@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 {10820, title = {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.}, journal = {Hamostaseologie}, volume = {39}, year = {2019}, month = {2019 Feb}, pages = {87-94}, abstract = {

-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.

}, issn = {2567-5761}, doi = {10.1055/s-0038-1645840}, author = {Zaninetti, Carlo and De Rocco, Daniela and Giangregorio, Tania and Bozzi, Valeria and Demeter, Judit and Leoni, Pietro and Noris, Patrizia and Ryh{\"a}nen, Samppa and Barozzi, Serena and Pecci, Alessandro and Savoia, Anna} } @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 {10819, title = {MYH9: Structure, functions and role of non-muscle myosin IIA in human disease.}, journal = {Gene}, volume = {664}, year = {2018}, month = {2018 Jul 20}, pages = {152-167}, abstract = {

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.

}, keywords = {Animals, Cell Line, Deafness, Hearing Loss, Sensorineural, Humans, Mice, Molecular Motor Proteins, Mutation, Myosin Heavy Chains, Neoplasms, Nonmuscle Myosin Type IIA, Phosphorylation, Renal Insufficiency, Chronic, Thrombocytopenia}, issn = {1879-0038}, doi = {10.1016/j.gene.2018.04.048}, author = {Pecci, Alessandro and Ma, Xuefei and Savoia, Anna and Adelstein, Robert S} } @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 {10480, title = {MYH9 gene mutations associated with bleeding.}, journal = {Platelets}, volume = {28}, year = {2017}, month = {2017 05}, pages = {312-315}, keywords = {Asymptomatic Diseases, Blood Platelets, Cell Size, Chromosomes, Human, Pair 22, Exons, Gene Expression, Genetic Association Studies, Genotype, Hearing Loss, Sensorineural, Hemorrhage, Humans, Molecular Motor Proteins, Mutation, Myosin Heavy Chains, Phenotype, Platelet Count, Protein Domains, Severity of Illness Index, Thrombocytopenia}, issn = {1369-1635}, doi = {10.1080/09537104.2017.1294250}, author = {Savoia, Anna and De Rocco, Daniela and Pecci, Alessandro} } @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 {7718, title = {Nonmuscle Myosin Heavy Chain IIA Mutation Predicts Severity and Progression of Sensorineural Hearing Loss in Patients With MYH9-Related Disease.}, journal = {Ear Hear}, volume = {37}, year = {2016}, month = {2016 Jan-Feb}, pages = {112-20}, abstract = {

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.

}, issn = {1538-4667}, doi = {10.1097/AUD.0000000000000198}, author = {Verver, Eva J J and Topsakal, Vedat and Kunst, Henricus P M and Huygen, Patrick L M and Heller, Paula G and Pujol-Moix, N{\'u}ria and Savoia, Anna and Benazzo, Marco and Fierro, Tiziana and Grolman, Wilko and Gresele, Paolo and Pecci, Alessandro} } @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 {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 {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 {3550, title = {Mutations of cytochrome c identified in patients with thrombocytopenia THC4 affect both apoptosis and cellular bioenergetics.}, journal = {Biochim Biophys Acta}, volume = {1842}, year = {2014}, month = {2014 Feb}, pages = {269-74}, abstract = {

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.

}, keywords = {Amino Acid Sequence, Animals, Apoptosis, Base Sequence, Cells, Cultured, Child, Preschool, Cytochromes c, DNA Mutational Analysis, Embryo, Mammalian, Energy Metabolism, Family Health, Female, Fibroblasts, Humans, Lung, Male, Mice, Molecular Sequence Data, Mutation, Missense, Oxygen Consumption, Pedigree, Saccharomyces cerevisiae, Sequence Homology, Amino Acid, Thrombocytopenia}, issn = {0006-3002}, doi = {10.1016/j.bbadis.2013.12.002}, author = {De Rocco, Daniela and Cerqua, Cristina and Goffrini, Paola and Russo, Giovanna and Pastore, Annalisa and Meloni, Francesca and Nicchia, Elena and Moraes, Carlos T and Pecci, Alessandro and Salviati, Leonardo and Savoia, Anna} } @article {3635, title = {MYH9-related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations.}, journal = {Hum Mutat}, volume = {35}, year = {2014}, month = {2014 Feb}, pages = {236-47}, abstract = {

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{\textquoteright} clinical management and genetic counseling and are discussed in view of molecular pathogenesis of MYH9-RD.

