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10 results on '"Malattia MYH9 associata"'

1. MYH9related disease: A novel missense Ala95Asp mutation of theMYH9gene

Author

Alessandro Pecci, Giorgia Girotto, Daniela De Rocco, Paula G. Heller, Annalisa Pastore, Ana C. Glembotsky, Felisa C. Molinas, Rosana F. Marta, Anna Savoia, Valeria Bozzi, DE ROCCO, Daniela, Heller, Pg, Girotto, Giorgia, Pastore, A, Glembotsky, Ac, Marta, Rf, Bozzi, V, Pecci, A, Molinas, Fc, Savoia, Anna, de Rocco, D., Heller, P. G., Girotto, G., Pastore, Annalisa, Glembotsky, A. C., Marta, R. F., Bozzi, V., Pecci, Alessandro, Molinas, F. C., and Savoia, A.

Subjects
Adult, Male, Models, Molecular, CIENCIAS MÉDICAS Y DE LA SALUD, neutrophil aggregate, DNA Mutational Analysis, Molecular Sequence Data, MYH9 gene, Mutation, Missense, Disease, MYH9-related disease, Malattia MYH9 associata, Biology, Inclusion bodies, mutational screening, Myosin, macrothrombocytopenia, medicine, Animals, Humans, Missense mutation, Amino Acid Sequence, Gene, Genetics, Aspartic Acid, Alanine, Base Sequence, Myosin Heavy Chains, Molecular Motor Proteins, Hematology, General Medicine, Bioquímica y Biología Molecular, medicine.disease, Pedigree, Protein Structure, Tertiary, Medicina Básica, Mutation (genetic algorithm), Immunology, Female, Sequence Alignment, Nephritis, Kidney disease
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 nephritis leading to end-stage renal failure. In a family with eight individuals suffering from macrothrombocytopenia and hearing impairment we identified a novel c.Ala95Asp mutation. Affecting the motor domain of the protein, the mutation is likely to be associated with a severe phenotype. Therefore, this family should be carefully monitored to follow-up the renal status even though the affected members do not seem to be at risk of early kidney disease. Fil: de Rocco, Daniela. Università degli Studi di Trieste; Italia Fil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Girotto, Giorgia. Università degli Studi di Trieste; Italia Fil: Pastore, Annalisa. National Institute for Medical Research; Reino Unido Fil: Glembotsky, Ana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Marta, Rosana Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Bozzi, Valeria. Universita Degli Studi Di Pavia; Italia Fil: Pecci, Alessandro. Universita Degli Studi Di Pavia; Italia Fil: Molinas, Felisa Concepción. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Savoia, Anna. Università degli Studi di Trieste; Italia

Published
2009
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2. MYH9-Related Disease: A Novel Prognostic Model to Predict the Clinical Evolution of the Disease Based on Genotype-Phenotype Correlations

Author

Pecci, A, Klersy, C, Gresele, P, Lee, K, De Rocco, D, Bozzi, V, Russo, G, Heller, Pg, Loffredo, G, Ballmaier, M, Fabris, F, Beggiato, E, Kahr, Wha, Pujol-Moix, N, Platokouki, H, Matthijs, G, Noris, P, Yerram, P, Hermans, C, Batzios, S, De Groot, M, Zieger, B, De Candia, E, Fraticelli, V, Kersseboom, R, Piccoli, Gb, Zimmermann, S, Zaninetti, C, Nicchia, E, Baronci, C, Seri, M, Knight, Pj, Balduini, Cl, Savoia, A, Van Geet, C, Geber, B, Economou, M, Fierro, T, Glembotsky, Ac, Vianello, F, Guthner, C., Pecci, A, Klersy, C, Gresele, P, Lee, Kj, De Rocco, D, Bozzi, V, Russo, G, Heller, Pg, Loffredo, G, Ballmaier, M, Fabris, F, Beggiato, E, Kahr, Wh, Pujol-Moix, N, Platokouki, H, Van Geet, C, Noris, P, Yerram, P, Hermans, C, Gerber, B, Economou, M, De Groot, M, Zieger, B, De Candia, E, Fraticelli, V, Kersseboom, R, Piccoli, Gb, Zimmermann, S, Fierro, T, Glembotsky, Ac, Vianello, F, Zaninetti, C, Nicchia, E, Güthner, C, Baronci, C, Seri, M, Knight, Pj, Balduini, Cl, Savoia, A., DE ROCCO, Daniela, Pujol Moix, N, Nicchia, Elena, Savoia, Anna, and University of Zurich

