Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and α-granule deficiency

Autores
Bottega, Roberta; Pecci, Alessandro; de Candia, Erica; Pujol Moix, Nuria; Heller, Paula Graciela; Noris, Patrizia; de Rocco, Daniela; Podda, Gian Marco; Glembotsky, Ana Claudia; Cattaneo Marco; Balduini, Carlo L.; Savoia, Anna
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The gray platelet syndrome is a rare inherited bleeding disorder characterized by macrothrombocytopenia and deficiency of alpha (α)-granules in platelets. The genetic defect responsible for gray platelet syndrome was recently identified in biallelic mutations in the NBEAL2 gene. We studied 11 consecutive families with inherited macrothrombocytopenia of unknown origin and α-granule deficiency. All of them underwent NBEAL2 DNA sequencing and evaluation of the platelet phenotype, including a systematic assessment of the α-granule content by immunofluorescence analysis for α-granule secretory proteins. We identified 9 novel mutations hitting the two alleles of NBEAL2 in 4 probands. They included missense, nonsense and frameshift mutations, as well as nucleotide substitutions that altered the splicing mechanisms as determined at the RNA level. All the individuals with NBEAL2 biallelic mutations showed almost complete absence of platelet α-granules. Interestingly, the 13 individuals assumed to be asymptomatic because carriers of a mutated allele had platelet macrocytosis and significant reduction of the α-granule content. However, they were not thrombocytopenic. In the remaining 7 probands, we did not identify any NBEAL2 alterations, suggesting that other genetic defect(s) are responsible for their platelet phenotype. Of note, these patients were characterized by a lower severity of the α-granule deficiency than individuals with two NBEAL2 mutated alleles. Our data extend the spectrum of mutations responsible for gray platelet syndrome and demonstrate that macrothrombocytopenia with α-granule deficiency is a genetic heterogeneous trait. In terms of practical applications, the screening of NBEAL2 is worthwhile only in patients with macrothrombocytopenia and severe reduction of the α-granules. Finally, individuals carrying one NBEAL2 mutated allele have mild laboratory abnormalities, suggesting that even haploinsufficiency has an effect on platelet phenotype.
Fil: Bottega, Roberta. Università degli Studi di Trieste; Italia
Fil: Pecci, Alessandro. Universita Degli Studi Di Pavia; Italia
Fil: de Candia, Erica. Università Cattolica del Sacro Cuore; Argentina
Fil: Pujol Moix, Nuria. Universitat Autònoma de Barcelona; España
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: Noris, Patrizia. Universita Degli Studi Di Pavia; Italia
Fil: de Rocco, Daniela. No especifíca;
Fil: Podda, Gian Marco. Università degli Studi di Milano; 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: Cattaneo Marco. Università degli Studi di Milano; Italia
Fil: Balduini, Carlo L.. Universita Degli Studi Di Pavia; Italia
Fil: Savoia, Anna. Università degli Studi di Trieste; Italia
Materia
Gray Platelet Syndrome
Nbeal2
Thrombospondin 1
Thrombocytopenia
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/1514
Acceder
id CONICETDig_50f63006a7c9d3858bc024facbacc651
oai_identifier_str oai:ri.conicet.gov.ar:11336/1514
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and α-granule deficiencyBottega, RobertaPecci, Alessandrode Candia, EricaPujol Moix, NuriaHeller, Paula GracielaNoris, Patriziade Rocco, DanielaPodda, Gian MarcoGlembotsky, Ana ClaudiaCattaneo MarcoBalduini, Carlo L.Savoia, AnnaGray Platelet SyndromeNbeal2Thrombospondin 1Thrombocytopeniahttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3The gray platelet syndrome is a rare inherited bleeding disorder characterized by macrothrombocytopenia and deficiency of alpha (α)-granules in platelets. The genetic defect responsible for gray platelet syndrome was recently identified in biallelic mutations in the NBEAL2 gene. We studied 11 consecutive families with inherited macrothrombocytopenia of unknown origin and α-granule deficiency. All of them underwent NBEAL2 DNA sequencing and evaluation of the platelet phenotype, including a systematic assessment of the α-granule content by immunofluorescence