%0 Journal Article %J Br J Haematol %D 2018 %T ACTN1 mutations lead to a benign form of platelet macrocytosis not always associated with thrombocytopenia. %A Faleschini, Michela %A Melazzini, Federica %A Marconi, Caterina %A Giangregorio, Tania %A Pippucci, Tommaso %A Cigalini, Elena %A Pecci, Alessandro %A Bottega, Roberta %A Ramenghi, Ugo %A Siitonen, Timo %A Seri, Marco %A Pastore, Annalisa %A Savoia, Anna %A Noris, Patrizia %X

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.

%B Br J Haematol %V 183 %P 276-288 %8 2018 Oct %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30351444?dopt=Abstract %R 10.1111/bjh.15531 %0 Journal Article %J Blood Coagul Fibrinolysis %D 2015 %T Abnormal cytoplasmic extensions associated with active αIIbβ3 are probably the cause for macrothrombocytopenia in Glanzmann thrombasthenia-like syndrome. %A Hauschner, Hagit %A Mor-Cohen, Ronit %A Messineo, Stefania %A Mansour, Wissam %A Seligsohn, Uri %A Savoia, Anna %A Rosenberg, Nurit %K Animals %K Cell Line %K Cricetinae %K Cytoskeleton %K DNA, Complementary %K Fibrinogen %K Genetic Vectors %K Humans %K Integrin alpha2 %K Integrin beta3 %K Megakaryocytes %K Mesocricetus %K Microtubules %K Mutation, Missense %K Platelet Glycoprotein GPIIb-IIIa Complex %K Protein Conformation %K Protein Interaction Mapping %K Protein Structure, Tertiary %K Recombinant Fusion Proteins %K Sequence Deletion %K Thrombasthenia %K Tubulin %K von Willebrand Factor %X

Mutations in the ITGA2B or ITGB3 genes that encode for the αIIbβ3 platelet integrin usually cause Glanzmann thrombasthenia, a severe autosomal recessive bleeding disorder characterized by absence of platelet aggregation, but normal platelet number and size. Several rare mutations cause a Glanzmann-like syndrome which manifests macrothrombocytopenia and usually displays autosomal dominant inheritance. The exact mechanism causing Glanzmann-like syndrome is unknown. One typical example of Glanzmann-like mutations causes deletion of 40 amino acids (p.647-686) in the β3 β-tail domain (βTD_del) that was found in the heterozygous state in Italian and Japanese families. A second example is a missense mutation, C560R, located in the epidermal growth factor-like domain, found in the homozygous state in a French patient. Both mutations cause constitutive activation of αIIbβ3, but differ in their surface expression. In the current study, we generated cultured cells expressing β3-βTD_del or β3-C560R mutations along with wild-type αIIb, and examined the cells' ability to create tubulin-dependent protrusions compared to cells expressing wild-type αIIbβ3. Unlike cells expressing wild-type αIIbβ3, cells harboring each of the mutations exhibited abnormal cytoplasmic extensions on immobilized fibrinogen or Von Willebrand factor, which resembled extensions formed in megakaryocyte leading to proplatelets. Moreover, we showed that formation of abnormal extensions occurred also in wild-type αIIbβ3 cells when activated by activating antibody. These results suggest that the active conformation of αIIbβ3 can induce cytoskeletal rearrangements that lead to impaired proplatelet formation.

%B Blood Coagul Fibrinolysis %V 26 %P 302-8 %8 2015 Apr %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/25806962?dopt=Abstract %R 10.1097/MBC.0000000000000241 %0 Journal Article %J Blood %D 2015 %T ACTN1-related thrombocytopenia: identification of novel families for phenotypic characterization. %A Bottega, Roberta %A Marconi, Caterina %A Faleschini, Michela %A Baj, Gabriele %A Cagioni, Claudia %A Pecci, Alessandro %A Pippucci, Tommaso %A Ramenghi, Ugo %A Pardini, Simonetta %A Ngu, Loretta %A Baronci, Carlo %A Kunishima, Shinji %A Balduini, Carlo L %A Seri, Marco %A Savoia, Anna %A Noris, Patrizia %K Actinin %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Blood Platelets %K Case-Control Studies %K Child %K Child, Preschool %K Female %K Gene Expression %K Genotype %K Heterozygote %K Humans %K Male %K Middle Aged %K Mutation, Missense %K Pedigree %K Phenotype %K Platelet Count %K Severity of Illness Index %K Thrombocytopenia %K Thrombopoiesis %K Thrombopoietin %X

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.