Subjects
Male, Oncology, thrombocytopenia, Medicina Clínica, Disease, Malattia MYH9 associata, Myh9 related disease, MYH9 RELATED DISEASE, Myh9, MYH9, Risk Factors, purl.org/becyt/ford/3.2 [https], Genotype, Genetics(clinical), CRYSTAL-STRUCTURE, Age of Onset, IIA, Genetics (clinical), deafne, MYOSIN HEAVY-CHAIN, EPSTEIN-SYNDROME, Molecular Motor Proteins, FECHTNER SYNDROMES, Trombocitopenia, Penetrance, POWER STROKE STATE, Phenotype, Italy, nephropathy, Female, purl.org/becyt/ford/3 [https], Miosina No Muscular Iia, Adult, 2716 Genetics (clinical), medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, MOTOR DOMAIN, Hearing Loss, Sensorineural, Genetic counseling, 610 Medicine & health, Biology, nonmuscle myosin, Article, Cataract, Nephropathy, 1311 Genetics, Internal medicine, deafness, Genetics, medicine, Humans, Hematología, Gene, Genetic Association Studies, Hereditaria, Myosin Heavy Chains, MUTATIONS, Settore MED/09 - MEDICINA INTERNA, medicine.disease, Amino Acid Substitution, Epstein Syndrome, Mutation, 10032 Clinic for Oncology and Hematology, Linear Models, SMOOTH-MUSCLE MYOSIN
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' clinical management and genetic counseling and are discussed in view of molecular pathogenesis of MYH9-RD. Fil: Pecci, Alessandro. University of Pavia; Italia Fil: Klersy, Catherine. IRCCS Policlinico San Matteo Foundation; Italia Fil: Gresele, Paolo. Università di Perugia; Italia Fil: Lee, Kieran J. D.. University of Leeds; Reino Unido Fil: De Rocco, Daniela. Università degli Studi di Trieste; Italia Fil: Bozzi, Valeria. University of Pavia; Italia Fil: Russo, Giovanna. University of Catania; Italia Fil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Loffredo, Giuseppe. Pausilipon Hospital. Department of Oncology; Italia Fil: Ballmaier, Matthias. Hannover Medical School; Alemania Fil: Fabris, Fabrizio. Università di Padova; Italia Fil: Beggiato, Eloise. Hospital “Città della Salute e Della Scienza”; Italia Fil: Kahr, Walter H. A.. University of Toronto; Canadá. Hospital for Sick Children. Division of Hematology/Oncology; Canadá Fil: Pujol Moix, Nuria. Universitat Autònoma de Barcelona; España Fil: Platokouki, Helen. “Aghia Sophia” Children's Hospital; Grecia Fil: Van Geet, Christel. University of Leuven. Center for Molecular and Vascular Biology; Bélgica Fil: Noris, Patrizia. University of Pavia; Italia Fil: Yerram, Preethi. University of Missouri; Estados Unidos Fil: Hermans, Cedric. St-Luc University Hospital; Bélgica Fil: Gerber, Bernhard. University Hospital Zurich, Division of Hematology; Suiza Fil: Economou, Marina. Aristotle University; Grecia Fil: De Groot, Marco. University of Groningen; Países Bajos Fil: Zieger, Barbara. University Medical Center Freiburg; Alemania Fil: De Candia, Erica. Catholic University of Rome; Italia Fil: Fraticelli, Vincenzo. Giovanni Paolo II Foundation; Italia Fil: Kersseboom, Rogier. Erasmus Medical Centre; Países Bajos Fil: Piccoli, Giorgina B.. Università di Torino; Italia Fil: Zimmermann, Stefanie. Goethe Universitat Frankfurt; Alemania Fil: Fierro, Tiziana. Università di Perugia; Italia Fil: Glembotsky, Ana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Vianello, Fabrizio. Università di Padova; Italia Fil: Zaninetti, Carlo. University of Pavia; Italia Fil: Nicchia, Elena. Università degli Studi di Trieste; Italia Fil: Güthner, Christiane. Stadtspital Triemli. Department of Medical Oncology and Hematology; Italia Fil: Baronci, Carlo. Pediatric Hospital "Bambino Gesù"; Italia Fil: Seri, Marco. Università di Bologna; Italia Fil: Knight, Peter J.. University of Leeds; Reino Unido Fil: Balduini, Carlo L.. University of Pavia; Italia Fil: Savoia, Anna. Università degli Studi di Trieste; Italia