analysis for α-granule secretory proteins. We identified 9 novel mutations hitting the two alleles of NBEAL2 in 4 probands. They included missense, nonsense and frameshift mutations, as well as nucleotide substitutions that altered the splicing mechanisms as determined at the RNA level. All the individuals with NBEAL2 biallelic mutations showed almost complete absence of platelet α-granules. Interestingly, the 13 individuals assumed to be asymptomatic because carriers of a mutated allele had platelet macrocytosis and significant reduction of the α-granule content. However, they were not thrombocytopenic. In the remaining 7 probands, we did not identify any NBEAL2 alterations, suggesting that other genetic defect(s) are responsible for their platelet phenotype. Of note, these patients were characterized by a lower severity of the α-granule deficiency than individuals with two NBEAL2 mutated alleles. Our data extend the spectrum of mutations responsible for gray platelet syndrome and demonstrate that macrothrombocytopenia with α-granule deficiency is a genetic heterogeneous trait. In terms of practical applications, the screening of NBEAL2 is worthwhile only in patients with macrothrombocytopenia and severe reduction of the α-granules. Finally, individuals carrying one NBEAL2 mutated allele have mild laboratory abnormalities, suggesting that even haploinsufficiency has an effect on platelet phenotype.Fil: Bottega, Roberta. Università degli Studi di Trieste; ItaliaFil: Pecci, Alessandro. Universita Degli Studi Di Pavia; ItaliaFil: de Candia, Erica. Università Cattolica del Sacro Cuore; ArgentinaFil: Pujol Moix, Nuria. Universitat Autònoma de Barcelona; EspañaFil: 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; ArgentinaFil: Noris, Patrizia. Universita Degli Studi Di Pavia; ItaliaFil: de Rocco, Daniela. No especifíca;Fil: Podda, Gian Marco. Università degli Studi di Milano; ItaliaFil: 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; ArgentinaFil: Cattaneo Marco. Università degli Studi di Milano; ItaliaFil: Balduini, Carlo L.. Universita Degli Studi Di Pavia; ItaliaFil: Savoia, Anna. Università degli Studi di Trieste; ItaliaFerrata Storti Foundation2013-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/1514Bottega, Roberta; Pecci, Alessandro; de Candia, Erica; Pujol Moix, Nuria; Heller, Paula Graciela; et al.; Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and α-granule deficiency; Ferrata Storti Foundation; Haematologica; 98; 6; 6-2013; 868-8740390-60781592-8721enginfo:eu-repo/semantics/altIdentifier/doi/10.3324/haematol.2012.075861info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:29:50Zoai:ri.conicet.gov.ar:11336/1514instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:29:50.717CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and α-granule deficiency
title Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and α-granule deficiency
spellingShingle Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and α-granule deficiency
Bottega, Roberta
Gray Platelet Syndrome
Nbeal2
Thrombospondin 1
Thrombocytopenia
title_short Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and α-granule deficiency
title_full Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and α-granule deficiency
title_fullStr Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and α-granule deficiency
title_full_unstemmed Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and α-granule deficiency
title_sort Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and α-granule deficiency
dc.creator.none.fl_str_mv Bottega, Roberta
Pecci, Alessandro
de Candia, Erica
Pujol Moix, Nuria
Heller, Paula Graciela
Noris, Patrizia
de Rocco, Daniela
Podda, Gian Marco
Glembotsky, Ana Claudia
Cattaneo Marco
Balduini, Carlo L.
Savoia, Anna
author Bottega, Roberta
author_facet Bottega, Roberta
Pecci, Alessandro
de Candia, Erica
Pujol Moix, Nuria
Heller, Paula Graciela
Noris, Patrizia
de Rocco, Daniela
Podda, Gian Marco
Glembotsky, Ana Claudia
Cattaneo Marco
Balduini, Carlo L.
Savoia, Anna
author_role author
author2 Pecci, Alessandro
de Candia, Erica
Pujol Moix, Nuria
Heller, Paula Graciela
Noris, Patrizia
de Rocco, Daniela
Podda, Gian Marco
Glembotsky, Ana Claudia
Cattaneo Marco
Balduini, Carlo L.