%B Blood %V 125 %P 869-72 %8 2015 Jan 29 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/25361813?dopt=Abstract %R 10.1182/blood-2014-08-594531 %0 Journal Article %J Haematologica %D 2014 %T Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. %A Noris, Patrizia %A Schlegel, Nicole %A Klersy, Catherine %A Heller, Paula G %A Civaschi, Elisa %A Pujol-Moix, Núria %A Fabris, Fabrizio %A Favier, Rémi %A Gresele, Paolo %A Latger-Cannard, Véronique %A Cuker, Adam %A Nurden, Paquita %A Greinacher, Andreas %A Cattaneo, Marco %A De Candia, Erica %A Pecci, Alessandro %A Hurtaud-Roux, Marie-Françoise %A Glembotsky, Ana C %A Muñiz-Diaz, Eduardo %A Randi, Maria Luigia %A Trillot, Nathalie %A Bury, Loredana %A Lecompte, Thomas %A Marconi, Caterina %A Savoia, Anna %A Balduini, Carlo L %A Bayart, Sophie %A Bauters, Anne %A Benabdallah-Guedira, Schéhérazade %A Boehlen, Françoise %A Borg, Jeanne-Yvonne %A Bottega, Roberta %A Bussel, James %A De Rocco, Daniela %A de Maistre, Emmanuel %A Faleschini, Michela %A Falcinelli, Emanuela %A Ferrari, Silvia %A Ferster, Alina %A Fierro, Tiziana %A Fleury, Dominique %A Fontana, Pierre %A James, Chloé %A Lanza, Francois %A Le Cam Duchez, Véronique %A Loffredo, Giuseppe %A Magini, Pamela %A Martin-Coignard, Dominique %A Menard, Fanny %A Mercier, Sandra %A Mezzasoma, Annamaria %A Minuz, Pietro %A Nichele, Ilaria %A Notarangelo, Lucia D %A Pippucci, Tommaso %A Podda, Gian Marco %A Pouymayou, Catherine %A Rigouzzo, Agnes %A Royer, Bruno %A Sie, Pierre %A Siguret, Virginie %A Trichet, Catherine %A Tucci, Alessandra %A Saposnik, Béatrice %A Veneri, Dino %K Adult %K Female %K Humans %K Infant, Newborn %K Pregnancy %K Pregnancy Complications, Hematologic %K Retrospective Studies %K Thrombocytopenia %K Young Adult %X

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.

%B Haematologica %V 99 %P 1387-94 %8 2014 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/24763399?dopt=Abstract %R 10.3324/haematol.2014.105924 %0 Journal Article %J PLoS One %D 2012 %T Alteration of liver enzymes is a feature of the MYH9-related disease syndrome. %A Pecci, Alessandro %A Biino, Ginevra %A Fierro, Tiziana %A Bozzi, Valeria %A Mezzasoma, Annamaria %A Noris, Patrizia %A Ramenghi, Ugo %A Loffredo, Giuseppe %A Fabris, Fabrizio %A Momi, Stefania %A Magrini, Umberto %A Pirastu, Mario %A Savoia, Anna %A Balduini, Carlo %A Gresele, Paolo %K Abnormalities, Multiple %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Biopsy %K Case-Control Studies %K Child %K Child, Preschool %K Demography %K Female %K Follow-Up Studies %K Humans %K Immunohistochemistry %K Infant %K Liver %K Liver Function Tests %K Male %K Middle Aged %K Molecular Motor Proteins %K Mutation %K Myosin Heavy Chains %K Odds Ratio %K Syndrome %K Young Adult %X

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.

%B PLoS One %V 7 %P e35986 %8 2012 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/22558294?dopt=Abstract %R 10.1371/journal.pone.0035986