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

The gray platelet syndrome is a rare inherited bleeding disorder characterized by macrothrombocytopenia and deficiency of alpha (alpha)-granules in platelets. The genetic defect responsible for gray platelet syndrome was recently identified in biallelic mutations in the NBEAL2 gene. We studied 11 co...

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Authors: Bottega, R, Pecci, A, De Candia, E, Pujol-Moix, N, Heller, PG, Noris, P, De Rocco, D, Podda, GM, Glembotsky, AC, Cattaneo, M, Balduini, CL, Savoia, A
Format: article
Status:Published version
Publication Date:2013
Country:España
Institution:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repository:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p9983
Online Access:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=9983
Access Level:Open access
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spelling Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and alpha-granule deficiencyBottega, RPecci, ADe Candia, EPujol-Moix, NHeller, PGNoris, PDe Rocco, DPodda, GMGlembotsky, ACCattaneo, MBalduini, CLSavoia, AThe gray platelet syndrome is a rare inherited bleeding disorder characterized by macrothrombocytopenia and deficiency of alpha (alpha)-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 alpha-granule deficiency. All of them underwent NBEAL2 DNA sequencing and evaluation of the platelet phenotype, including a systematic assessment of the alpha-granule content by immunofluorescence analysis for alpha-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 alpha-granules. Interestingly, the 13 individuals assumed to be asymptomatic because carriers of a mutated allele had platelet macrocytosis and significant reduction of the alpha-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 alpha-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 alpha-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 alpha-granules. Finally, individuals carrying one NBEAL2 mutated allele have mild laboratory abnormalities, suggesting that even haploinsufficiency has an effect on platelet phenotype.FERRATA STORTI FOUNDATION2013info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=9983HAEMATOLOGICAISSN: 07182295ISSNe: 15928721ISSNl: 03906078reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p99832026-06-14T12:41:47Z
dc.title.none.fl_str_mv Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and alpha-granule deficiency
title Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and alpha-granule deficiency
spellingShingle Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and alpha-granule deficiency
Bottega, R
title_short Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and alpha-granule deficiency
title_full Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and alpha-granule deficiency
title_fullStr Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and alpha-granule deficiency
title_full_unstemmed Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and alpha-granule deficiency
title_sort Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and alpha-granule deficiency
dc.creator.none.fl_str_mv Bottega, R
Pecci, A
De Candia, E
Pujol-Moix, N
Heller, PG
Noris, P
De Rocco, D
Podda, GM
Glembotsky, AC
Cattaneo, M
Balduini, CL
Savoia, A
author Bottega, R
author_facet Bottega, R
Pecci, A
De Candia, E
Pujol-Moix, N
Heller, PG
Noris, P
De Rocco, D
Podda, GM
Glembotsky, AC
Cattaneo, M
Balduini, CL
Savoia, A
author_role author
author2 Pecci, A
De Candia, E
Pujol-Moix, N
Heller, PG
Noris, P
De Rocco, D
Podda, GM
Glembotsky, AC
Cattaneo, M
Balduini, CL
Savoia, A
author2_role author
author
author
author
author
author
author
author
author
author
author
description The gray platelet syndrome is a rare inherited bleeding disorder characterized by macrothrombocytopenia and deficiency of alpha (alpha)-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 alpha-granule deficiency. All of them underwent NBEAL2 DNA sequencing and evaluation of the platelet phenotype, including a systematic assessment of the alpha-granule content by immunofluorescence analysis for alpha-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 alpha-granules. Interestingly, the 13 individuals assumed to be asymptomatic because carriers of a mutated allele had platelet macrocytosis and significant reduction of the alpha-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 alpha-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 alpha-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 alpha-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
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=9983
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=9983
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv FERRATA STORTI FOUNDATION
publisher.none.fl_str_mv FERRATA STORTI FOUNDATION
dc.source.none.fl_str_mv HAEMATOLOGICA
ISSN: 07182295
ISSNe: 15928721
ISSNl: 03906078
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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