%0 Journal Article %J Ear Hear %D 2016 %T Nonmuscle Myosin Heavy Chain IIA Mutation Predicts Severity and Progression of Sensorineural Hearing Loss in Patients With MYH9-Related Disease. %A Verver, Eva J J %A Topsakal, Vedat %A Kunst, Henricus P M %A Huygen, Patrick L M %A Heller, Paula G %A Pujol-Moix, Núria %A Savoia, Anna %A Benazzo, Marco %A Fierro, Tiziana %A Grolman, Wilko %A Gresele, Paolo %A Pecci, Alessandro %X

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.

%B Ear Hear %V 37 %P 112-20 %8 2016 Jan-Feb %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26226608?dopt=Abstract %R 10.1097/AUD.0000000000000198 %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 Hum Mutat %D 2014 %T MYH9-related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations. %A Pecci, Alessandro %A Klersy, Catherine %A Gresele, Paolo %A Lee, Kieran J D %A De Rocco, Daniela %A Bozzi, Valeria %A Russo, Giovanna %A Heller, Paula G %A Loffredo, Giuseppe %A Ballmaier, Matthias %A Fabris, Fabrizio %A Beggiato, Eloise %A Kahr, Walter H A %A Pujol-Moix, Núria %A Platokouki, Helen %A Van Geet, Christel %A Noris, Patrizia %A Yerram, Preethi %A Hermans, Cedric %A Gerber, Bernhard %A Economou, Marina %A De Groot, Marco %A Zieger, Barbara %A De Candia, Erica %A Fraticelli, Vincenzo %A Kersseboom, Rogier %A Piccoli, Giorgina B %A Zimmermann, Stefanie %A Fierro, Tiziana %A Glembotsky, Ana C %A Vianello, Fabrizio %A Zaninetti, Carlo %A Nicchia, Elena %A Güthner, Christiane %A Baronci, Carlo %A Seri, Marco %A Knight, Peter J %A Balduini, Carlo L %A Savoia, Anna %K Adult %K Age of Onset %K Amino Acid Substitution %K Cataract %K Female %K Genetic Association Studies %K Genotype %K Hearing Loss, Sensorineural %K Humans %K Italy %K Linear Models %K Male %K Molecular Motor Proteins %K Mutation %K Myosin Heavy Chains %K Phenotype %K Risk Factors %K Thrombocytopenia %X

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.

%B Hum Mutat %V 35 %P 236-47 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24186861?dopt=Abstract %R 10.1002/humu.22476 %0 Journal Article %J Blood %D 2014 %T Platelet diameters in inherited thrombocytopenias: analysis of 376 patients with all known disorders. %A Noris, Patrizia %A Biino, Ginevra %A Pecci, Alessandro %A Civaschi, Elisa %A Savoia, Anna %A Seri, Marco %A Melazzini, Federica %A Loffredo, Giuseppe %A Russo, Giovanna %A Bozzi, Valeria %A Notarangelo, Lucia Dora %A Gresele, Paolo %A Heller, Paula G %A Pujol-Moix, Núria %A Kunishima, Shinji %A Cattaneo, Marco %A Bussel, James %A De Candia, Erica %A Cagioni, Claudia %A Ramenghi, Ugo %A Barozzi, Serena %A Fabris, Fabrizio %A Balduini, Carlo L %K Adolescent %K Adult %K Blood Platelets %K Case-Control Studies %K Cell Size %K Child %K Child, Preschool %K Diagnosis, Differential %K Female %K Hearing Loss, Sensorineural %K Humans %K Infant %K Male %K Middle Aged %K Molecular Motor Proteins %K Mutation %K Myosin Heavy Chains %K Purpura, Thrombocytopenic, Idiopathic %K Thrombocytopenia %K Young Adult %X

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.

%B Blood %V 124 %P e4-e10 %8 2014 Aug 7 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/24990887?dopt=Abstract %R 10.1182/blood-2014-03-564328 %0 Journal Article %J Hum Mutat %D 2014 %T Spectrum of the mutations in Bernard-Soulier syndrome. %A Savoia, Anna %A Kunishima, Shinji %A De Rocco, Daniela %A Zieger, Barbara %A Rand, Margaret L %A Pujol-Moix, Núria %A Caliskan, Umran %A Tokgoz, Huseyin %A Pecci, Alessandro %A Noris, Patrizia %A Srivastava, Alok %A Ward, Christopher %A Morel-Kopp, Marie-Christine %A Alessi, Marie-Christine %A Bellucci, Sylvia %A Beurrier, Philippe %A de Maistre, Emmanuel %A Favier, Rémi %A Hézard, Nathalie %A Hurtaud-Roux, Marie-Françoise %A Latger-Cannard, Véronique %A Lavenu-Bombled, Cécile %A Proulle, Valérie %A Meunier, Sandrine %A Négrier, Claude %A Nurden, Alan %A Randrianaivo, Hanitra %A Fabris, Fabrizio %A Platokouki, Helen %A Rosenberg, Nurit %A HadjKacem, Basma %A Heller, Paula G %A Karimi, Mehran %A Balduini, Carlo L %A Pastore, Annalisa %A Lanza, Francois %K Alleles %K Bernard-Soulier Syndrome %K Databases, Nucleic Acid %K Founder Effect %K Genetic Variation %K Humans %K Mutation %K Platelet Glycoprotein GPIb-IX Complex %K Polymorphism, Single Nucleotide %K von Willebrand Diseases %K Web Browser %X

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.

