic seam in the NMMHC-IIA head domain or substitutions at R1165 associated with high risk of deafness but low risk of nephropathy or cataract. Patients with p.E1841K, p.D1424N, and C-terminal deletions had low risk of noncongenital defects. These findings are essential to patients' clinical management and genetic counseling and are discussed in view of molecular pathogenesis of MYH9-RD.

VL - 35 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24186861?dopt=Abstract ER - TY - JOUR T1 - Platelet diameters in inherited thrombocytopenias: analysis of 376 patients with all known disorders. JF - Blood Y1 - 2014 A1 - Noris, Patrizia A1 - Biino, Ginevra A1 - Pecci, Alessandro A1 - Civaschi, Elisa A1 - Savoia, Anna A1 - Seri, Marco A1 - Melazzini, Federica A1 - Loffredo, Giuseppe A1 - Russo, Giovanna A1 - Bozzi, Valeria A1 - Notarangelo, Lucia Dora A1 - Gresele, Paolo A1 - Heller, Paula G A1 - Pujol-Moix, Núria A1 - Kunishima, Shinji A1 - Cattaneo, Marco A1 - Bussel, James A1 - De Candia, Erica A1 - Cagioni, Claudia A1 - Ramenghi, Ugo A1 - Barozzi, Serena A1 - Fabris, Fabrizio A1 - Balduini, Carlo L KW - Adolescent KW - Adult KW - Blood Platelets KW - Case-Control Studies KW - Cell Size KW - Child KW - Child, Preschool KW - Diagnosis, Differential KW - Female KW - Hearing Loss, Sensorineural KW - Humans KW - Infant KW - Male KW - Middle Aged KW - Molecular Motor Proteins KW - Mutation KW - Myosin Heavy Chains KW - Purpura, Thrombocytopenic, Idiopathic KW - Thrombocytopenia KW - Young Adult AB -

Abnormalities of platelet size are one of the distinguishing features of inherited thrombocytopenias (ITs), and evaluation of blood films is recommended as an essential step for differential diagnosis of these disorders. Nevertheless, what we presently know about this subject is derived mainly from anecdotal evidence. To improve knowledge in this field, we evaluated platelet size on blood films obtained from 376 patients with all 19 forms of IT identified so far and found that these conditions differ not only in mean platelet diameter, but also in platelet diameter distribution width and the percentage of platelets with increased or reduced diameters. On the basis of these findings, we propose a new classification of ITs according to platelet size. It distinguishes forms with giant platelets, with large platelets, with normal or slightly increased platelet size, and with normal or slightly decreased platelet size. We also measured platelet diameters in 87 patients with immune thrombocytopenia and identified cutoff values for mean platelet diameter and the percentage of platelets with increased or reduced size that have good diagnostic accuracy in differentiating ITs with giant platelets and with normal or slightly decreased platelet size from immune thrombocytopenia and all other forms of IT.

VL - 124 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24990887?dopt=Abstract ER - TY - JOUR T1 - Spectrum of the mutations in Bernard-Soulier syndrome. JF - Hum Mutat Y1 - 2014 A1 - Savoia, Anna A1 - Kunishima, Shinji A1 - De Rocco, Daniela A1 - Zieger, Barbara A1 - Rand, Margaret L A1 - Pujol-Moix, Núria A1 - Caliskan, Umran A1 - Tokgoz, Huseyin A1 - Pecci, Alessandro A1 - Noris, Patrizia A1 - Srivastava, Alok A1 - Ward, Christopher A1 - Morel-Kopp, Marie-Christine A1 - Alessi, Marie-Christine A1 - Bellucci, Sylvia A1 - Beurrier, Philippe A1 - de Maistre, Emmanuel A1 - Favier, Rémi A1 - Hézard, Nathalie A1 - Hurtaud-Roux, Marie-Françoise A1 - Latger-Cannard, Véronique A1 - Lavenu-Bombled, Cécile A1 - Proulle, Valérie A1 - Meunier, Sandrine A1 - Négrier, Claude A1 - Nurden, Alan A1 - Randrianaivo, Hanitra A1 - Fabris, Fabrizio A1 - Platokouki, Helen A1 - Rosenberg, Nurit A1 - HadjKacem, Basma A1 - Heller, Paula G A1 - Karimi, Mehran A1 - Balduini, Carlo L A1 - Pastore, Annalisa A1 - Lanza, Francois KW - Alleles KW - Bernard-Soulier Syndrome KW - Databases, Nucleic Acid KW - Founder Effect KW - Genetic Variation KW - Humans KW - Mutation KW - Platelet Glycoprotein GPIb-IX Complex KW - Polymorphism, Single Nucleotide KW - von Willebrand Diseases KW - Web Browser AB -

