Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA.
Program in Neuroscience and Harvard/MIT MD-PHD Program, Harvard Medical School, Boston, MA, USA.
Genet Med. 2020 Jun;22(6):1040-1050. doi: 10.1038/s41436-020-0758-9. Epub 2020 Feb 27.
The exocyst complex is a conserved protein complex that mediates fusion of intracellular vesicles to the plasma membrane and is implicated in processes including cell polarity, cell migration, ciliogenesis, cytokinesis, autophagy, and fusion of secretory vesicles. The essential role of these genes in human genetic disorders, however, is unknown.
We performed homozygosity mapping and exome sequencing of consanguineous families with recessively inherited brain development disorders. We modeled an EXOC7 splice variant in vitro and examined EXOC7 messenger RNA (mRNA) expression in developing mouse and human cortex. We modeled exoc7 loss-of-function in a zebrafish knockout.
We report variants in exocyst complex members, EXOC7 and EXOC8, in a novel disorder of cerebral cortex development. In EXOC7, we identified four independent partial loss-of-function (LOF) variants in a recessively inherited disorder characterized by brain atrophy, seizures, and developmental delay, and in severe cases, microcephaly and infantile death. In EXOC8, we found a homozygous truncating variant in a family with a similar clinical disorder. We modeled exoc7 deficiency in zebrafish and found the absence of exoc7 causes microcephaly.
Our results highlight the essential role of the exocyst pathway in normal cortical development and how its perturbation causes complex brain disorders.
外被体复合物是一种保守的蛋白质复合物，介导细胞内囊泡与质膜融合，涉及细胞极性、细胞迁移、纤毛发生、胞质分裂、自噬和分泌囊泡融合等过程。然而，这些基因在人类遗传疾病中的重要作用尚不清楚。
我们对具有隐性遗传性脑发育障碍的近亲家庭进行了纯合子作图和外显子组测序。我们在体外模拟了 EXOC7 剪接变异体，并检测了发育中的小鼠和人皮层中 EXOC7 信使 RNA（mRNA）的表达。我们在斑马鱼敲除模型中模拟了 exoc7 功能丧失。
我们报道了外被体复合物成员 EXOC7 和 EXOC8 中的变异体，这些变异体与一种新的大脑皮层发育障碍有关。在 EXOC7 中，我们在一种以大脑萎缩、癫痫发作和发育迟缓为特征的隐性遗传疾病中发现了四个独立的部分功能丧失（LOF）变异体，在严重的情况下还会出现小头畸形和婴儿死亡。在 EXOC8 中，我们在一个具有相似临床疾病的家族中发现了一个纯合截短变异体。我们在斑马鱼中模拟了 exoc7 缺陷，发现 exoc7 的缺失会导致小头畸形。
我们的结果强调了外被体途径在正常皮层发育中的重要作用，以及其异常如何导致复杂的脑疾病。
