Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37

Schulze, Harald; Schlagenhauf, Axel; Manukjan, Georgi; Beham‐Schmid, Christine; Andrés, Oliver; Klopocki, Eva; König, Eva-Maria; Haidl, Harald; Panzer, Simon; Althaus, Karina; Muntean, W.; Schwinger, Wolfgang; Urban, Christian; Greinacher, Andreas; Bakchoul, Tamam; Seidel, Markus G.

doi:10.3324/haematol.2017.167957

Cited by 16 publications

(20 citation statements)

References 17 publications

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“…To date, increased CD34 expression on platelets and megakaryocytes has been observed in different families with GFI1B mutations; however, the mechanism remains unknown . We demonstrate that CD34 is a transcriptional target of GFI1B, and show that all three variants reported (C168F, c.2520 + 1_2520 + 8delGTGGGCAC splice variant, and H294 fs) cause derepression at this promoter, suggesting that increased CD34 expression in GFI1B pedigrees is secondary to transcriptional dysregulation.…”

Section: Introductionmentioning

confidence: 69%

“…In all three variants described here, increased CD34 expression is independent of the site of mutation, and appears to be a general marker of perturbed GFI1B function. As increased CD34 expression has also been reported with other GFI1B variants , CD34 protein expression may serve as a screening assay for the presence of GFI1B mutations in the setting of familial platelet disorders.…”

Section: Discussionmentioning

confidence: 90%

“…Increased CD34 expression in platelets has been reported to be associated with GFI1B mutations . To further explore this observation, flow cytometry was used to measure CD34 surface expression on platelets of individuals with the GFI1B mutations C168F (pedigrees A, B, and C; n = 10) and H294 fs (previously reported pedigree ; n = 2), and the GFI1B splice mutation (pedigree D; n = 7).…”

Section: Resultsmentioning

confidence: 99%

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Thrombocytopenia and CD34 expression is decoupled from α‐granule deficiency with mutation of the first growth factor‐independent 1B zinc finger

Morel-Kopp

Chen

et al. 2017

Journal of Thrombosis and Haemostasis

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Background Mutation of the growth factor-independent 1B (GFI1B) fifth DNA-binding zinc-finger domain causes macrothrombocytopenia and α-granule deficiency leading to clinical bleeding. The phenotypes associated with GFI1B variants disrupting non-DNA-binding zinc-fingers remain uncharacterized. Objectives To determine the functional and phenotypic consequences of GFI1B variants disrupting non-DNA-binding zinc-finger domains. Methods The GFI1B C168F variant and a novel GFI1B c.2520 + 1_2520 + 8delGTGGGCAC splice variant were identified in four unrelated families. Phenotypic features, DNA-binding properties and transcriptional effects were determined and compared with those in individuals with a GFI1B H294 fs mutation of the fifth DNA-binding zinc-finger. Patient-specific induced pluripotent stem cell (iPSC)-derived megakaryocytes were generated to facilitate disease modeling. Results The DNA-binding GFI1B variant C168F, which is predicted to disrupt the first non-DNA-binding zinc-finger domain, is associated with macrothrombocytopenia without α-granule deficiency or bleeding symptoms. A GFI1B splice variant, c.2520 + 1_2520 + 8delGTGGGCAC, which generates a short GFI1B isoform that lacks non-DNA-binding zinc-fingers 1 and 2, is associated with increased platelet CD34 expression only, without quantitative or morphologic platelet abnormalities. GFI1B represses the CD34 promoter, and this repression is attenuated by different GFI1B zinc-finger mutations, suggesting that deregulation of CD34 expression occurs at a direct transcriptional level. Patient-specific iPSC-derived megakaryocytes phenocopy these observations. Conclusions Disruption of GFI1B non-DNA-binding zinc-finger 1 is associated with mild to moderate thrombocytopenia without α-granule deficiency or bleeding symptomatology, indicating that the site of GFI1B mutation has important phenotypic implications. Platelet CD34 expression appears to be a common feature of perturbed GFI1B function, and may have diagnostic utility.