}, keywords = {Adult, Age of Onset, Amino Acid Substitution, Cataract, Female, Genetic Association Studies, Genotype, Hearing Loss, Sensorineural, Humans, Italy, Linear Models, Male, Molecular Motor Proteins, Mutation, Myosin Heavy Chains, Phenotype, Risk Factors, Thrombocytopenia}, issn = {1098-1004}, doi = {10.1002/humu.22476}, author = {Pecci, Alessandro and Klersy, Catherine and Gresele, Paolo and Lee, Kieran J D and De Rocco, Daniela and Bozzi, Valeria and Russo, Giovanna and Heller, Paula G and Loffredo, Giuseppe and Ballmaier, Matthias and Fabris, Fabrizio and Beggiato, Eloise and Kahr, Walter H A and Pujol-Moix, N{\'u}ria and Platokouki, Helen and Van Geet, Christel and Noris, Patrizia and Yerram, Preethi and Hermans, Cedric and Gerber, Bernhard and Economou, Marina and De Groot, Marco and Zieger, Barbara and De Candia, Erica and Fraticelli, Vincenzo and Kersseboom, Rogier and Piccoli, Giorgina B and Zimmermann, Stefanie and Fierro, Tiziana and Glembotsky, Ana C and Vianello, Fabrizio and Zaninetti, Carlo and Nicchia, Elena and G{\"u}thner, Christiane and Baronci, Carlo and Seri, Marco and Knight, Peter J and Balduini, Carlo L and Savoia, Anna} } @article {3634, title = {Platelet diameters in inherited thrombocytopenias: analysis of 376 patients with all known disorders.}, journal = {Blood}, volume = {124}, year = {2014}, month = {2014 Aug 7}, pages = {e4-e10}, abstract = {

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.

}, keywords = {Adolescent, Adult, Blood Platelets, Case-Control Studies, Cell Size, Child, Child, Preschool, Diagnosis, Differential, Female, Hearing Loss, Sensorineural, Humans, Infant, Male, Middle Aged, Molecular Motor Proteins, Mutation, Myosin Heavy Chains, Purpura, Thrombocytopenic, Idiopathic, Thrombocytopenia, Young Adult}, issn = {1528-0020}, doi = {10.1182/blood-2014-03-564328}, author = {Noris, Patrizia and Biino, Ginevra and Pecci, Alessandro and Civaschi, Elisa and Savoia, Anna and Seri, Marco and Melazzini, Federica and Loffredo, Giuseppe and Russo, Giovanna and Bozzi, Valeria and Notarangelo, Lucia Dora and Gresele, Paolo and Heller, Paula G and Pujol-Moix, N{\'u}ria and Kunishima, Shinji and Cattaneo, Marco and Bussel, James and De Candia, Erica and Cagioni, Claudia and Ramenghi, Ugo and Barozzi, Serena and Fabris, Fabrizio and Balduini, Carlo L} } @article {3552, title = {Spectrum of the mutations in Bernard-Soulier syndrome.}, journal = {Hum Mutat}, volume = {35}, year = {2014}, month = {2014 Sep}, pages = {1033-45}, abstract = {

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.

}, keywords = {Alleles, Bernard-Soulier Syndrome, Databases, Nucleic Acid, Founder Effect, Genetic Variation, Humans, Mutation, Platelet Glycoprotein GPIb-IX Complex, Polymorphism, Single Nucleotide, von Willebrand Diseases, Web Browser}, issn = {1098-1004}, doi = {10.1002/humu.22607}, author = {Savoia, Anna and Kunishima, Shinji and De Rocco, Daniela and Zieger, Barbara and Rand, Margaret L and Pujol-Moix, N{\'u}ria and Caliskan, Umran and Tokgoz, Huseyin and Pecci, Alessandro and Noris, Patrizia and Srivastava, Alok and Ward, Christopher and Morel-Kopp, Marie-Christine and Alessi, Marie-Christine and Bellucci, Sylvia and Beurrier, Philippe and de Maistre, Emmanuel and Favier, R{\'e}mi and H{\'e}zard, Nathalie and Hurtaud-Roux, Marie-Fran{\c c}oise and Latger-Cannard, V{\'e}ronique and Lavenu-Bombled, C{\'e}cile and Proulle, Val{\'e}rie and Meunier, Sandrine and N{\'e}grier, Claude and Nurden, Alan and Randrianaivo, Hanitra and Fabris, Fabrizio and Platokouki, Helen and Rosenberg, Nurit and HadjKacem, Basma and Heller, Paula G and Karimi, Mehran and Balduini, Carlo L and Pastore, Annalisa and Lanza, Francois} } @article {1993, title = {MYH9-related disease: five novel mutations expanding the spectrum of causative mutations and confirming genotype/phenotype correlations.}, journal = {Eur J Med Genet}, volume = {56}, year = {2013}, month = {2013 Jan}, pages = {7-12}, abstract = {

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.

