Familial macrothrombocytopenia due to a double mutation <i>in cis</i> in the alpha‐actinin 1 gene (<i>ACTN1</i>), previously considered to be chronic immune thrombocytopenic purpura

Kanhai, Danny A; Mulder, René; Amstel, Hans Kristian Ploos van; Schutgens, Roger E. G.; Lukens, Michaël V.; Tamminga, R. Y. J.

doi:10.1002/pbc.27418

Cited by 4 publications

(4 citation statements)

References 13 publications

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“…of the novel mutation (NM_001130004: c.398_399insTGCG, p.F134AfsX60) carriers (II-1 and III-2) were consistent with mice model and other reported patients, which further confirmed the pathogenicity of this novel mutation (19,20). IMTP can easily be misdiagnosed as immune thrombocytopenic purpura, which may further make problems in therapy and management of patients (8). Hence, precise diagnosis is necessary for IMTP patients, especially for the IMTP patients caused by ACTN1 mutations.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, some syndromes are also typically characterized by low platelet counts and severe bleeding tendency, such as Wiskott-Aldrich syndrome, Bernard-Soulier syndrome, Di George syndrome, and so on (5)(6)(7). However, because of varying mutations and clinical manifestations, the IMTP shows obvious heterogeneity, which challenges the clear diagnosis of IMTP and leads to the misdiagnosis as immune thrombocytopenic purpura (8).…”

Section: Introductionmentioning

confidence: 99%

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Case Report: Exome Sequencing Identified a Novel Frameshift Mutation of α-Actin 1 in a Chinese Family With Macrothrombocytopenia and Mild Bleeding

et al. 2021

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Inherited macrothrombocytopenia (IMTP) is a rare disorder characterized by a reduced platelet count and abnormally large platelets. The main clinical symptom of IMTP is mild bleeding in some patients. At present, more than 30 genes have been identified in patients with syndromic and non-syndromic IMTP. In this study, a 3-year-old boy and his mother who presented with mild epistaxis and/or gingival bleeding were diagnosed as having IMTP. Wen then selected whole sequencing to explore the genetic lesion of the patients. After data filtering and mutation validation, a novel frameshift mutation (NM_001130004: c.398_399insTGCG, p.F134AfsX60) of α-actin 1 (ACTN1) was identified in the proband and his mother but absent in other unaffected individuals. Previous studies have proven that mutations in ACTN1 may lead to IMTP with mild to absent bleeding phenotype. The novel mutation, resulting in a truncated protein in exon 4 of the ACTN1 gene, was absent in the public database, such as 1000G and genomAD. Further Western blot revealed that the expression of α-actin 1 in the proband was decreased overtly, which indicated that the novel frameshift mutation may induce non-sense-mediated mRNA decay. In summary, this study not only broadened the variants spectrum of ACTN1 gene, which may contribute to the genetic counseling of IMTP, but also confirmed the diagnosis of IMTP, which may help the management and prognosis for the family members.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Case Report: Exome Sequencing Identified a Novel Frameshift Mutation of α-Actin 1 in a Chinese Family With Macrothrombocytopenia and Mild Bleeding

et al. 2021

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“…Similarly, as a scaffolding protein, α-actinin coordinates the organization of various actin-based structures, from sarcomeres to focal adhesions [ 84 ]. Mutations in α-actinin isoforms are linked to several human diseases, such as autosomal-dominant congenital macrothrombocytopenia [ 85 , 86 ], dilated or hypertrophic cardiomyopathy [ 87 ], familial focal segmental glomerulosclerosis (FFSG) [ 88 , 89 ], carcinomas [ 90 , 91 ], and immunological diseases [ 92 ].…”

Section: Actin-bundling Proteinsmentioning

confidence: 99%

Actin Bundles Dynamics and Architecture

2023

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Cells use the actin cytoskeleton for many of their functions, including their division, adhesion, mechanosensing, endo- and phagocytosis, migration, and invasion. Actin bundles are the main constituent of actin-rich structures involved in these processes. An ever-increasing number of proteins that crosslink actin into bundles or regulate their morphology is being identified in cells. With recent advances in high-resolution microscopy and imaging techniques, the complex process of bundles formation and the multiple forms of physiological bundles are beginning to be better understood. Here, we review the physiochemical and biological properties of four families of highly conserved and abundant actin-bundling proteins, namely, α-actinin, fimbrin/plastin, fascin, and espin. We describe the similarities and differences between these proteins, their role in the formation of physiological actin bundles, and their properties—both related and unrelated to their bundling abilities. We also review some aspects of the general mechanism of actin bundles formation, which are known from the available information on the activity of the key actin partners involved in this process.

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“…Subsequently, these and additional novel mutations were identified in other patient cohorts. A review in 2017 catalogued 20 mutations [4] and more recent studies have brought the total number of different CMTP-causing actinin-1 mutations identified to approximately 40 [86][87][88][89][90]. With one exception (Luo 21; see below), these are all missense mutations that change a single amino acid within the actinin-1 protein, and all appear to be inherited in a dominant fashion.…”

Section: Discovery Of Cmtp-causing Actinin-1 Mutationsmentioning

confidence: 99%

The Importance of Alpha-Actinin Proteins in Platelet Formation and Function, and Their Causative Role in Congenital Macrothrombocytopenia

O’Sullivan

Cahill

Young

2021

IJMS

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The actin cytoskeleton plays a central role in platelet formation and function. Alpha-actinins (actinins) are actin filament crosslinking proteins that are prominently expressed in platelets and have been studied in relation to their role in platelet activation since the 1970s. However, within the past decade, several groups have described mutations in ACTN1/actinin-1 that cause congenital macrothrombocytopenia (CMTP)—accounting for approximately 5% of all cases of this condition. These findings are suggestive of potentially novel functions for actinins in platelet formation from megakaryocytes in the bone marrow and/or platelet maturation in circulation. Here, we review some recent insights into the well-known functions of actinins in platelet activation before considering possible roles for actinins in platelet formation that could explain their association with CMTP. We describe what is known about the consequences of CMTP-linked mutations on actinin-1 function at a molecular and cellular level and speculate how these changes might lead to the alterations in platelet count and morphology observed in CMTP patients. Finally, we outline some unanswered questions in this area and how they might be addressed in future studies.

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Familial macrothrombocytopenia due to a double mutation in cis in the alpha‐actinin 1 gene (ACTN1), previously considered to be chronic immune thrombocytopenic purpura

Cited by 4 publications

References 13 publications

Case Report: Exome Sequencing Identified a Novel Frameshift Mutation of α-Actin 1 in a Chinese Family With Macrothrombocytopenia and Mild Bleeding

Case Report: Exome Sequencing Identified a Novel Frameshift Mutation of α-Actin 1 in a Chinese Family With Macrothrombocytopenia and Mild Bleeding

Actin Bundles Dynamics and Architecture

The Importance of Alpha-Actinin Proteins in Platelet Formation and Function, and Their Causative Role in Congenital Macrothrombocytopenia

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