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Section: Introductionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

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Thrombocytopenia and CD34 expression is decoupled from α‐granule deficiency with mutation of the first growth factor‐independent 1B zinc finger

Morel-Kopp

Chen

et al. 2017

Journal of Thrombosis and Haemostasis

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“…4,5 In humans, mutations in GFI1B may cause bleeding disorders with thrombocytopenia and compromised platelet function, although the observed phenotypes are variable. [6][7][8] In addition, common genetic variants in GFI1B have been associated with variation in platelet and other blood cell counts. 2,9 Notably, the C168F GFI1B variant identified in our patient has been recently found to segregate in an autosomal dominant manner in three unrelated families with mild to moderate macrothrombocytopenia, but without significant bruising or bleeding symptoms.…”

Section: The C168f Variant In Gfi1bmentioning

confidence: 99%

Macrothrombocytopenia associated with a rare GFI1B missense variant confounding the presentation of immune thrombocytopenia

Cheng

Bao

Fiorini

et al. 2019

Pediatric Blood & Cancer

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Growth factor‐independent 1B (GFI1B) variants are a rare cause of thrombocytopenia. We report on a male child who was initially diagnosed with immune thrombocytopenia. However, subtle clinical signs led to suspicion of a genetic cause of thrombocytopenia. Gene panel sequencing revealed a rare variant in GFI1B (C168F), which has recently been reported in several families with thrombocytopenia. We demonstrate that this variant significantly alters platelet parameters in population studies. This case highlights how diagnoses of exclusion, such as immune thrombocytopenia, can be confounded by genetic variation. Our understanding of blood disorders will undoubtedly evolve from an increased knowledge of human genetic variation.

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“…Die Patienten haben ebenfalls reduzierte α-Granula-Inhaltsstoffe. Der Reifungsmarker CD34 bleibt jedoch auf den Thrombozyten erhalten [17,18]. Gen führt zum δ-Granula-Defekt.…”

Section: Gfi1b-mutation -Grey-platelet-like-defektunclassified

Diagnose der Thrombozytenfunktionsstörungen – eine Herausforderung im Labor

Althaus¹,

Wagner

Bakchoul

2019

Transfusionsmedizin

Self Cite

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ZusammenfassungDie Ursache von Thrombozytenfunktionsstörungen kann erblich bedingt sein, aber auch infolge von Begleiterkrankungen und Arzneimittelwirkungen auftreten. Die Thrombozytenfunktionsuntersuchung ist jedoch komplex und kaum standardisiert. Die Bestimmung der Thrombozytenzahl und die morphologische Untersuchung der Blutplättchen sind auch für eine erste Beurteilung der Thrombozytenfunktion extrem hilfreich. Bei Patienten mit Verdacht auf eine Thrombozytenfunktionsstörung sollte nach Bestimmung der Thrombozytenzahl und der ersten morphologischen Untersuchung die Lichttransmissionsaggregometrie (LTA) und wenn möglich die Sekretionsanalyse z.B. in der Durchflusszytometrie bzw. die Immunfluoreszenzmikroskopie durchgeführt werden. Bei auffälligen Befunden können weitere spezialisierte Verfahren wie z.B. die Elektronenmikroskopie und genetische Untersuchungen zielführend sein. Hierbei ist eine Vereinheitlichung von Thrombozytenfunktionsanalysen und Antikörperuntersuchungen zwischen den verschiedenen Laboren extrem wichtig, um die Diagnostik auf diesem Gebiet zu optimieren. Wir möchten uns in diesem Artikel auf die angeborene Thrombozytenfunktionsstörung und die derzeit aktuellen Labormethoden fokussieren, um die zugrunde liegenden molekularen und genetischen Defekte genauer bestimmen zu können. Ziel ist es, eine optimale Anwendung des diagnostischen und therapeutischen Ansatzes für die Behandlung von Patienten mit erblichen Thrombozytenfunktionsstörungen zu ermöglichen.

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Recessive grey platelet-like syndrome with unaffected erythropoiesis in the absence of the splice isoform GFI1B-p37

Cited by 16 publications

References 17 publications

Thrombocytopenia and CD34 expression is decoupled from α‐granule deficiency with mutation of the first growth factor‐independent 1B zinc finger

Thrombocytopenia and CD34 expression is decoupled from α‐granule deficiency with mutation of the first growth factor‐independent 1B zinc finger

Macrothrombocytopenia associated with a rare GFI1B missense variant confounding the presentation of immune thrombocytopenia

Diagnose der Thrombozytenfunktionsstörungen – eine Herausforderung im Labor

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