Published
2014

3. Apparent genotype–phenotype mismatch in a patient with MYH9-related disease: When the exception proves the rule

Author

Tiziana Fierro, Anna Maria Mezzasoma, Alessandro Pecci, Daniela De Rocco, Paolo Gresele, Loredana Bury, Anna Savoia, P., Gresele, DE ROCCO, Daniela, L., Bury, T., Fierro, A. M., Mezzasoma, A., Pecci, and Savoia, Anna

Subjects
Genetics, Pathology, medicine.medical_specialty, business.industry, Vascular biology, Hematology, Disease, 030204 cardiovascular system & hematology, Malattia MYH9 associata, Myh9 related disease, Phenotype, Genotype phenotype, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Genotype, Medicine, Base sequence, business
Abstract

Apparent genotype–phenotype mismatch in a patient with MYH9-related disease: When the exception proves the rule

Published
2013

4. MYH9-related disease: Five novel mutations expanding the spectrum of causative mutations and confirming genotype/phenotype correlations

Author

Daniela De Rocco, Alessandro Pecci, Helen Pergantou, Annalisa Pastore, Barbara Zieger, Patrizia Noris, Roberta Bottega, Anna Savoia, Helen Platokouki, Paula G. Heller, Serena Barozzi, Ana C. Glembotsky, Carlo L. Balduini, DE ROCCO, Daniela, Zieger, B., Platokouki, H., Heller, P. G., Pastore, A., Bottega, Roberta, Noris, P., Barozzi, S., Glembotsky, A. C., Pergantou, H., Balduini, C. L., Savoia, Anna, Pecci, A., De Rocco, D., Bottega, R., Glembotsky, A., Balduini, C., and Savoia, A.

Subjects
Male, Models, Molecular, Genotype-phenotype correlation, Protein Conformation, Medicina Clínica, MYH9-related disease, Malattia MYH9 associata, medicine.disease_cause, Inclusion bodies, MYH9 related disease, Mutational screening, Exon, purl.org/becyt/ford/3.2 [https], Myosin, Missense mutation, Child, Genetics (clinical), Genes, Dominant, Genetics, Mutation, Genotype–phenotype correlation, Molecular Motor Proteins, Exons, Syndrome, General Medicine, Middle Aged, Phenotype, Pedigree, In frame deletion/duplication, Child, Preschool, Female, purl.org/becyt/ford/3 [https], Adult, CIENCIAS MÉDICAS Y DE LA SALUD, Adolescent, Molecular Sequence Data, MYH9 gene, Settore BIO/11 - Biologia Molecolare, Biology, Nephropathy, Young Adult, Clinical Research, in frame deletions/insertions, medicine, Humans, Hematología, Amino Acid Sequence, Gene, Genetic Association Studies, Base Sequence, Myosin Heavy Chains, medicine.disease, Thrombocytopenia, Molecular biology, Amino Acid Substitution, Sequence Alignment
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. Fil: de Rocco, Daniela. Istituto di Ricovero e Cura a Carattere Scientifico "Burlo Garofolo"; Italia Fil: Zieger, Barbara. University of Freiburg; Alemania Fil: Platokouki, Helen. “Aghia Sophia” Children; Grecia Fil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Pastore, Annalisa. National Institute for Medical Research; Reino Unido Fil: Bottega, Roberta. Istituto di Ricovero e Cura a Carattere Scientifico "Burlo Garofolo"; Italia Fil: Noris, Patrizia. Istituto di Ricovero e Cura a Carattere Scientifico "Burlo Garofolo"; Italia. University of Pavia; Italia Fil: Barozzi, Serena. Istituto di Ricovero e Cura a Carattere Scientifico "Burlo Garofolo"; Italia. University of Pavia; Italia Fil: Glembotsky, Ana Claudia. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; Argentina Fil: Pergantou, Helen. “Aghia Sophia” Children; Grecia Fil: Balduini, Carlo L.. Istituto di Ricovero e Cura a Carattere Scientifico "Burlo Garofolo"; Italia. University of Pavia; Italia Fil: Savoia, Anna. Istituto di Ricovero e Cura a Carattere Scientifico "Burlo Garofolo"; Italia. Universita Degli Studi Di Trieste; Italia Fil: Pecci, Alessandro. Istituto di Ricovero e Cura a Carattere Scientifico "Burlo Garofolo"; Italia. University of Pavia; Italia

