Thrombocytopenia resulting from mutations in filamin A can be expressed as an isolated syndrome

Nurden, Paquita; Debili, Najet; Coupry, Isabelle; Bryckaert, Marijke; Youlyouz-Marfak, Ibtissam; Solé, Guilhem; Pons, Anne-Cécile; Berrou, Eliane; Adam, Frédéric; Kauskot, Alexandre; Lamazière, Jean-Marie Daniel; Rameau, Philippe; Fergelot, Patricia; Rooryck, Caroline; Cailley, Dorothée; Arveiler, Benoı̂t; Lacombe, Didier; Vainchenker, William; Goizet, Cyril

doi:10.1182/blood-2011-07-365601

Cited by 148 publications

(139 citation statements)

References 33 publications

Supporting

Mentioning

133

Contrasting

Unclassified

Order By: Relevance

“…35,36 Impaired actin remodeling in megakaryocytes may thus perturb platelet formation, and in fact defects in actin-related proteins were shown to lead to thrombocytopenia and to the production of platelets with altered dimensions. [44][45][46][47] We induced actin polymerization by incubating control megakaryocytes with jasplakinolide and indeed we observed impaired proplatelet formation.…”

Section: A B Cmentioning

confidence: 71%

Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia

et al. 2015

View full text Add to dashboard Cite

Several patients have been reported to have variant dominant forms of Glanzmann thrombasthenia, associated with macrothrombocytopenia and caused by gain-of-function mutations of ITGB3 or ITGA2B leading to reduced surface expression and constitutive activation of integrin α IIb β 3 . The mechanisms leading to a bleeding phenotype of these patients have never been addressed. The aim of this study was to unravel the mechanism by which ITGB3 mutations causing activation of α IIb β 3 lead to platelet dysfunction and macrothrombocytopenia. Using platelets from two patients carrying the β 3 del647-686 mutation and Chinese hamster ovary cells expressing different α IIb β 3 -activating mutations, we showed that reduced surface expression of α IIb β 3 is due to receptor internalization. Moreover, we demonstrated that permanent triggering of α IIb β 3 -mediated outside-in signaling causes an impairment of cytoskeletal reorganization arresting actin turnover at the stage of polymerization. The induction of actin polymerization by jasplakinolide, a natural toxin that promotes actin nucleation and prevents depolymerization of stress fibers, in control platelets produced an impairment of platelet function similar to that of patients with variant forms of dominant Glanzmann thrombasthenia. del647-686β 3 -transduced murine megakaryocytes generated proplatelets with a reduced number of large tips and asymmetric barbell-proplatelets, suggesting that impaired cytoskeletal rearrangement is the cause of macrothrombocytopenia. These data show that impaired cytoskeletal remodeling caused by a constitutively activated α IIb β 3 is the main effector of platelet dysfunction and macrothrombocytopenia, and thus of bleeding, in variant forms of dominant Glanzmann thrombasthenia. Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia

show abstract

Section: A B Cmentioning

confidence: 71%

Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia

et al. 2015

View full text Add to dashboard Cite

show abstract

“…In females, loss-of-function mutations in FLNA are associated with periventricular nodular heterotopia (PVNH), cardiovascular complications, thrombocytopenia and Ehlers-Danlos syndrome. [6][7][8][9][10] PVNH is characterized by the presence of nodules of neurons along the walls of the lateral ventricles, an inappropriate location caused by abnormal neuronal migration during cerebral cortex development. Cardiovascular complications are characterized by valvular insufficiency because of thickening of heart valves and a dilatation of large vessels.…”

Section: Introductionmentioning

confidence: 99%

Exon skipping causes atypical phenotypes associated with a loss-of-function mutation in FLNA by restoring its protein function

et al. 2015

View full text Add to dashboard Cite

Loss-of-function mutations in filamin A (FLNA) cause an X-linked dominant disorder with multiple organ involvement. Affected females present with periventricular nodular heterotopia (PVNH), cardiovascular complications, thrombocytopenia and EhlersDanlos syndrome. These mutations are typically lethal to males, and rare male survivors suffer from failure to thrive, PVNH, and severe cardiovascular and gastrointestinal complications. Here we report two surviving male siblings with a loss-of-function mutation in FLNA. They presented with multiple complications, including valvulopathy, intestinal malrotation and chronic intestinal pseudo-obstruction (CIPO). However, these siblings had atypical clinical courses, such as a lack of PVNH and a spontaneous improvement of CIPO. Trio-based whole-exome sequencing revealed a 4-bp deletion in exon 40 that was predicted to cause a lethal premature protein truncation. However, molecular investigations revealed that the mutation induced in-frame skipping of the mutated exon, which led to the translation of a mutant FLNA missing an internal region of 41 amino acids. Functional analyses of the mutant protein suggested that its binding affinity to integrin, as well as its capacity to induce focal adhesions, were comparable to those of the wild-type protein. These results suggested that exon skipping of FLNA partially restored its protein function, which could contribute to amelioration of the siblings' clinical courses. This study expands the diversity of the phenotypes associated with loss-of-function mutations in FLNA.

show abstract

“…Nurden and colleagues described three female patients with thrombocytopenia caused by monoallelic FLNA mutations. In two subjects with large FLNA deletions, thrombocytopenia associated with periventricular nodular heterotopia, a neurologic disorder due to impaired neuronal migration, while in the third patient macrothrombocytopenia was the only manifestation of a missense mutation [6,57]. Mks of these subjects showed preserved in vitro development and a quantitative defect in PPF.…”

Section: Defective Ppf From Mature Mksmentioning

confidence: 93%

“…Mks of these subjects showed preserved in vitro development and a quantitative defect in PPF. In addition, mature Mks had ultrastructural abnormalities consistent with reduced cytoskeletal stability [6].…”

Section: Defective Ppf From Mature Mksmentioning

confidence: 99%

See 1 more Smart Citation

Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists

Pecci

2013

Int J Hematol

View full text Add to dashboard Cite

Knowledge in the field of inherited thrombocytopenias (ITs) has considerably improved over the recent years. In the last 5 years, nine new genes whose mutations are responsible for thrombocytopenia have been identified, and this also led to the recognition of several novel nosographic entities, such as thrombocytopenias deriving from mutations in CYCS, TUBB1, FLNA, ITGA2B/ITGB3, ANKRD26 and ACTN1. The identification of novel molecular alterations causing thrombocytopenia together with improvement of methodologies to study megakaryopoiesis led to considerable advances in understanding pathophysiology of ITs, thus providing the background for proposing new treatments. Thrombopoietin-receptor agonists (TPO-RAs) represent an appealing therapeutic hypothesis for ITs and have been tested in a limited number of patients. In this review, we provide an updated description of pathogenetic mechanisms of thrombocytopenia in the different forms of ITs and recapitulate the current management of these disorders. Moreover, we report the available clinical and preclinical data about the role of TPO-RAs in ITs and discuss the rationale for the use of these molecules in view of pathogenesis of the different forms of thrombocytopenia of genetic origin.

show abstract

Thrombocytopenia resulting from mutations in filamin A can be expressed as an isolated syndrome

Cited by 148 publications

References 33 publications

Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia

Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia

Exon skipping causes atypical phenotypes associated with a loss-of-function mutation in FLNA by restoring its protein function

Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists

Contact Info

Product

Resources

About