Bernard-Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder characterized by defects of the GPIb-IX-V complex, a platelet receptor for von Willebrand factor (VWF). Most of the mutations identified in the genes encoding for the GP1BA (GPIbα), GP1BB (GPIbβ), and GP9 (GPIX) subunits prevent expression of the complex at the platelet membrane or more rarely its interaction with VWF. As a consequence, platelets are unable to adhere to the vascular subendothelium and agglutinate in response to ristocetin. In order to collect information on BSS patients, we established an International Consortium for the study of BSS, allowing us to enrol and genotype 132 families (56 previously unreported). With 79 additional families for which molecular data were gleaned from the literature, the 211 families characterized so far have mutations in the GP1BA (28%), GP1BB (28%), or GP9 (44%) genes. There is a wide spectrum of mutations with 112 different variants, including 22 novel alterations. Consistent with the rarity of the disease, 85% of the probands carry homozygous mutations with evidence of founder effects in some geographical areas. This overview provides the first global picture of the molecular basis of BSS and will lead to improve patient diagnosis and management.

VL - 35 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24934643?dopt=Abstract ER - TY - JOUR T1 - MYH9-related disease: five novel mutations expanding the spectrum of causative mutations and confirming genotype/phenotype correlations. JF - Eur J Med Genet Y1 - 2013 A1 - De Rocco, Daniela A1 - Zieger, Barbara A1 - Platokouki, Helen A1 - Heller, Paula G A1 - Pastore, Annalisa A1 - Bottega, Roberta A1 - Noris, Patrizia A1 - Barozzi, Serena A1 - Glembotsky, Ana C A1 - Pergantou, Helen A1 - Balduini, Carlo L A1 - Savoia, Anna A1 - Pecci, Alessandro KW - Adolescent KW - Adult KW - Amino Acid Sequence KW - Amino Acid Substitution KW - Base Sequence KW - Child KW - Child, Preschool KW - Exons KW - Female KW - Genes, Dominant KW - Genetic Association Studies KW - Humans KW - Male KW - Middle Aged KW - Models, Molecular KW - Molecular Motor Proteins KW - Molecular Sequence Data KW - Mutation KW - Myosin Heavy Chains KW - Pedigree KW - Protein Conformation KW - Sequence Alignment KW - Syndrome KW - Thrombocytopenia KW - Young Adult AB -

MYH9-related disease (MYH9-RD) is a rare autosomal dominant syndromic disorder caused by mutations in MYH9, the gene encoding for the heavy chain of non-muscle myosin IIA (myosin-9). MYH9-RD is characterized by congenital macrothrombocytopenia and typical inclusion bodies in neutrophils associated with a variable risk of developing sensorineural deafness, presenile cataract, and/or progressive nephropathy. The spectrum of mutations responsible for MYH9-RD is limited. We report five families, each with a novel MYH9 mutation. Two mutations, p.Val34Gly and p.Arg702Ser, affect the motor domain of myosin-9, whereas the other three, p.Met847_Glu853dup, p.Lys1048_Glu1054del, and p.Asp1447Tyr, hit the coiled-coil tail domain of the protein. The motor domain mutations were associated with more severe clinical phenotypes than those in the tail domain.

