Thrombocytopenia Microcephaly Syndrome - a novel phenotype associated with ACTB mutations
Thrombocytopenia Microcephaly Syndrome - a novel phenotype associated with ACTB mutations
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DOI：
10.1101/303909
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发表时间：
2018-04
期刊：
影响因子：
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通讯作者：
Sharissa L. Latham;Nadja Ehmke;P. Reinke;M. Taft;M. Lyons;M. Friez;Jennifer A. Lee;Ramona Hecker;M. Frühwald;K. Becker;T. Neuhann;D. Horn;E. Schrock;Katharina Sarnow;Konrad Grützmann;Luzie Gawehn;B. Klink;A. Rump;C. Chaponnier;R. Knöfler;D. Manstein;N. Di Donato
中科院分区：
文献类型：
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作者：
Sharissa L. Latham;Nadja Ehmke;P. Reinke;M. Taft;M. Lyons;M. Friez;Jennifer A. Lee;Ramona Hecker;M. Frühwald;K. Becker;T. Neuhann;D. Horn;E. Schrock;Katharina Sarnow;Konrad Grützmann;Luzie Gawehn;B. Klink;A. Rump;C. Chaponnier;R. Knöfler;D. Manstein;N. Di Donato
直到最近，ACTB中编码普遍表达的β-胞质肌动蛋白（CYA）的错义种系突变仅与Baraitser-Winter脑额面综合征（BWCFF）（一种复杂的发育障碍）相关1，2。在这里，我们报告了6例以前未描述的杂合变异聚集在3 '编码区的ACTB。这些患者的临床特征与BWCFF不同，包括血小板减少症、小头畸形和轻度发育障碍。患者来源的细胞在形态和功能上与对照不同。细胞骨架成分的评估确定了这些细胞中改变的离散细丝群，其包括已知与血小板减少症相关的力产生和传递肌动蛋白结合蛋白（ABP）3 -8。计算机模拟和分子动力学（MD）模拟支持这些ABP和突变体β-CYA之间的相互作用改变。我们的研究结果描述了一种新的临床综合征与ACTB突变与一个独特的基因型-表型相关性，确定了一个细胞骨架蛋白相互作用网络至关重要的血小板生成，并提供支持这些放线菌病突变的亚形性。
Until recently missense germ-line mutations in ACTB, encoding the ubiquitously expressed β-cytoplasmic actin (CYA), were exclusively associated with Baraitser-Winter Cerebrofrontofacial syndrome (BWCFF), a complex developmental disorder1,2. Here, we report six patients with previously undescribed heterozygous variants clustered in the 3’-coding region of ACTB. These patients present with clinical features different from BWCFF, including thrombocytopenia, microcephaly, and mild developmental disability. Patient derived cells are morphologically and functionally distinct from controls. Assessment of cytoskeletal constituents identified a discrete filament population altered in these cells, which comprises force generating and transmitting actin binding proteins (ABP) known to be associated with thrombocytopenia3–8. In silico modelling and molecular dynamics (MD)-simulations support altered interactions between these ABP and mutant β-CYA. Our results describe a new clinical syndrome associated with ACTB mutations with a distinct genotype-phenotype correlation, identify a cytoskeletal protein interaction network crucial for thrombopoiesis, and provide support for the hypomorphic nature of these actinopathy mutations.