%B Hum Mutat %V 35 %P 1033-45 %8 2014 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/24934643?dopt=Abstract %R 10.1002/humu.22607 %0 Journal Article %J Blood %D 2011 %T Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families. %A Noris, Patrizia %A Perrotta, Silverio %A Seri, Marco %A Pecci, Alessandro %A Gnan, Chiara %A Loffredo, Giuseppe %A Pujol-Moix, Núria %A Zecca, Marco %A Scognamiglio, Francesca %A De Rocco, Daniela %A Punzo, Francesca %A Melazzini, Federica %A Scianguetta, Saverio %A Casale, Maddalena %A Marconi, Caterina %A Pippucci, Tommaso %A Amendola, Giovanni %A Notarangelo, Lucia D %A Klersy, Catherine %A Civaschi, Elisa %A Balduini, Carlo L %A Savoia, Anna %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Ankyrin Repeat %K Child %K Cohort Studies %K Family %K Female %K Gene Frequency %K Humans %K Inheritance Patterns %K Male %K Middle Aged %K Mutation %K Pedigree %K Thrombocytopenia %K Transcription Factors %K Young Adult %X

Until recently, thrombocytopenia 2 (THC2) was considered an exceedingly rare form of autosomal dominant thrombocytopenia and only 2 families were known. However, we recently identified mutations in the 5'-untranslated region of the ANKRD26 gene in 9 THC2 families. Here we report on 12 additional pedigrees with ANKRD26 mutations, 6 of which are new. Because THC2 affected 21 of the 210 families in our database, it has to be considered one of the less rare forms of inherited thrombocytopenia. Analysis of all 21 families with ANKRD26 mutations identified to date revealed that thrombocytopenia and bleeding tendency were usually mild. Nearly all patients had no platelet macrocytosis, and this characteristic distinguishes THC2 from most other forms of inherited thrombocytopenia. In the majority of cases, platelets were deficient in glycoprotein Ia and α-granules, whereas in vitro platelet aggregation was normal. Bone marrow examination and serum thrombopoietin levels suggested that thrombocytopenia was derived from dysmegakaryopoiesis. Unexplained high values of hemoglobin and leukocytes were observed in a few cases. An unexpected finding that warrants further investigation was a high incidence of acute leukemia. Given the scarcity of distinctive characteristics, the ANKRD26-related thrombocytopenia has to be taken into consideration in the differential diagnosis of isolated thrombocytopenias.

%B Blood %V 117 %P 6673-80 %8 2011 Jun 16 %G eng %N 24 %1 http://www.ncbi.nlm.nih.gov/pubmed/21467542?dopt=Abstract %R 10.1182/blood-2011-02-336537 %0 Journal Article %J Am J Hum Genet %D 2011 %T Mutations in the 5' UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2. %A Pippucci, Tommaso %A Savoia, Anna %A Perrotta, Silverio %A Pujol-Moix, Núria %A Noris, Patrizia %A Castegnaro, Giovanni %A Pecci, Alessandro %A Gnan, Chiara %A Punzo, Francesca %A Marconi, Caterina %A Gherardi, Samuele %A Loffredo, Giuseppe %A De Rocco, Daniela %A Scianguetta, Saverio %A Barozzi, Serena %A Magini, Pamela %A Bozzi, Valeria %A Dezzani, Luca %A Di Stazio, Mariateresa %A Ferraro, Marcella %A Perini, Giovanni %A Seri, Marco %A Balduini, Carlo L %K Ankyrin Repeat %K Base Sequence %K Chromosome Breakage %K Chromosome Disorders %K Conserved Sequence %K Female %K Genes, Dominant %K Genetic Loci %K Haploinsufficiency %K Humans %K Male %K Molecular Sequence Data %K Mutation %K Pedigree %K Thrombocytopenia %X

THC2, an autosomal-dominant thrombocytopenia described so far in only two families, has been ascribed to mutations in MASTL or ACBD5. Here, we show that ANKRD26, another gene within the THC2 locus, and neither MASTL nor ACBD5, is mutated in eight unrelated families. ANKRD26 was also found to be mutated in the family previously reported to have an ACBD5 mutation. We identified six different ANKRD26 mutations, which were clustered in a highly conserved 19 bp sequence located in the 5' untranslated region. Mutations were not detected in 500 controls and are absent from the 1000 Genomes database. Available data from an animal model and Dr. Watson's genome give evidence against haploinsufficiency as the pathogenetic mechanism for ANKRD26-mediated thrombocytopenia. The luciferase reporter assay suggests that these 5' UTR mutations might enhance ANKRD26 expression. ANKRD26 is the ancestor of a family of primate-specific genes termed POTE, which have been recently identified as a family of proapoptotic proteins. Dysregulation of apoptosis might therefore be the pathogenetic mechanism, as demonstrated for another thrombocytopenia, THC4. Further investigation is needed to provide evidence supporting this hypothesis.

%B Am J Hum Genet %V 88 %P 115-20 %8 2011 Jan 7 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/21211618?dopt=Abstract %R 10.1016/j.ajhg.2010.12.006