VL - 56 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23123319?dopt=Abstract ER - TY - JOUR T1 - Alteration of liver enzymes is a feature of the MYH9-related disease syndrome. JF - PLoS One Y1 - 2012 A1 - Pecci, Alessandro A1 - Biino, Ginevra A1 - Fierro, Tiziana A1 - Bozzi, Valeria A1 - Mezzasoma, Annamaria A1 - Noris, Patrizia A1 - Ramenghi, Ugo A1 - Loffredo, Giuseppe A1 - Fabris, Fabrizio A1 - Momi, Stefania A1 - Magrini, Umberto A1 - Pirastu, Mario A1 - Savoia, Anna A1 - Balduini, Carlo A1 - Gresele, Paolo KW - Abnormalities, Multiple KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Biopsy KW - Case-Control Studies KW - Child KW - Child, Preschool KW - Demography KW - Female KW - Follow-Up Studies KW - Humans KW - Immunohistochemistry KW - Infant KW - Liver KW - Liver Function Tests KW - Male KW - Middle Aged KW - Molecular Motor Proteins KW - Mutation KW - Myosin Heavy Chains KW - Odds Ratio KW - Syndrome KW - Young Adult AB -

BACKGROUND: MYH9-related disease (MYH9-RD) is a rare autosomal dominant genetic syndrome characterized by congenital thrombocytopenia associated with the risk of developing progressive nephropathy, sensorineural deafness, and presenile cataract. During the collection of a large case-series of patients with MYH9-RD we noticed several cases with unexplained elevation of liver enzymes. Our aim was to evaluate if the alteration of liver tests is a feature of the MYH9-RD and to define its clinical significance.

METHODS AND FINDINGS: Data concerning liver tests, prospectively recorded in the Italian Registry for MYH9-RD, were collected and compared with those of three control populations: patients with autoimmune thrombocytopenia, patients with inherited thrombocytopenias other than MYH9-RD, and the participants to a large epidemiologic survey in an Italian geographic isolate. Thirty-eight of 75 evaluable MYH9-RD patients (50.7%) showed an elevation of ALT and/or AST, and 17 of 63 (27.0%) an increase of GGT. The increases ranged from 1.9 ± 0.7 to 2.7 ± 1.6 fold the upper normal limit. The prevalence of liver test alterations was significantly higher in MYH9-RD patients than in each of the control populations, with odds ratios ranging from 8.2 (95% CIs 2.2-44.8) to 24.7 (14.8-40.8). Clinical follow-up and more detailed liver studies of a subset of patients, including ultrasound liver scan, liver elastography and liver biopsy in one case, did not show any significant structural damage or evolution towards liver insufficiency.

CONCLUSIONS: Elevation of liver enzymes is a frequent and previously unrecognized feature of the MYH9-RD syndrome; however, this defect does not appear to have poor prognostic value.

VL - 7 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22558294?dopt=Abstract ER - TY - JOUR T1 - Clinical and laboratory features of 103 patients from 42 Italian families with inherited thrombocytopenia derived from the monoallelic Ala156Val mutation of GPIbα (Bolzano mutation). JF - Haematologica Y1 - 2012 A1 - Noris, Patrizia A1 - Perrotta, Silverio A1 - Bottega, Roberta A1 - Pecci, Alessandro A1 - Melazzini, Federica A1 - Civaschi, Elisa A1 - Russo, Sabina A1 - Magrin, Silvana A1 - Loffredo, Giuseppe A1 - Di Salvo, Veronica A1 - Russo, Giovanna A1 - Casale, Maddalena A1 - De Rocco, Daniela A1 - Grignani, Claudio A1 - Cattaneo, Marco A1 - Baronci, Carlo A1 - Dragani, Alfredo A1 - Albano, Veronica A1 - Jankovic, Momcilo A1 - Scianguetta, Saverio A1 - Savoia, Anna A1 - Balduini, Carlo L KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Bernard-Soulier Syndrome KW - Child KW - Child, Preschool KW - Family Health KW - Female KW - Heterozygote KW - Humans KW - Infant KW - Italy KW - Male KW - Membrane Glycoproteins KW - Middle Aged KW - Mutation, Missense KW - Platelet Aggregation KW - Platelet Count KW - Platelet Glycoprotein GPIb-IX Complex KW - Polymorphism, Genetic KW - Thrombocytopenia KW - Thrombopoietin KW - Tubulin KW - Young Adult AB -