}, keywords = {Adolescent, Adult, Amino Acid Sequence, Amino Acid Substitution, Base Sequence, Child, Child, Preschool, Exons, Female, Genes, Dominant, Genetic Association Studies, Humans, Male, Middle Aged, Models, Molecular, Molecular Motor Proteins, Molecular Sequence Data, Mutation, Myosin Heavy Chains, Pedigree, Protein Conformation, Sequence Alignment, Syndrome, Thrombocytopenia, Young Adult}, issn = {1878-0849}, doi = {10.1016/j.ejmg.2012.10.009}, author = {De Rocco, Daniela and Zieger, Barbara and Platokouki, Helen and Heller, Paula G and Pastore, Annalisa and Bottega, Roberta and Noris, Patrizia and Barozzi, Serena and Glembotsky, Ana C and Pergantou, Helen and Balduini, Carlo L and Savoia, Anna and Pecci, Alessandro} } @article {1921, title = {Alteration of liver enzymes is a feature of the MYH9-related disease syndrome.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e35986}, abstract = {

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 {\textpm} 0.7 to 2.7 {\textpm} 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.

}, keywords = {Abnormalities, Multiple, Adolescent, Adult, Aged, Aged, 80 and over, Biopsy, Case-Control Studies, Child, Child, Preschool, Demography, Female, Follow-Up Studies, Humans, Immunohistochemistry, Infant, Liver, Liver Function Tests, Male, Middle Aged, Molecular Motor Proteins, Mutation, Myosin Heavy Chains, Odds Ratio, Syndrome, Young Adult}, issn = {1932-6203}, doi = {10.1371/journal.pone.0035986}, author = {Pecci, Alessandro and Biino, Ginevra and Fierro, Tiziana and Bozzi, Valeria and Mezzasoma, Annamaria and Noris, Patrizia and Ramenghi, Ugo and Loffredo, Giuseppe and Fabris, Fabrizio and Momi, Stefania and Magrini, Umberto and Pirastu, Mario and Savoia, Anna and Balduini, Carlo and Gresele, Paolo} } @article {1922, title = {Clinical and laboratory features of 103 patients from 42 Italian families with inherited thrombocytopenia derived from the monoallelic Ala156Val mutation of GPIbα (Bolzano mutation).}, journal = {Haematologica}, volume = {97}, year = {2012}, month = {2012 Jan}, pages = {82-8}, abstract = {

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.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Bernard-Soulier Syndrome, Child, Child, Preschool, Family Health, Female, Heterozygote, Humans, Infant, Italy, Male, Membrane Glycoproteins, Middle Aged, Mutation, Missense, Platelet Aggregation, Platelet Count, Platelet Glycoprotein GPIb-IX Complex, Polymorphism, Genetic, Thrombocytopenia, Thrombopoietin, Tubulin, Young Adult}, issn = {1592-8721}, doi = {10.3324/haematol.2011.050682}, author = {Noris, Patrizia and Perrotta, Silverio and Bottega, Roberta and Pecci, Alessandro and Melazzini, Federica and Civaschi, Elisa and Russo, Sabina and Magrin, Silvana and Loffredo, Giuseppe and Di Salvo, Veronica and Russo, Giovanna and Casale, Maddalena and De Rocco, Daniela and Grignani, Claudio and Cattaneo, Marco and Baronci, Carlo and Dragani, Alfredo and Albano, Veronica and Jankovic, Momcilo and Scianguetta, Saverio and Savoia, Anna and Balduini, Carlo L} } @article {1920, title = {MYH9-related disorders: report on a patient of Greek origin presenting with macroscopic hematuria and presenile cataract, caused by an R1165C mutation.}, journal = {J Pediatr Hematol Oncol}, volume = {34}, year = {2012}, month = {2012 Aug}, pages = {412-5}, abstract = {

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{\textquoteright}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.

}, keywords = {Adolescent, Cataract, Diagnosis, Differential, DNA Mutational Analysis, Greece, Hematuria, Humans, Male, Molecular Motor Proteins, Myosin Heavy Chains, Point Mutation}, issn = {1536-3678}, doi = {10.1097/MPH.0b013e318257a64b}, author = {Economou, Marina and Batzios, Spyros P and Pecci, Alessandro and Printza, Nikoletta and Savoia, Anna and Barozzi, Serena and Theodoridou, Stamatia and Teli, Aikaterini and Psillas, Georgios and Zafeiriou, Dimitrios I} } @article {1697, title = {Clinical and genetic aspects of Bernard-Soulier syndrome: searching for genotype/phenotype correlations.}, journal = {Haematologica}, volume = {96}, year = {2011}, month = {2011 Mar}, pages = {417-23}, abstract = {

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{\textquoteright} 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.

