SINE-VNTR-Alu retrotransposon insertion as a novel mutational event underlying Glanzmann thrombasthenia.
Glanzmann thrombasthenia
ITGB3
SINE-VNTR-Alu retrotransposon
high-throughput sequencing
platelet
Journal
Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508
Informations de publication
Date de publication:
12 2023
12 2023
Historique:
received:
09
01
2023
revised:
01
08
2023
accepted:
06
08
2023
medline:
27
11
2023
pubmed:
22
8
2023
entrez:
21
8
2023
Statut:
ppublish
Résumé
Glanzmann thrombasthenia (GT) is an autosomal recessive platelet aggregation disorder caused by mutations in ITGA2B or ITGB3. We aimed to assess the phenotype and investigate the genetic etiology of a GT pedigree. A patient with bleeding manifestations and mild mental retardation was enrolled. Complete blood count, coagulation, and platelet aggregation tests were performed. Causal mutations were identified via whole exome and genome sequencing and subsequently confirmed through polymerase chain reaction and Sanger sequencing. The transcription of ITGB3 was characterized using RNA sequencing and reverse transcription polymerase chain reaction. The αⅡb and β3 biosynthesis was investigated via whole blood flow cytometry and in vitro studies. GT was diagnosed in a patient with defective platelet aggregation. Novel compound heterozygous ITGB3 variants were identified, with a maternal nonsense mutation (c.2222G>A, p.Trp741∗) and a paternal SINE-VNTR-Alu (SVA) retrotransposon insertion. The 5' truncated SVA element was inserted in a sense orientation in intron 11 of ITGB3, resulting in aberrant splicing of ITGB3 and significantly reducing β3 protein content. Meanwhile, both the expression and transportation of β3 were damaged by the ITGB3 c.2222G>A. Almost no αⅡb and β3 expressions were detected on the patient's platelets surface. Novel compound heterozygous ITGB3 mutations were identified in the GT pedigree, resulting in defects of αⅡbβ3 biosynthesis. This is the first report of SVA retrotransposon insertion in the genetic pathogenesis of GT. Our study highlights the importance of combining multiple high-throughput sequencing technologies for the molecular diagnosis of genetic disorders.
Sections du résumé
BACKGROUND
Glanzmann thrombasthenia (GT) is an autosomal recessive platelet aggregation disorder caused by mutations in ITGA2B or ITGB3.
OBJECTIVES
We aimed to assess the phenotype and investigate the genetic etiology of a GT pedigree.
METHODS
A patient with bleeding manifestations and mild mental retardation was enrolled. Complete blood count, coagulation, and platelet aggregation tests were performed. Causal mutations were identified via whole exome and genome sequencing and subsequently confirmed through polymerase chain reaction and Sanger sequencing. The transcription of ITGB3 was characterized using RNA sequencing and reverse transcription polymerase chain reaction. The αⅡb and β3 biosynthesis was investigated via whole blood flow cytometry and in vitro studies.
RESULTS
GT was diagnosed in a patient with defective platelet aggregation. Novel compound heterozygous ITGB3 variants were identified, with a maternal nonsense mutation (c.2222G>A, p.Trp741∗) and a paternal SINE-VNTR-Alu (SVA) retrotransposon insertion. The 5' truncated SVA element was inserted in a sense orientation in intron 11 of ITGB3, resulting in aberrant splicing of ITGB3 and significantly reducing β3 protein content. Meanwhile, both the expression and transportation of β3 were damaged by the ITGB3 c.2222G>A. Almost no αⅡb and β3 expressions were detected on the patient's platelets surface.
CONCLUSION
Novel compound heterozygous ITGB3 mutations were identified in the GT pedigree, resulting in defects of αⅡbβ3 biosynthesis. This is the first report of SVA retrotransposon insertion in the genetic pathogenesis of GT. Our study highlights the importance of combining multiple high-throughput sequencing technologies for the molecular diagnosis of genetic disorders.
Identifiants
pubmed: 37604334
pii: S1538-7836(23)00640-2
doi: 10.1016/j.jtha.2023.08.012
pii:
doi:
Substances chimiques
Retroelements
0
Platelet Glycoprotein GPIIb-IIIa Complex
0
Integrin beta3
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3597-3607Informations de copyright
Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interests The authors declare no competing financial interests.