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Novel ACTN1 variants in cases of thrombocytopenia.

ABSTRACT: The ACTN1 gene has been implicated in inherited macrothrombocytopenia. To decipher the spectrum of variants and phenotype of ACTN1-related thrombocytopenia, we sequenced the ACTN1 gene in 272 cases of unexplained chronic or familial thrombocytopenia. We identified 15 rare, monoallelic, nonsynonymous and likely pathogenic ACTN1 variants in 20 index cases from 20 unrelated families. Thirty-one family members exhibited thrombocytopenia. Targeted sequencing was carried out on 12 affected relatives, which confirmed presence of the variant. Twenty-eight of 32 cases with monoallelic ACTN1 variants had mild to no bleeding complications. Eleven cases harbored 11 different unreported ACTN1 variants that were monoallelic and likely pathogenic. Nine variants were located in the α-actinin-1 (ACTN1) rod domain and were predicted to hinder dimer formation. These variants displayed a smaller increase in platelet size compared with variants located outside the rod domain. In vitro expression of the new ACTN1 variants induced actin network disorganization and led to increased thickness of actin fibers. These findings expand the repertoire of ACTN1 variants associated with thrombocytopenia and highlight the high frequency of ACTN1-related thrombocytopenia cases. The rod domain, like other ACTN1 functional domains, may be mutated resulting in actin disorganization in vitro and thrombocytopenia with normal platelet size in most cases.

SUBMITTER: Vincenot A

PROVIDER: S-EPMC6900141 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Novel ACTN1 variants in cases of thrombocytopenia.

Vincenot Anne A Saultier Paul P Kunishima Shinji S Poggi Marjorie M Hurtaud-Roux Marie-Françoise MF Roussel Alain A Actn Study Coinvestigators Schlegel Nicole N Alessi Marie-Christine MC

Human mutation 20191106 12

The ACTN1 gene has been implicated in inherited macrothrombocytopenia. To decipher the spectrum of variants and phenotype of ACTN1-related thrombocytopenia, we sequenced the ACTN1 gene in 272 cases of unexplained chronic or familial thrombocytopenia. We identified 15 rare, monoallelic, nonsynonymous and likely pathogenic ACTN1 variants in 20 index cases from 20 unrelated families. Thirty-one family members exhibited thrombocytopenia. Targeted sequencing was carried out on 12 affected relatives, ...[more]

PMID: 31237726

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Project description:Purpose:Oral squamous cell carcinoma (OSCC) is a common malignancy of the oral cavity. As the survival rate of OSCC patients is low, it is crucial to explore new markers and therapeutic targets for early diagnosis of the disease. A high level of actinin alpha 1 (ACTN1) in patients could serve as an independent prognostic factor of acute myeloid leukemia. However, the role of ACTN1 in OSCC remains unclear. In the present study, we aimed to investigate the role of ACTN1 in OSCC. Methods:ACTN1 protein levels in tissues were determined by immunohistochemical (IHC) staining. The correlation of ACTN1 expression with clinicopathological features and prognosis was analyzed. Univariate and multivariate analyses were performed. The effect of ACTN1 knockdown on cell proliferation, migration, invasion, apoptosis, epithelial-mesenchymal transition (EMT), and the cell cycle was evaluated using Western blotting, Cell Counting Kit?8 (CCK8) assays, flow cytometry analysis, transwell assays, wound?-healing assays, and nude mouse models of subcutaneous xenograft and pulmonary metastasis. Results:Based on the total score of ACTN1 IHC staining analysis, ACTN1 expression was found to be low in 10 normal mucosal tissues, 48 normal mucosal tissues adjacent to OSCC, and 19 OSCC tissues, but high in 29 OSCC tissues. ACTN1 protein levels were significantly associated with the clinical stage and node metastasis, and a high ACTN1 protein level indicated poor prognosis. Moreover, ACTN1 expression was an independent predictor of poor prognosis of OSCC. Using in vitro assays, we found that ACTN1 knockdown could induce cell cycle arrest, promote apoptosis, and inhibit EMT and cell proliferation, migration, and invasion in the OSCC cell lines, SCC-15 and HSC-3. Moreover, ACTN1 knockdown inhibited subcutaneous tumor growth and pulmonary metastasis in vivo. Conclusion:ACTN1 levels were significantly associated with the clinical stage and node metastasis, and a high ACTN1 protein level indicated poor prognosis. Moreover, ACTN1 knockdown could suppress cell proliferation and metastasis of OSCC. Our results suggested that ACTN1 may serve as a diagnostic and prognostic marker of OSCC.

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Novel ACTN1 variants in cases of thrombocytopenia.

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Novel ACTN1 variants in cases of thrombocytopenia.

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