BACKGROUND: Bernard-Soulier syndrome is a very rare form of inherited thrombocytopenia that derives from mutations in GPIbα, GPIbβ, or GPIX and is typically inherited as a recessive disease. However, some years ago it was shown that the monoallelic c.515C>T transition in the GPIBA gene (Bolzano mutation) was responsible for macrothrombocytopenia in a few Italian patients.

DESIGN AND METHODS: Over the past 10 years, we have searched for the Bolzano mutation in all subjects referred to our institutions because of an autosomal, dominant form of thrombocytopenia of unknown origin.

RESULTS: We identified 42 new Italian families (103 cases) with a thrombocytopenia induced by monoallelic Bolzano mutation. Analyses of the geographic origin of affected pedigrees and haplotypes indicated that this mutation originated in southern Italy. Although the clinical expression was variable, patients with this mutation typically had a mild form of Bernard-Soulier syndrome with mild thrombocytopenia and bleeding tendency. The most indicative laboratory findings were enlarged platelets and reduced GPIb/IX/V platelet expression; in vitro platelet aggregation was normal in nearly all of the cases.

CONCLUSIONS: Our study indicates that monoallelic Bolzano mutation is the most frequent cause of inherited thrombocytopenia in Italy, affecting 20% of patients recruited at our institutions during the last 10 years. Because many people from southern Italy have emigrated during the last century, this mutation may have spread to other countries.

VL - 97 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21933849?dopt=Abstract ER - TY - JOUR T1 - MYH9-related disorders: report on a patient of Greek origin presenting with macroscopic hematuria and presenile cataract, caused by an R1165C mutation. JF - J Pediatr Hematol Oncol Y1 - 2012 A1 - Economou, Marina A1 - Batzios, Spyros P A1 - Pecci, Alessandro A1 - Printza, Nikoletta A1 - Savoia, Anna A1 - Barozzi, Serena A1 - Theodoridou, Stamatia A1 - Teli, Aikaterini A1 - Psillas, Georgios A1 - Zafeiriou, Dimitrios I KW - Adolescent KW - Cataract KW - Diagnosis, Differential KW - DNA Mutational Analysis KW - Greece KW - Hematuria KW - Humans KW - Male KW - Molecular Motor Proteins KW - Myosin Heavy Chains KW - Point Mutation AB -

Myosin heavy chain-9 (MYH9)-related disorders represent a heterogenous group of hereditary diseases caused by mutations in the gene encoding the heavy chain of nonmuscle myosin IIA. May-Hegglin anomaly and Fechtner, Sebastian, and Epstein syndromes are the four phenotypes of the disease, characterized by congenital macrothrombocytopenia and distinguished by different combinations of clinical signs that may include glomerulonephritis, sensorineural hearing loss, and presenile cataract. The spectrum of mutations responsible for the disease is wide and the existence of genotype-phenotype correlation remains a critical issue. We report the first case of an MYH9-RD in a patient of Greek origin presenting with macroscopic hematuria and presenile cataract caused by a p.R1165C mutation. The same mutation was present in the patient's father, who exhibited no extrahematological features of the disease. The p.R1165C mutation is one of the MYH9 alterations whose prognostic significance is still poorly defined. Thus, the patients described add to the limited existing data on the MYH9 mutations and their resultant phenotypes.

