van Kogelenberg Margriet, Clark Alice R, Jenkins Zandra, Morgan Tim, Anandan Ananda, Sawyer Gregory M, Edwards Matthew, Dudding Tracy, Homfray Tessa, Castle Bruce, Tolmie John, Stewart Fiona, Kivuva Emma, Pilz Daniela T, Gabbett Michael, Sutherland-Smith Andrew J, Robertson Stephen P
Department of Paediatrics and Child Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand.
J Mol Med (Berl). 2015 Jul;93(7):773-82. doi: 10.1007/s00109-015-1261-7. Epub 2015 Feb 18.
Filamin A, the filamentous protein encoded by the X-linked gene FLNA, cross-links cytoskeletal actin into three-dimensional networks, facilitating its role as a signalling scaffold and a mechanosensor of extrinsic shear forces. Central to these functions is the ability of FLNA to form V-shaped homodimers through its C-terminal located filamin repeat 24. Additionally, many proteins that interact with FLNA have a binding site that includes the C-terminus of the protein. Here, a cohort of patients with mutations affecting this region of the protein is studied, with particular emphasis on the phenotype of male hemizygotes. Seven unrelated families are reported, with five exhibiting a typical female presentation of periventricular heterotopia (PH), a neuronal migration disorder typically caused by loss-of-function mutations in FLNA. One male presents with widespread PH consistent with previous male phenotypes attributable to hypomorphic mutations in FLNA. In stark contrast, two brothers are described with a mild PH presentation, due to a missense mutation (p.Gly2593Glu) inserting a large negatively charged amino acid into the hydrophobic dimerisation interface of FLNA. Co-immunoprecipitation, in vitro cross-linking studies and gel filtration chromatography all demonstrated that homodimerisation of isolated FLNA repeat 24 is abolished by this p.Gly2593Glu substitution but that extended FLNA(Gly2593Glu) repeat 16-24 constructs exhibit dimerisation. These observations imply that other interactions apart from those mediated by the canonical repeat 24 dimerisation interface contribute to FLNA homodimerisation and that mutations affecting this region of the protein can have broad phenotypic effects.
• Mutations in the X-linked gene FLNA cause a spectrum of syndromes. • Genotype-phenotype correlations are emerging but still remain unclear. • C-term mutations can confer male lethality, survival or connective tissue defects. • Mutations leading to the latter affect filamin dimerisation. • This deficit is compensated for by remotely acting domains elsewhere in FLNA.
细丝蛋白A由X连锁基因FLNA编码，它将细胞骨架肌动蛋白交联成三维网络，促进其作为信号支架和外在剪切力机械传感器的作用。FLNA通过其位于C末端的细丝蛋白重复序列24形成V形同源二聚体的能力是这些功能的核心。此外，许多与FLNA相互作用的蛋白质具有包含该蛋白质C末端的结合位点。在此，对一组影响该蛋白质这一区域的突变患者进行了研究，特别关注男性半合子的表型。报告了7个无关家族，其中5个表现出典型的女性室周异位（PH）表现，这是一种通常由FLNA功能丧失突变引起的神经元迁移障碍。一名男性表现出广泛的PH，与先前归因于FLNA低表达突变的男性表型一致。与之形成鲜明对比的是，描述了两名兄弟有轻度的PH表现，这是由于一个错义突变（p.Gly2593Glu）在FLNA的疏水二聚化界面插入了一个大的带负电荷的氨基酸。免疫共沉淀、体外交联研究和凝胶过滤色谱均表明，这种p.Gly2593Glu取代消除了分离的FLNA重复序列24的同源二聚化，但扩展的FLNA（Gly2593Glu）重复序列16 - 24构建体表现出二聚化。这些观察结果表明，除了由典型的重复序列24二聚化界面介导的相互作用之外，其他相互作用也有助于FLNA同源二聚化，并且影响该蛋白质这一区域的突变可产生广泛的表型效应。
• X连锁基因FLNA中的突变会导致一系列综合征。
• 基因型 - 表型相关性正在显现，但仍不清楚。
• C末端突变可导致男性致死、存活或结缔组织缺陷。
• 导致后者的突变影响细丝蛋白二聚化。
• 这种缺陷由FLNA其他部位的远程作用结构域补偿。