Published
2013

5. Recent advances in the understanding and management of MYH9-related inherited thrombocytopenias

Author

Alessandro Pecci, Carlo L. Balduini, Anna Savoia, Balduini, C. L., Pecci, A., and Savoia, Anna

Subjects
piastrinopenia ereditaria, medicine.medical_specialty, Genotype, Disease, Malattia MYH9 associata, Mice, Megakaryocyte, Cataracts, Internal medicine, medicine, Coagulopathy, Animals, Humans, Genetic Predisposition to Disease, Thrombopoietin, gene MYH9, Myosin Type II, Hematology, Myosin Heavy Chains, business.industry, Molecular Motor Proteins, miosina non muscolare IIA, medicine.disease, Thrombocytopenia, Disease Models, Animal, Phenotype, medicine.anatomical_structure, Epstein Syndrome, Mutation, Immunology, May–Hegglin anomaly, business
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.

Published
2011

6. 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

Author

Fabrizio Fabris, Bernhard Gerber, Alessandro Pecci, Daniela De Rocco, Silvia Vettore, Carlo L. Balduini, Anna Monica Bianco, Raffaella Scandellari, Anna Savoia, Vettore, S., DE ROCCO, Daniela, Gerber, B., Scandellari, R., Bianco, ANNA MONICA ROSARIA, Balduini, C. L., Pecci, A., Fabris, F., and Savoia, Anna

Subjects
Adult, Blood Platelets, Adolescent, Neutrophils, RNA Splicing, Malattia MYH9 associata, piastrinopenia congenita, gene MYH9, Mutation, Missense, Biology, medicine.disease_cause, Exon, Genetics, medicine, Humans, Missense mutation, Transversion, Gene, Genetics (clinical), Inclusion Bodies, Mutation, Myosin Heavy Chains, Nucleotides, Molecular Motor Proteins, Nonmuscle Myosin Type IIA, Computational Biology, RNA, Exons, General Medicine, Thrombocytopenia, Molecular biology, RNA splicing, Kidney Failure, Chronic, Female, Minigene
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’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.

Published
2010

7. Megakaryocyte and platelet abnormalities in a patient with a W33C mutation in the conserved SH3-like domain of myosin heavy chain IIA

Author

Sheila Butchart, Ling Li, Chanchai Traivaree, Julie D. Forman-Kay, Elliott J. Stollar, Hilary Christensen, Fred G. Pluthero, Victor S. Blanchette, Daniela De Rocco, Walter H. A. Kahr, Anna Savoia, Julie Curtin, Kahr, Wh, Savoia, Anna, Pluthero, Fg, Li, L, Christensen, H, DE ROCCO, Daniela, Traivaree, C, Butchart, Se, Curtin, J, Stollar, Ej, Forman Kay, Jd, and Blanchette, V. S.