VL - 34 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22627578?dopt=Abstract ER - TY - JOUR T1 - Clinical and genetic aspects of Bernard-Soulier syndrome: searching for genotype/phenotype correlations. JF - Haematologica Y1 - 2011 A1 - Savoia, Anna A1 - Pastore, Annalisa A1 - De Rocco, Daniela A1 - Civaschi, Elisa A1 - Di Stazio, Mariateresa A1 - Bottega, Roberta A1 - Melazzini, Federica A1 - Bozzi, Valeria A1 - Pecci, Alessandro A1 - Magrin, Silvana A1 - Balduini, Carlo L A1 - Noris, Patrizia KW - Adolescent KW - Adult KW - Amino Acid Sequence KW - Bernard-Soulier Syndrome KW - Blood Platelets KW - Cell Shape KW - Child KW - Child, Preschool KW - Female KW - Genetic Association Studies KW - Genetic Markers KW - Hemorrhage KW - Homozygote KW - Humans KW - Italy KW - Male KW - Membrane Glycoproteins KW - Middle Aged KW - Molecular Sequence Data KW - Platelet Aggregation KW - Platelet Count KW - Platelet Glycoprotein GPIb-IX Complex KW - Point Mutation KW - Polymerase Chain Reaction KW - Ristocetin KW - Thrombocytopenia KW - von Willebrand Factor KW - Young Adult AB -

BACKGROUND: Bernard-Soulier syndrome is a severe bleeding disease due to a defect of GPIb/IX/V, a platelet complex that binds the von Willebrand factor. Due to the rarity of the disease, there are reports only on a few cases compromising any attempt to establish correlations between genotype and phenotype. In order to identify any associations, we describe the largest case series ever reported, which was evaluated systematically at the same center.

DESIGN AND METHODS: Thirteen patients with the disease and seven obligate carriers were enrolled. We collected clinical aspects and determined platelet features, including number and size, expression of membrane glycoproteins, and ristocetin induced platelet aggregation. Mutations were identified by direct sequencing of the GP1BA, GP1BB, and GP9 genes and their effect was shown by molecular modeling analyses.

RESULTS: Patients all had a moderate thrombocytopenia with giant platelets and a bleeding tendency whose severity varied among individuals. Consistent with expression levels of GPIbα always lower than 10% of control values, platelet aggregation was absent or severely reduced. Homozygous mutations were identified in the GP1BA, GP1BB and GP9 genes; six were novel alterations expected to destabilize the conformation of the respective protein. Except for obligate carriers of a GP9 mutation with a reduced GPIb/IX/V expression and defective aggregation, all the other carriers had no obvious anomalies.

CONCLUSIONS: Regardless of mutations identified, the patients' bleeding diathesis did not correlate with thrombocytopenia, which was always moderate, and platelet GPIbα expression, which was always severely impaired. Obligate carriers had features similar to controls though their GPIb/IX/V expression showed discrepancies. Aware of the limitations of our cohort, we cannot define any correlations. However, further investigations should be encouraged to better understand the causes of this rare and underestimated disease.

VL - 96 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21173099?dopt=Abstract ER - TY - JOUR T1 - Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families. JF - Blood Y1 - 2011 A1 - Noris, Patrizia A1 - Perrotta, Silverio A1 - Seri, Marco A1 - Pecci, Alessandro A1 - Gnan, Chiara A1 - Loffredo, Giuseppe A1 - Pujol-Moix, Núria A1 - Zecca, Marco A1 - Scognamiglio, Francesca A1 - De Rocco, Daniela A1 - Punzo, Francesca A1 - Melazzini, Federica A1 - Scianguetta, Saverio A1 - Casale, Maddalena A1 - Marconi, Caterina A1 - Pippucci, Tommaso A1 - Amendola, Giovanni A1 - Notarangelo, Lucia D A1 - Klersy, Catherine A1 - Civaschi, Elisa A1 - Balduini, Carlo L A1 - Savoia, Anna KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Ankyrin Repeat KW - Child KW - Cohort Studies KW - Family KW - Female KW - Gene Frequency KW - Humans KW - Inheritance Patterns KW - Male KW - Middle Aged KW - Mutation KW - Pedigree KW - Thrombocytopenia KW - Transcription Factors KW - Young Adult AB -

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'-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.

