An essential role for α4A-tubulin in platelet biogenesis

Strassel, Catherine; Magiera, Maria M.; Dupuis, Arnaud; Batzenschlager, Morgane; Hovasse, Agnès; Pleines, Irina; Guéguen, Paul; Eckly, Anita; Moog, Sylvie; Mallo, Léa; Kimmerlin, Quentin; Chappaz, Stéphane; Strub, Jean‐Marc; Natarajan, Kathiresan; Salle, Henri; Dorsselaer, Alain Van; Férec, Claude; Py, Jean-Yves; Gachet, Christian; Schaeffer-Reiss, Christine; Kile, Benjamin T.; Janke, Carsten; Lanza, François

doi:10.26508/lsa.201900309

Cited by 42 publications

(52 citation statements)

References 40 publications

(54 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, little is known about the role of specific α-tubilin isotypes. It has been reported recently, however, that an α4A-tubulin enrichment in platelets and an increase in its expression occur during the late stages of megakaryocyte differentiation [17].…”

Section: Platelet Cytoskeletonmentioning

confidence: 99%

Tubulin in Platelets: When the Shape Matters

Cuenca-Zamora

Ferrer‐Marín

Rivera

et al. 2019

IJMS

View full text Add to dashboard Cite

Platelets are anuclear cells with a short lifespan that play an essential role in many pathophysiological processes, including haemostasis, inflammation, infection, vascular integrity, and metastasis. Billions of platelets are produced daily from megakaryocytes (platelet precursors). Despite this high production, the number of circulating platelets is stable and, under resting conditions, they maintain their typical discoid shape thanks to cytoskeleton proteins. The activation of platelets is associated with dynamic and rapid changes in the cytoskeleton. Two cytoskeletal polymer systems exist in megakaryocytes and platelets: actin filaments and microtubules, based on actin, and α- and β-tubulin heterodimers, respectively. Herein, we will focus on platelet-specific tubulins and their alterations and role of the microtubules skeleton in platelet formation (thrombopoiesis). During this process, microtubules mediate elongation of the megakaryocyte extensions (proplatelet) and granule trafficking from megakaryocytes to nascent platelets. In platelets, microtubules form a subcortical ring, the so-called marginal band, which confers the typical platelet discoid shape and is also responsible for changes in platelet morphology upon activation. Molecular alterations in the gene encoding β1 tubulin and microtubules post-translational modifications may result in quantitative or qualitative changes in tubulin, leading to altered cytoskeleton reorganization that may induce changes in the platelet number (thrombocytopenia), morphology or function. Consequently, β1-tubulin modifications may participate in pathological and physiological processes, such as development.

show abstract

Section: Platelet Cytoskeletonmentioning

confidence: 99%

Tubulin in Platelets: When the Shape Matters

Cuenca-Zamora

Ferrer‐Marín

Rivera

et al. 2019

IJMS

View full text Add to dashboard Cite

show abstract

“…It has been proposed that the mutation weakens the longitudinal interaction between tubulin subunits within a protofilament by disrupting proper hydrogen bonding across the interface . Recent reports have revealed new pathogenic tubulin missense mutations, several of which occur at interfaces, including in TUBB8 causing female infertility by preventing correct meiotic spindle formation and in TUBA4 and TUBB1 associated with blood disorders such as low platelet counts . We predict that more isotype‐specific tubulin missense mutations will be reported in other disorders, given the central role of tubulin in all eukaryotes.…”

Section: Mutations That Perturb Protein Interactionsmentioning

confidence: 90%

The role of protein complexes in human genetic disease

et al. 2019

View full text Add to dashboard Cite

Many human genetic disorders are caused by mutations in protein-coding regions of DNA. Taking protein structure into account has therefore provided key insight into the molecular mechanisms underlying human genetic disease. Although most studies have focused on the intramolecular effects of mutations, the critical role of the assembly of proteins into complexes is being increasingly recognized. Here, we review multiple ways in which consideration of protein complexes can help us to understand and explain the effects of pathogenic mutations. First, we discuss disorders caused by mutations that perturb intersubunit interactions in homomeric and heteromeric complexes. Second, we address how protein complex assembly can facilitate a dominant-negative mechanism, whereby mutated subunits can disrupt the activity of wild-type protein. Third, we show how mutations that change protein expression levels can lead to damaging stoichiometric imbalances. Finally, we review how mutations affecting different subunits of the same heteromeric complex often cause similar diseases, whereas mutations in different interfaces of the same subunit can cause distinct phenotypes.

show abstract

“…The remaining gene, TUBA4A, was included based on the then unpublished observations in mice. 27 A total of 68 rare variants including missense, canonical splice site, frameshift, and nonsense and inframe variants were identified in 11 of the 13 genes under study. Adopting a conservative and unbiased strategy, we classified six variants as pathogenic and another five as likely pathogenic.…”

Section: Discussionmentioning

confidence: 99%

Pathogenic and likely pathogenic variants in at least five genes account for approximately 3% of mild isolated nonsyndromic thrombocytopenia

Guéguen

Dupuis

et al. 2020

Transfusion

Self Cite

View full text Add to dashboard Cite

Background: Thrombocytopenia has a variety of different etiologies, both acquired and hereditary. Inherited thrombocytopenia may be associated with other symptoms (syndromic forms) or may be strictly isolated. To date, only about half of all the familial forms of thrombocytopenia have been accounted for in terms of well-defined genetic abnormalities. However, data are limited on the nature and frequency of the underlying causative genetic variants in individuals with mild isolated nonsyndromic thrombocytopenia. Study Design and Methods: Thirteen known or candidate genes for isolated thrombocytopenia were included in a gene panel analysis in which targeted next-generation sequencing was performed on 448 French blood donors with mild isolated nonsyndromic thrombocytopenia. Results: A total of 68 rare variants, including missense, splice site, frameshift, nonsense, and in-frame variants (all heterozygous) were identified in 11 of the 13 genes screened. Twenty-nine percent (N = 20) of the variants detected were absent from both the French Exome Project and gnomAD exome databases. Using stringent criteria and an unbiased approach, we classified seven predicted loss-of-function variants (three in ITGA2B and four in TUBB1) and four missense variants (one in GP1BA, two in ITGB3 and one in ACTN1) as

show abstract

An essential role for α4A-tubulin in platelet biogenesis

Abstract: Alpha4A-tubulin is the predominant α-tubulin isotype in platelets. Mutations in α4A-tubulin cause abnormal platelet biogenesis and marginal band formation in mice and in a patient, establishing an essential role of this tubulin isotype.

Cited by 42 publications

References 40 publications

Tubulin in Platelets: When the Shape Matters

Tubulin in Platelets: When the Shape Matters

The role of protein complexes in human genetic disease

Pathogenic and likely pathogenic variants in at least five genes account for approximately 3% of mild isolated nonsyndromic thrombocytopenia

Contact Info

Product

Resources

About