含有FERM的蛋白质(四点一,ezrin,radixin,和moesin)结构域将质膜与特定细胞位置的细胞骨架结构连接,并与细胞膜相关蛋白和/或磷酸肌醇的定位有关。含FERM结构域的蛋白5(FRMD5)定位于细胞粘附的连接处并稳定细胞-细胞接触。迄今为止,FRMD5的变异与OMIM的孟德尔病无关。这里,我们描述了8个在FRMD5中具有罕见杂合错义变异的先证者,这些先证者具有发育迟缓,智力残疾,共济失调,癫痫发作,和眼球运动的异常。所有可以进行父母测试的变体都是从头的(八个先证者中有六个),和人类基因数据集表明,FRMD5对功能丧失(LoF)不耐受。我们发现FRMD5,CG5022(dFrmd)的果蝇直系同源,在幼虫和成体中枢神经系统中表达,它存在于神经元中,但不存在于神经胶质中。dFrmdLoF突变果蝇是可行的,但对热休克非常敏感,导致严重的癫痫发作。突变体也表现出对光的缺陷响应。人FRMD5参考(Ref)cDNA拯救果蝇dFrmdLoF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,测试的两个变异体具有显性负效应.总之,证据支持观察到的FRMD5变异体在人类中引起神经系统症状.
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 in
FRMD5 have not been associated with a Mendelian disease in OMIM. Here, we describe eight probands with rare heterozygous missense variants in FRMD5 who present with developmental delay, intellectual disability, ataxia, seizures, and abnormalities of eye movement. The variants are de novo in all for whom parental testing was available (six out of eight probands), and human genetic datasets suggest that FRMD5 is intolerant to loss of function (LoF). We found that the fly ortholog of
FRMD5, CG5022 (dFrmd), is expressed in the larval and adult central nervous systems where it is present in neurons but not in glia. dFrmd LoF mutant flies are viable but are extremely sensitive to heat shock, which induces severe seizures. The mutants also exhibit defective responses to light. The human
FRMD5 reference (Ref) cDNA rescues the fly dFrmd LoF phenotypes. In contrast, all the
FRMD5 variants 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 in FRMD5 cause neurological symptoms in humans.