VL - 117 IS - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21467542?dopt=Abstract ER - TY - JOUR T1 - Mutations in the 5' UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2. JF - Am J Hum Genet Y1 - 2011 A1 - Pippucci, Tommaso A1 - Savoia, Anna A1 - Perrotta, Silverio A1 - Pujol-Moix, Núria A1 - Noris, Patrizia A1 - Castegnaro, Giovanni A1 - Pecci, Alessandro A1 - Gnan, Chiara A1 - Punzo, Francesca A1 - Marconi, Caterina A1 - Gherardi, Samuele A1 - Loffredo, Giuseppe A1 - De Rocco, Daniela A1 - Scianguetta, Saverio A1 - Barozzi, Serena A1 - Magini, Pamela A1 - Bozzi, Valeria A1 - Dezzani, Luca A1 - Di Stazio, Mariateresa A1 - Ferraro, Marcella A1 - Perini, Giovanni A1 - Seri, Marco A1 - Balduini, Carlo L KW - Ankyrin Repeat KW - Base Sequence KW - Chromosome Breakage KW - Chromosome Disorders KW - Conserved Sequence KW - Female KW - Genes, Dominant KW - Genetic Loci KW - Haploinsufficiency KW - Humans KW - Male KW - Molecular Sequence Data KW - Mutation KW - Pedigree KW - Thrombocytopenia AB -

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' 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's genome give evidence against haploinsufficiency as the pathogenetic mechanism for ANKRD26-mediated thrombocytopenia. The luciferase reporter assay suggests that these 5' 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.

VL - 88 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21211618?dopt=Abstract ER - TY - JOUR T1 - Recent advances in the understanding and management of MYH9-related inherited thrombocytopenias. JF - Br J Haematol Y1 - 2011 A1 - Balduini, Carlo L A1 - Pecci, Alessandro A1 - Savoia, Anna KW - Animals KW - Disease Models, Animal KW - Genetic Predisposition to Disease KW - Genotype KW - Humans KW - Mice KW - Molecular Motor Proteins KW - Mutation KW - Myosin Heavy Chains KW - Myosin Type II KW - Phenotype KW - Thrombocytopenia AB -

MYH9-related disease (MYH9-RD) is one of the most frequent forms of inherited thrombocytopenia. It is transmitted in an autosomal dominant fashion and derives from mutations of MYH9, the gene for the heavy chain of non-muscle myosin IIA. Patients present with congenital macrothrombocytopenia with mild bleeding tendency and may develop kidney dysfunction, deafness and cataracts later in life. The term MYH9-RD encompasses four autosomal-dominant thrombocytopenias that were previously described as distinct disorders, namely May-Hegglin Anomaly, Sebastian, Fechtner and Epstein syndromes. Thrombocytopenia is usually mild and derives from complex defects of megakaryocyte maturation and platelet formation. It is easily diagnosed, in that the presence of giant platelets in peripheral blood raises the suspicion of MYH9-RD and a simple immunofluorescence test on blood films confirms the diagnostic hypothesis. However, genotype/phenotype correlations have been recognized and mutation screening is therefore required to define the risk of acquiring extra-haematological defects. Results of a small clinical study suggested that a non-peptide thrombopoietin mimetic might greatly benefit both thrombocytopenia and bleeding tendency of MYH9-RD patients.