Subjects
Blood Platelets, Male, Models, Molecular, Heterozygote, MYH9-related disorder: megakaryocytes, Mutation, Missense, Biology, Malattia MYH9 associata, Immunoglobulin light chain, medicine.disease_cause, myosin IIA, Inclusion bodies, src Homology Domains, chemistry.chemical_compound, Megakaryocyte, Microscopy, Electron, Transmission, Myosin, medicine, Missense mutation, Inherited macrothrombocytopenia, Humans, Platelet, Child, emperipolesis, Conserved Sequence, Inclusion Bodies, Mutation, Myosin Heavy Chains, Molecular Motor Proteins, Hematology, Molecular biology, Thrombocytopenia, Adenosine diphosphate, medicine.anatomical_structure, chemistry, Biochemistry, Amino Acid Substitution, Case-Control Studies, Female, Blood Platelet Disorders, Megakaryocytes, Granulocytes
Abstract

SummaryHeterozygous mutations in MYH9, which encodes non-muscle myosin heavy chain IIA (MHC-IIA),result in autosomal dominant inherited MYH9-related disorders characterised by macrothrombocytopenia, granulocyte inclusions, variable sensorineural deafness, cataracts and nephritis. MHC-IIA is assembled into a complex consisting of two pairs of light chains and two heavy chains, where the latter contain a neck region, SH3-like, motor and rod domains. We describe a patient with a Trp33Cys missense mutation in the SH3-like domain of MHC-IIA. Abnormal platelet function was observed using platelet aggregometry with the agonists epinephrine and adenosine diphosphate (ADP). Patient granulocytes and megakaryocytes, but not platelets, contained abnormal MHC-IIA inclusions visualised by confocal immunofluorescence or electron microscopy. Megakaryocytes grown in culture were smaller and contained hypolobulated nuclei compared to controls. Bone marrow-derived megakaryocytes revealed a preponderance of immature forms, the presence of structurally diverse inclusion bodies, and frequent emperipolesis as assessed by electron microscopy. Platelets and leukocytes contained indistinguishable amounts of total MHCIIA determined by immunoblotting. Molecular modelling studies indicated that mutation of Trp33 destabilises the interface between the SH3-like and motor domain of MHC-IIA, which is close to previously described motor domain mutations, implying an important structural and/or functional role for this region in MHC-IIA.

Published
2009

8. Identification of the first duplication in MYH9-related disease: A hot spot for hot unequal crossing-over within exon 24 of the MYH9 gene

Author

Flavio Faletra, Valeria Bozzi, Nuria Pujol-Moix, Carlo L. Balduini, Daniela De Rocco, Alessandro Pecci, Anna Savoia, DE ROCCO, Daniela, PUJOL MOIX, N, Pecci, A, Faletra, F, Bozzi, V, Balduini, Cl, and Savoia, Anna

Subjects
Adult, Blood Platelets, Male, Unequal crossing over, Erythrocytes, Presenile cataracts, Sequence analysis, DNA Mutational Analysis, Molecular Sequence Data, Biology, Malattia MYH9 associata, Cytoplasmic Granules, Cataract, Frameshift mutation, Exon, Gene Duplication, Gene duplication, Genetics, Missense mutation, Humans, Crossing Over, Genetic, Gene, Genetics (clinical), Genes, Dominant, Inclusion Bodies, Base Sequence, Myosin Heavy Chains, Molecular Motor Proteins, Nonmuscle Myosin Type IIA, General Medicine, Exons, Sequence Analysis, DNA, Middle Aged, Molecular biology, Fluorescent Antibody Technique, Direct, Mutation, Female
Abstract

MYH9-related disease (MYH9RD) is a rare autosomal dominant disorder caused by mutations in MYH9, the gene encoding the heavy chain of non-muscle myosin IIA. All patients present with congenital macrothrombocytopenia and inclusion bodies in neutrophils. Some of them can also develop sensorineural deafness, presenile cataracts, and/or progressive nephritis leading to end-stage renal failure. The spectrum of mutations so far identified is peculiar, consisting of mostly missense mutations. Others are nonsense and frameshift mutations, all localized in the COOH terminus of the protein, or in-frame deletions. We report a family with three affected members carrying a novel mutation, the first duplication (p.E1066_A1072dup), of MYH9. The mutation was localized within exon 24, where the presence of a 16 nucleotide repeat was likely to be responsible for unequal crossing-over. Of note, a deletion of the same amino acids 1066_1072 was also identified in another MHY9RD family. Since two of the four patients with the duplication or the deletion in exon 24 were affected with bilateral neonatal cataracts, we speculate that these mutations might correlate with the ocular defect, which is reported only in 16% of MYH9RD patients.

