@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 {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 {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 {3549, title = {Molecular analysis of Fanconi anemia: the experience of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Onco-Hematology.}, journal = {Haematologica}, volume = {99}, year = {2014}, month = {2014 Jun}, pages = {1022-31}, abstract = {

Fanconi anemia is an inherited disease characterized by congenital malformations, pancytopenia, cancer predisposition, and sensitivity to cross-linking agents. The molecular diagnosis of Fanconi anemia is relatively complex for several aspects including genetic heterogeneity with mutations in at least 16 different genes. In this paper, we report the mutations identified in 100 unrelated probands enrolled into the National Network of the Italian Association of Pediatric Hematoly and Oncology. In approximately half of these cases, mutational screening was carried out after retroviral complementation analyses or protein analysis. In the other half, the analysis was performed on the most frequently mutated genes or using a next generation sequencing approach. We identified 108 distinct variants of the FANCA, FANCG, FANCC, FANCD2, and FANCB genes in 85, 9, 3, 2, and 1 families, respectively. Despite the relatively high number of private mutations, 45 of which are novel Fanconi anemia alleles, 26\% of the FANCA alleles are due to 5 distinct mutations. Most of the mutations are large genomic deletions and nonsense or frameshift mutations, although we identified a series of missense mutations, whose pathogenetic role was not always certain. The molecular diagnosis of Fanconi anemia is still a tiered procedure that requires identifying candidate genes to avoid useless sequencing. Introduction of next generation sequencing strategies will greatly improve the diagnostic process, allowing a rapid analysis of all the genes.

}, keywords = {Amino Acid Substitution, Cell Line, Cohort Studies, Computational Biology, Databases, Nucleic Acid, Fanconi Anemia, Fanconi Anemia Complementation Group Proteins, Founder Effect, Genotype, Humans, Italy, Mosaicism, Mutation, Polymorphism, Single Nucleotide}, issn = {1592-8721}, doi = {10.3324/haematol.2014.104224}, author = {De Rocco, Daniela and Bottega, Roberta and Cappelli, Enrico and Cavani, Simona and Criscuolo, Maria and Nicchia, Elena and Corsolini, Fabio and Greco, Chiara and Borriello, Adriana and Svahn, Johanna and Pillon, Marta and Mecucci, Cristina and Casazza, Gabriella and Verzegnassi, Federico and Cugno, Chiara and Locasciulli, Anna and Farruggia, Piero and Longoni, Daniela and Ramenghi, Ugo and Barberi, Walter and Tucci, Fabio and Perrotta, Silverio and Grammatico, Paola and Hanenberg, Helmut and Della Ragione, Fulvio and Dufour, Carlo and Savoia, Anna} } @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 {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 {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 {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 {1696, title = {MYH9-related disease: Report on five German families and description of a novel mutation.}, journal = {Ann Hematol}, volume = {89}, year = {2010}, month = {2010 Oct}, pages = {1057-9}, keywords = {Adult, Aged, Child, Chromosome Disorders, DNA Mutational Analysis, Germany, Humans, Infant, Molecular Motor Proteins, Mutation, Myosin Heavy Chains, Young Adult}, issn = {1432-0584}, doi = {10.1007/s00277-010-0928-y}, author = {Savoia, Anna and Germeshausen, Manuela and De Rocco, Daniela and Henschel, Bettina and Kratz, Christian P and Kuhlen, Michaela and Rath, Bettina and Steuhl, Klaus-Peter and Wermes, Cornelia and Ballmaier, Matthias} }