VL - 154 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21542825?dopt=Abstract ER - TY - JOUR T1 - Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations. JF - Blood Y1 - 2010 A1 - Pecci, Alessandro A1 - Gresele, Paolo A1 - Klersy, Catherine A1 - Savoia, Anna A1 - Noris, Patrizia A1 - Fierro, Tiziana A1 - Bozzi, Valeria A1 - Mezzasoma, Anna Maria A1 - Melazzini, Federica A1 - Balduini, Carlo L KW - Administration, Oral KW - Adolescent KW - Adult KW - Benzoates KW - Dose-Response Relationship, Drug KW - Female KW - Genetic Predisposition to Disease KW - Humans KW - Hydrazines KW - Male KW - Molecular Motor Proteins KW - Mutation KW - Myosin Heavy Chains KW - Platelet Aggregation KW - Platelet Count KW - Pyrazoles KW - Receptors, Thrombopoietin KW - Survival Rate KW - Thrombocytopenia KW - Treatment Outcome KW - Young Adult AB -

Platelet transfusion is currently the primary medical treatment for reducing thrombocytopenia in patients with inherited thrombocytopenias. To evaluate whether stimulating megakaryopoiesis could increase platelet count in these conditions, we treated patients with a severe thrombocytopenia induced by MYH9 mutations (MYH9-related disease) with a nonpeptide thrombopoietin receptor agonist, eltrombopag. Twelve adult patients with MYH9-RD and platelet counts of less than 50 × 10(9)/L received 50 mg of eltrombopag orally per day for 3 weeks. Patients who achieved a platelet count higher than 150 × 10(9)/L stopped therapy, those with 100 to 150 platelets × 10(9)/L continued treatment at the same eltrombopag dose for 3 additional weeks, while those with less than 100 platelets × 10(9)/L increased the eltrombopag dose to 75 mg for 3 weeks. Major responses (platelet count of at least 100 × 10(9)/L or 3 times the baseline value) were obtained in 8 patients, minor responses (platelet counts at least twice the baseline value) in 3. One patient did not respond. Bleeding tendency disappeared in 8 of 10 patients with bleeding symptoms at baseline. Mild adverse events were reported in 2 patients. The availability of thrombopoietin mimetics opened new prospects in the treatment of inherited thrombocytopenias. This study is registered at www.clinicaltrials.gov as NCT01133860 (European Union Drug Regulating Authorities Clinical Trials number 2008-001903-42).

VL - 116 IS - 26 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20844233?dopt=Abstract ER - TY - JOUR T1 - A G to C transversion at the last nucleotide of exon 25 of the MYH9 gene results in a missense mutation rather than in a splicing defect. JF - Eur J Med Genet Y1 - 2010 A1 - Vettore, Silvia A1 - De Rocco, Daniela A1 - Gerber, Bernhard A1 - Scandellari, Raffaella A1 - Bianco, Anna Monica A1 - Balduini, Carlo L A1 - Pecci, Alessandro A1 - Fabris, Fabrizio A1 - Savoia, Anna KW - Adolescent KW - Adult KW - Blood Platelets KW - Computational Biology KW - Exons KW - Female KW - Humans KW - Inclusion Bodies KW - Kidney Failure, Chronic KW - Molecular Motor Proteins KW - Mutation, Missense KW - Myosin Heavy Chains KW - Neutrophils KW - Nonmuscle Myosin Type IIA KW - Nucleotides KW - RNA Splicing KW - Thrombocytopenia AB -

MYH9-related disease (MYH9-RD) is a rare autosomal dominant disorder caused by mutations in MYH9, the gene encoding the heavy chain of non-muscle myosin IIA. Patients present with congenital macrothrombocytopenia and inclusion bodies in neutrophils and might develop sensorineural deafness, presenile cataract, and/or progressive nephropathy leading to end-stage renal failure. In two families with macrothrombocytopenia we identified a novel c.3485G > C mutation in the last nucleotide of exon 25. Bioinformatic tools for splice site prediction and minigene functional test predicted splicing anomalies of exon 25. However, analysis of RNA purified from patient's peripheral blood did not allowed us to detect any anomalies, suggesting that RNA processing is correct at least in this tissue. Therefore, we concluded that c.3485G > C leads to a novel missense mutation (p.Arg1162Thr) of myosin-9, which resulted to be slightly degraded in patient platelets. A precise definition of the effect of mutations is fundamental to improve our knowledge into the pathogenetic mechanisms responsible for the disease.

VL - 53 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20603234?dopt=Abstract ER -