Published
2009

9. Correlation between the clinical phenotype of MYH9-related disease and tissue distribution of class II non-muscle myosin heavy chains

Author

Mariateresa Di Stazio, Valeria Marigo, Alessandro Pecci, Alessandra Nigro, Donatella Montanaro, Carlo L. Balduini, Anna Savoia, Marigo, V, Nigro, A, Pecci, A, Montanaro, D, DI STAZIO, Mariateresa, Balduini, Cl, and Savoia, Anna

Subjects
Gene isoform, mRNA, Gene Expression, Deafness, Granulocyte, Biology, Malattia MYH9 associata, Eye, Kidney, Cataract, espressione in situ, Mice, catena pesante della miosina non-muscolare, Bone Marrow, Gene expression, MYH10, Myosin, Genetics, medicine, Animals, Humans, Tissue Distribution, RNA, Messenger, Gene, In Situ Hybridization, Inclusion Bodies, Myosin Type II, Nephritis, Myosin Heavy Chains, Molecular Motor Proteins, Syndrome, Embryo, Mammalian, Thrombocytopenia, Phenotype, Cochlea, Cell biology, medicine.anatomical_structure, Liver, Immunology, Granulocytes
Abstract

Nonmuscle myosin heavy chain II-A is responsible for MYH9-related disease, which is characterized by macrothrombocytopenia, granulocyte inclusions, deafness, cataracts, and renal failure. Since another two highly conserved nonmuscle myosins, II-B and II-C, are known, an analysis of their tissue distribution is fundamental for the understanding of their biological roles. In mouse, we found that all forms are ubiquitously expressed. However, megakaryocytic and granulocytic lineages express only II-A, suggesting that congenital features, macrothrombocytopenia, and leukocyte inclusions correlate with its exclusive presence. In kidney, eye, and ear, where clinical manifestations have a late onset, as well as in other tissues apparently not affected in patients, II-A and at least one of the other two isoforms are expressed, suggesting that II-B and II-C can partially compensate for each other. We hypothesize that cells expressing only II-A manifest the congenital defects, while tissues expressing additional myosin II isoforms show either late onset of abnormalities or no pathological sign.

Published
2004

10. Heavy chain myosin 9-related disease (MYH9 -RD): neutrophil inclusions of myosin-9 as a pathognomonic sign of the disorder

Author

Paula G. Heller, Andrew D Mumford, Fabrizio Fabris, Alessandro Pecci, Silvia Riondino, Marco R. de Groot, Daniela De Rocco, Marisa Giani, Nuria Pujol-Moix, Francesca Scognamiglio, Valeria Bozzi, Marco Seri, Giuseppe Loffredo, Patrizia Noris, Anna Savoia, Raffaella Scandellari, Emanuele Panza, Carlo L. Balduini, Paolo Freddi, Savoia A., De Rocco D., Panza E., Bozzi V., Scandellari R., Loffredo G., Mumford A., Heller P.G., Noris P., De Groot M.R., Giani M., Freddi P., Scognamiglio F., Riondino S., Pujol-Moix N., Fabris F., Seri M., Balduini C.L., Pecci A., Savoia, Anna, DE ROCCO, Daniela, Panza, E, Bozzi, V, Scandellari, R, Loffredo, G, Mumford, A, Heller, Pg, Noris, P, DE GROOT, Mr, Giani, M, Freddi, P, Scognamiglio, F, Riondino, S, PUJOL MOIX, N, Fabris, F, Seri, M, Balduini, Cl, and Pecci, A.