}, keywords = {Adolescent, Adult, Amino Acid Sequence, Bernard-Soulier Syndrome, Blood Platelets, Cell Shape, Child, Child, Preschool, Female, Genetic Association Studies, Genetic Markers, Hemorrhage, Homozygote, Humans, Italy, Male, Membrane Glycoproteins, Middle Aged, Molecular Sequence Data, Platelet Aggregation, Platelet Count, Platelet Glycoprotein GPIb-IX Complex, Point Mutation, Polymerase Chain Reaction, Ristocetin, Thrombocytopenia, von Willebrand Factor, Young Adult}, issn = {1592-8721}, doi = {10.3324/haematol.2010.032631}, author = {Savoia, Anna and Pastore, Annalisa and De Rocco, Daniela and Civaschi, Elisa and Di Stazio, Mariateresa and Bottega, Roberta and Melazzini, Federica and Bozzi, Valeria and Pecci, Alessandro and Magrin, Silvana and Balduini, Carlo L and Noris, Patrizia} } @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} } @article {1735, title = {Recent advances in the understanding and management of MYH9-related inherited thrombocytopenias.}, journal = {Br J Haematol}, volume = {154}, year = {2011}, month = {2011 Jul}, pages = {161-74}, abstract = {

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.

}, keywords = {Animals, Disease Models, Animal, Genetic Predisposition to Disease, Genotype, Humans, Mice, Molecular Motor Proteins, Mutation, Myosin Heavy Chains, Myosin Type II, Phenotype, Thrombocytopenia}, issn = {1365-2141}, doi = {10.1111/j.1365-2141.2011.08716.x}, author = {Balduini, Carlo L and Pecci, Alessandro and Savoia, Anna} } @article {1687, title = {Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations.}, journal = {Blood}, volume = {116}, year = {2010}, month = {2010 Dec 23}, pages = {5832-7}, abstract = {

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 {\texttimes} 10(9)/L received 50 mg of eltrombopag orally per day for 3 weeks. Patients who achieved a platelet count higher than 150 {\texttimes} 10(9)/L stopped therapy, those with 100 to 150 platelets {\texttimes} 10(9)/L continued treatment at the same eltrombopag dose for 3 additional weeks, while those with less than 100 platelets {\texttimes} 10(9)/L increased the eltrombopag dose to 75 mg for 3 weeks. Major responses (platelet count of at least 100 {\texttimes} 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).

}, keywords = {Administration, Oral, Adolescent, Adult, Benzoates, Dose-Response Relationship, Drug, Female, Genetic Predisposition to Disease, Humans, Hydrazines, Male, Molecular Motor Proteins, Mutation, Myosin Heavy Chains, Platelet Aggregation, Platelet Count, Pyrazoles, Receptors, Thrombopoietin, Survival Rate, Thrombocytopenia, Treatment Outcome, Young Adult}, issn = {1528-0020}, doi = {10.1182/blood-2010-08-304725}, author = {Pecci, Alessandro and Gresele, Paolo and Klersy, Catherine and Savoia, Anna and Noris, Patrizia and Fierro, Tiziana and Bozzi, Valeria and Mezzasoma, Anna Maria and Melazzini, Federica and Balduini, Carlo L} } @article {1712, title = {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.}, journal = {Eur J Med Genet}, volume = {53}, year = {2010}, month = {2010 Sep-Oct}, pages = {256-60}, abstract = {

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{\textquoteright}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.

}, keywords = {Adolescent, Adult, Blood Platelets, Computational Biology, Exons, Female, Humans, Inclusion Bodies, Kidney Failure, Chronic, Molecular Motor Proteins, Mutation, Missense, Myosin Heavy Chains, Neutrophils, Nonmuscle Myosin Type IIA, Nucleotides, RNA Splicing, Thrombocytopenia}, issn = {1878-0849}, doi = {10.1016/j.ejmg.2010.06.010}, author = {Vettore, Silvia and De Rocco, Daniela and Gerber, Bernhard and Scandellari, Raffaella and Bianco, Anna Monica and Balduini, Carlo L and Pecci, Alessandro and Fabris, Fabrizio and Savoia, Anna} }