Savoia, Anna
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Gray Platelet Syndrome
Nbeal2
Thrombospondin 1
Thrombocytopenia
topic Gray Platelet Syndrome
Nbeal2
Thrombospondin 1
Thrombocytopenia
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv The gray platelet syndrome is a rare inherited bleeding disorder characterized by macrothrombocytopenia and deficiency of alpha (α)-granules in platelets. The genetic defect responsible for gray platelet syndrome was recently identified in biallelic mutations in the NBEAL2 gene. We studied 11 consecutive families with inherited macrothrombocytopenia of unknown origin and α-granule deficiency. All of them underwent NBEAL2 DNA sequencing and evaluation of the platelet phenotype, including a systematic assessment of the α-granule content by immunofluorescence analysis for α-granule secretory proteins. We identified 9 novel mutations hitting the two alleles of NBEAL2 in 4 probands. They included missense, nonsense and frameshift mutations, as well as nucleotide substitutions that altered the splicing mechanisms as determined at the RNA level. All the individuals with NBEAL2 biallelic mutations showed almost complete absence of platelet α-granules. Interestingly, the 13 individuals assumed to be asymptomatic because carriers of a mutated allele had platelet macrocytosis and significant reduction of the α-granule content. However, they were not thrombocytopenic. In the remaining 7 probands, we did not identify any NBEAL2 alterations, suggesting that other genetic defect(s) are responsible for their platelet phenotype. Of note, these patients were characterized by a lower severity of the α-granule deficiency than individuals with two NBEAL2 mutated alleles. Our data extend the spectrum of mutations responsible for gray platelet syndrome and demonstrate that macrothrombocytopenia with α-granule deficiency is a genetic heterogeneous trait. In terms of practical applications, the screening of NBEAL2 is worthwhile only in patients with macrothrombocytopenia and severe reduction of the α-granules. Finally, individuals carrying one NBEAL2 mutated allele have mild laboratory abnormalities, suggesting that even haploinsufficiency has an effect on platelet phenotype.
Fil: Bottega, Roberta. Università degli Studi di Trieste; Italia
Fil: Pecci, Alessandro. Universita Degli Studi Di Pavia; Italia
Fil: de Candia, Erica. Università Cattolica del Sacro Cuore; Argentina
Fil: Pujol Moix, Nuria. Universitat Autònoma de Barcelona; España
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: Noris, Patrizia. Universita Degli Studi Di Pavia; Italia
Fil: de Rocco, Daniela. No especifíca;
Fil: Podda, Gian Marco. Università degli Studi di Milano; 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: Cattaneo Marco. Università degli Studi di Milano; Italia
Fil: Balduini, Carlo L.. Universita Degli Studi Di Pavia; Italia
Fil: Savoia, Anna. Università degli Studi di Trieste; Italia
description The gray platelet syndrome is a rare inherited bleeding disorder characterized by macrothrombocytopenia and deficiency of alpha (α)-granules in platelets. The genetic defect responsible for gray platelet syndrome was recently identified in biallelic mutations in the NBEAL2 gene. We studied 11 consecutive families with inherited macrothrombocytopenia of unknown origin and α-granule deficiency. All of them underwent NBEAL2 DNA sequencing and evaluation of the platelet phenotype, including a systematic assessment of the α-granule content by immunofluorescence analysis for α-granule secretory proteins. We identified 9 novel mutations hitting the two alleles of NBEAL2 in 4 probands. They included missense, nonsense and frameshift mutations, as well as nucleotide substitutions that altered the splicing mechanisms as determined at the RNA level. All the individuals with NBEAL2 biallelic mutations showed almost complete absence of platelet α-granules. Interestingly, the 13 individuals assumed to be asymptomatic because carriers of a mutated allele had platelet macrocytosis and significant reduction of the α-granule content. However, they were not thrombocytopenic. In the remaining 7 probands, we did not identify any NBEAL2 alterations, suggesting that other genetic defect(s) are responsible for their platelet phenotype. Of note, these patients were characterized by a lower severity of the α-granule deficiency than individuals with two NBEAL2 mutated alleles. Our data extend the spectrum of mutations responsible for gray platelet syndrome and demonstrate that macrothrombocytopenia with α-granule deficiency is a genetic heterogeneous trait. In terms of practical applications, the screening of NBEAL2 is worthwhile only in patients with macrothrombocytopenia and severe reduction of the α-granules. Finally, individuals carrying one NBEAL2 mutated allele have mild laboratory abnormalities, suggesting that even haploinsufficiency has an effect on platelet phenotype.
publishDate 2013
dc.date.none.fl_str_mv 2013-06
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/1514
Bottega, Roberta; Pecci, Alessandro; de Candia, Erica; Pujol Moix, Nuria; Heller, Paula Graciela; et al.; Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and α-granule deficiency; Ferrata Storti Foundation; Haematologica; 98; 6; 6-2013; 868-874
0390-6078
1592-8721
url http://hdl.handle.net/11336/1514
identifier_str_mv Bottega, Roberta; Pecci, Alessandro; de Candia, Erica; Pujol Moix, Nuria; Heller, Paula Graciela; et al.; Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and α-granule deficiency; Ferrata Storti Foundation; Haematologica; 98; 6; 6-2013; 868-874
0390-6078
1592-8721
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.3324/haematol.2012.075861
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Ferrata Storti Foundation
publisher.none.fl_str_mv Ferrata Storti Foundation
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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