Subjects
Male, Pathology, Cytoplasmic inclusion, Neutrophils, inclusioni in neutrofili, Mutant, DNA Mutational Analysis, piastrinopenia, Fluorescent Antibody Technique, Medicina Clínica, medicine.disease_cause, MYH9-related diseases, malattia MYH9 associata, Immunopathology, Myosin, Prospective Studies, Registries, Child, gene MYH9, Aged, 80 and over, Inclusion Bodies, Mutation, medicine.diagnostic_test, Molecular Motor Proteins, Hematology, Middle Aged, Italy, Child, Preschool, Sensorineural hearing loss, Female, Adult, medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, Adolescent, Giant platelets, MYH9 gene, Biology, Immunofluorescence, Sensitivity and Specificity, Young Adult, Predictive Value of Tests, medicine, Humans, Hematología, Aged, Myosin Heavy Chains, medicine.disease, Thrombocytopenia, Heavy chain disease, Microscopy, Fluorescence, Case-Control Studies, Neutrophil inclusions
Abstract

MYH9 -related disease ( MYH9 -RD) is an autosomal dominant thrombocytopenia with giant platelets variably associated with young-adult onset of progressive sensorineural hearing loss, presenile cataract, and renal damage. MYH9 -RD is caused by mutations of MYH9 , the gene encoding for non-muscle heavy-chain myosin-9. Wild-type and mutant myosin-9 aggregate as cytoplasmic inclusions in patients’ leukocytes, the identification of which by immunofluorescence has been proposed as a suitable tool for the diagnosis of MYH9 -RD. Since the predictive value of this assay, in terms of sensitivity and specificity, is unknown, we investigated 118 consecutive unrelated patients with a clinical presentation strongly consistent with MYH9 -RD. All patients prospectively underwent both the immunofluorescence assay for myosin-9 aggregate detection and molecular genetic analysis of the MYH9 gene. Myosin-9 aggregates were identified in 82 patients, 80 of which (98%) had also a MYH9 mutation. In the remaining 36 patients neither myosin-9 aggregates nor MYH9 mutations were found. Sensitivity and specificity of the immunofluorescence assay was evaluated to be 100% and 95%, respectively. Except for the presence of aggregates, we did not find any other significant difference between patients with or without aggregates, demonstrating that the myosin-9 inclusions in neutrophils are a pathognomonic sign of the disease. However, the identification of the specific MYH9 mutation is still of importance for prognostic aspects of MYH9 -RD. Fil: Savoia, Anna. Universita Degli Studi Di Trieste; Italia. Italian Registry for MYH9-Related Disease; Italia Fil: de Rocco, Daniela. Universita Degli Studi Di Trieste; Italia. Italian Registry for MYH9-Related Disease; Italia Fil: Panza, Emanuele. Italian Registry for MYH9-Related Disease; Italia. Universita Di Bologna; Italia Fil: Bozzi, Valeria. Italian Registry for MYH9-Related Disease; Italia. University of Pavia; Italia Fil: Scandellari, Raffaella. Italian Registry for MYH9-Related Disease; Italia. Universita Di Padova; Italia Fil: Loffredo, Giuseppe. Italian Registry for MYH9-Related Disease; Italia. Pausilipon Hospital; Italia Fil: Mumford, Andrew. University of Bristol; Reino Unido Fil: Heller, Paula Graciela. Italian Registry for MYH9-Related Disease; Italia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Noris, Patrizia. Italian Registry for MYH9-Related Disease; Italia Fil: de Groot, Marco R.. University of Bristol; Reino Unido Fil: Giani, Marisa. Italian Registry for MYH9-Related Disease; Italia. Istituto di Ricovero e Cura a Carattere Scientifico; Italia Fil: Freddi, Paolo. Italian Registry for MYH9-Related Disease; Italia Fil: Scognamiglio, Francesca. Italian Registry for MYH9-Related Disease; Italia Fil: Riondino, Silvia. Italian Registry for MYH9-Related Disease; Italia. Istituto di Ricovero e Cura a Carattere Scientifico; Italia Fil: Pujol Moix, Núria. Universitat Autonoma de Barcelona; España Fil: Fabris, Fabrizio. Italian Registry for MYH9-Related Disease; Italia. Universita Di Padova; Italia Fil: Seri, Marco. Italian Registry for MYH9-Related Disease; Italia. Universita Di Bologna; Italia Fil: Balduini, Carlo L.. Italian Registry for MYH9-Related Disease; Italia. University of Pavia; Italia Fil: Pecci, Alessandro. Italian Registry for MYH9-Related Disease; Italia. University of Pavia; Italia

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