Rabbolini David, Liang Hai Po Helena, Morel-Kopp Marie-Christine, Connor David, Whittaker Shane, Dunkley Scott, Donikian Dea, Kondo Mayuko, Chen Walter, Stevenson William S, Campbell Heather, Joseph Joanne, Ward Christopher, Brighton Timothy, Chen Vivien M
Department of Haematology, Lismore Base Hospital, Lismore, NSW, Australia.
Northern Blood Research Centre, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.
Platelets. 2022 Apr 3;33(3):432-442. doi: 10.1080/09537104.2021.1937593. Epub 2021 Jul 5.
Variants of the Diaphanous-Related Formin 1 () gene have recently been reported causing inherited macrothrombocytopenia. The essential/"diagnostic" characteristics associated with the disorder are emerging; however, robust and complete criteria are not established. Here, we report the first cases of -related disorder in Australia caused by the autosomal dominant gain-of-function DIAPH1 R1213X variant formed by truncation of the protein within the diaphanous auto-regulatory domain (DAD) with loss of regulatory motifs responsible for autoinhibitory interactions within the DIAPH1 protein. We affirm phenotypic changes induced by the DIAPH1 R1213X variant to include macrothrombocytopenia, early-onset progressive sensorineural hearing loss, and mild asymptomatic neutropenia. High-resolution microscopy confirms perturbations of cytoskeletal dynamics caused by the DIAPH1 variant and we extend the repertoire of changes generated by this variant to include alteration of procoagulant platelet formation and possible dental anomalies.
最近有报道称，与透明相关的成纤维蛋白1（）基因的变异会导致遗传性大血小板减少症。与该疾病相关的基本/“诊断”特征正在显现；然而，尚未建立完善且全面的标准。在此，我们报告了澳大利亚首例由常染色体显性功能获得性DIAPH1 R1213X变异引起的相关疾病，该变异是由于在透明自调节域（DAD）内蛋白质截断形成的，导致负责DIAPH1蛋白内自抑制相互作用的调节基序缺失。我们证实，DIAPH1 R1213X变异引起的表型变化包括大血小板减少症、早发性进行性感觉神经性听力丧失和轻度无症状中性粒细胞减少症。高分辨率显微镜检查证实了DIAPH1变异导致的细胞骨架动力学紊乱，并且我们将该变异产生的变化范围扩展到包括促凝血血小板形成的改变和可能的牙齿异常。
