دورية أكاديمية
Germline heterozygous variants in genes associated with familial hemophagocytic lymphohistiocytosis as a cause of increased bleeding.
| العنوان: | Germline heterozygous variants in genes associated with familial hemophagocytic lymphohistiocytosis as a cause of increased bleeding. |
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| المؤلفون: | Fager Ferrari M; a Department of Translational Medicine , Lund University , Malmö , Sweden., Leinoe E; b Department of Hematology, Rigshospitalet , Copenhagen University Hospital , Copenhagen , Denmark., Rossing M; c Department of Genomic Medicine, Rigshospitalet , Copenhagen University Hospital , Copenhagen , Denmark., Norström E; a Department of Translational Medicine , Lund University , Malmö , Sweden., Strandberg K; d Department of Laboratory Medicine , Lund University , Malmö , Sweden., Steen Sejersen T; e Department of Biomedical Sciences, Core Facility for Integrated Microscopy (CFIM) , University of Copenhagen , Denmark., Qvortrup K; e Department of Biomedical Sciences, Core Facility for Integrated Microscopy (CFIM) , University of Copenhagen , Denmark., Zetterberg E; a Department of Translational Medicine , Lund University , Malmö , Sweden. |
| المصدر: | Platelets [Platelets] 2018 Jan; Vol. 29 (1), pp. 56-64. Date of Electronic Publication: 2017 Apr 11. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Informa Healthcare Country of Publication: England NLM ID: 9208117 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1369-1635 (Electronic) Linking ISSN: 09537104 NLM ISO Abbreviation: Platelets Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: London : Informa Healthcare Original Publication: Edinburgh ; New York : Churchill Livingstone, c1990- |
| مواضيع طبية MeSH: | Genetic Predisposition to Disease* , Germ-Line Mutation* , Heterozygote* , Mutation*, Hemorrhage/*etiology , Lymphohistiocytosis, Hemophagocytic/*complications , Lymphohistiocytosis, Hemophagocytic/*genetics, Adolescent ; Adult ; Blood Platelets/metabolism ; Blood Platelets/ultrastructure ; Child ; Child, Preschool ; Comorbidity ; Female ; Flow Cytometry ; Humans ; Lymphohistiocytosis, Hemophagocytic/diagnosis ; Lymphohistiocytosis, Hemophagocytic/metabolism ; Male ; Membrane Proteins/genetics ; Middle Aged ; Models, Biological ; Munc18 Proteins/genetics ; Platelet Count ; Qa-SNARE Proteins/genetics ; Secretory Vesicles/metabolism ; Secretory Vesicles/ultrastructure ; Whole Genome Sequencing ; Young Adult |
| مستخلص: | Familial hemophagocytic lymphohistiocytosis (FHL) is caused by biallelic variants in genes regulating granule secretion in cytotoxic lymphocytes. In FHL3-5, the affected genes UNC13D, STX11 and STXBP2 have further been shown to regulate the secretion of platelet granules, giving rise to compromised platelet function. Therefore, we aimed to investigate platelet degranulation in patients heterozygous for variants in UNC13D, STX11 and STXBP2. During the work-up of patients referred to the Coagulation Unit, Skåne University Hospital, Malmö, Sweden and the Department of Hematology, Rigshospitalet, Copenhagen, Denmark due to bleeding tendencies, 12 patients harboring heterozygous variants in UNC13D, STX11 or STXBP2 were identified using targeted whole exome sequencing. Transmission electron microscopy (TEM) was used to assess the secretion of platelet dense granules following thrombin stimulation. Platelet degranulation, activation and aggregation were further assessed by flow cytometry (FC) and light transmission aggregometry (LTA) with lumi-aggregometry. In total, eight out of twelve (67%) patients showed impaired degranulation by at least one of the assays (TEM, FC and LTA). In the 12 patients, eight different heterozygous variants were identified. One variant was strongly associated with impaired degranulation, while four of the variants were associated with impaired granule secretion to a slightly lesser extent. One additional variant was found in six out of the twelve patients, and was associated with varying degrees of degranulation impairment. Accordingly, six out of the eight (75%) identified variants were associated with impaired platelet degranulation. Our results suggest that heterozygous variants in UNC13D, STX11 and STXBP2 are sufficient to cause platelet secretion defects resulting in increased bleeding. |
| فهرسة مساهمة: | Keywords: Bleeding; STX11; STXBP2; UNC13D; familial hemophagocytic lymphocytosis; platelet granules |
| المشرفين على المادة: | 0 (Membrane Proteins) 0 (Munc18 Proteins) 0 (Qa-SNARE Proteins) 0 (STX11 protein, human) 0 (STXBP2 protein, human) 0 (UNC13D protein, human) |
| تواريخ الأحداث: | Date Created: 20170413 Date Completed: 20180808 Latest Revision: 20180808 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1080/09537104.2017.1293808 |
| PMID: | 28399723 |
| قاعدة البيانات: | MEDLINE |
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