De novo variants in FRMD5 are associated with developmental delay, intellectual disability, ataxia, and abnormalities of eye movement.
De novo variants in FRMD5 are associated with developmental delay, intellectual disability, ataxia, and abnormalities of eye movement.
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DOI：
10.1016/j.ajhg.2022.09.005
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发表时间：
2022-10
影响因子：
9.8
通讯作者：
Shenzhao Lu;Mengqi Ma;Xiao Mao;C. Bacino;J. Jankovic;V. Sutton;J. Bartley;Xueying Wang;J. Rosenfeld;A. Beleza‐Meireles;Jaynee Chauhan;Xueyang Pan;Megan Li;Pengfei Liu;K. Prescott;Sam Amin;George Davies;M. Wangler;Yuwei Dai;H. Bellen
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文献类型：
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作者：
Shenzhao Lu;Mengqi Ma;Xiao Mao;C. Bacino;J. Jankovic;V. Sutton;J. Bartley;Xueying Wang;J. Rosenfeld;A. Beleza‐Meireles;Jaynee Chauhan;Xueyang Pan;Megan Li;Pengfei Liu;K. Prescott;Sam Amin;George Davies;M. Wangler;Yuwei Dai;H. Bellen
含有FERM(四点一、Ezrin、Radioxin和Moesin)结构域的蛋白质将质膜与特定细胞位置的细胞骨架结构连接起来，并参与细胞膜相关蛋白和/或磷脂酰肌醇的定位。FERM结构域包含蛋白5(FRMD5)定位于细胞，黏附连接，稳定细胞间的接触。到目前为止，FRMD5基因的变异还没有与OMIM中的孟德尔病相关。在这里，我们描述了8个FRMD5基因罕见杂合性错义变异的先证者，他们表现为发育迟缓、智力残疾、共济失调、癫痫发作和眼球运动异常。这些变异在所有可以进行父母检测的人中都是新的(8个先证者中有6个)，人类基因数据表明FRMD5对功能丧失(LoF)不耐受。我们发现FRMD5的同源基因CG5022(DFrmd)在幼虫和成年中枢神经系统中表达，其中它存在于神经元中，而不存在于胶质中。dFrmdLoF突变果蝇是存活的，但对热休克非常敏感，热休克会导致严重的癫痫发作。这些突变体对光的反应也有缺陷。人FRMD5Reference(Ref)cDNA挽救了flydFrmdLoF表型。相比之下，本研究中测试的所有FRMD5变体(c.340T>；C、c.1051a>；G、c.1053C>；G、c.1054T>；C、c.1045A>；C和c.1637A>；G)表现为部分LOF变体。此外，我们的结果表明，被测试的两个变量具有显性-负效应。综上所述，证据支持FRMD5的观察到的变异会导致人类的神经症状。
Proteins containing the FERM (four-point-one, ezrin, radixin, and moesin) domain link the plasma membrane with cytoskeletal structures at specific cellular locations and have been implicated in the localization of cell-membrane-associated proteins and/or phosphoinositides. FERM domain-containing protein 5 (FRMD5) localizes at cell adherens junctions and stabilizes cell-cell contacts. To date, variants inFRMD5have not been associated with a Mendelian disease in OMIM. Here, we describe eight probands with rare heterozygous missense variants inFRMD5who present with developmental delay, intellectual disability, ataxia, seizures, and abnormalities of eye movement. The variants arede novoin all for whom parental testing was available (six out of eight probands), and human genetic datasets suggest thatFRMD5is intolerant to loss of function (LoF). We found that the fly ortholog ofFRMD5,CG5022 (dFrmd), is expressed in the larval and adult central nervous systems where it is present in neurons but not in glia.dFrmdLoF mutant flies are viable but are extremely sensitive to heat shock, which induces severe seizures. The mutants also exhibit defective responses to light. The humanFRMD5reference (Ref) cDNA rescues the flydFrmdLoF phenotypes. In contrast, all theFRMD5variants tested in this study (c.340T>C, c.1051A>G, c.1053C>G, c.1054T>C, c.1045A>C, and c.1637A>G) behave as partial LoF variants. In addition, our results indicate that two variants that were tested have dominant-negative effects. In summary, the evidence supports that the observed variants inFRMD5cause neurological symptoms in humans.