Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel.
J Clin Invest. 2020 Aug 3;130(8):4081-4093. doi: 10.1172/JCI136727.
Several missense mutations in the orphan transporter FLVCR2 have been reported in Fowler syndrome. Affected subjects exhibit signs of severe neurological defects. We identified the mouse ortholog Mfsd7c as a gene expressed in the blood-brain barrier. Here, we report the characterizations of Mfsd7c-KO mice and compare these characterizations to phenotypic findings in humans with biallelic FLVCR2 mutations. Global KO of Mfsd7c in mice resulted in late-gestation lethality, likely due to CNS phenotypes. We found that the angiogenic growth of CNS blood vessels in the brain of Mfsd7c-KO embryos was inhibited in cortical ventricular zones and ganglionic eminences. Vascular tips were dilated and fused, resulting in glomeruloid vessels. Nonetheless, CNS blood vessels were intact, without hemorrhage. Both embryos and humans with biallelic FLVCR2 mutations exhibited reduced cerebral cortical layers, enlargement of the cerebral ventricles, and microcephaly. Transcriptomic analysis of Mfsd7cK-KO embryonic brains revealed upregulation of genes involved in glycolysis and angiogenesis. The Mfsd7c-KO brain exhibited hypoxia and neuronal cell death. Our results indicate that MFSD7c is required for the normal growth of CNS blood vessels and that ablation of this gene results in microcephaly-associated vasculopathy in mice and humans.
在法乐氏四联症（Fowler syndrome）中，已经报道了孤儿转运体 FLVCR2 的几个错义突变。受影响的受试者表现出严重的神经缺陷迹象。我们鉴定出了在血脑屏障中表达的小鼠直系同源物 Mfsd7c。在这里，我们报告了 Mfsd7c-KO 小鼠的特征，并将这些特征与具有双等位基因 FLVCR2 突变的人类表型发现进行了比较。Mfsd7c 在小鼠中的全局敲除导致晚孕期致死，可能是由于中枢神经系统表型所致。我们发现，Mfsd7c-KO 胚胎大脑中的中枢神经系统血管的血管生成性生长在皮质脑室区和神经节隆起处受到抑制。血管尖端扩张并融合，导致肾小球样血管。尽管如此，中枢神经系统血管仍然完整，没有出血。具有双等位基因 FLVCR2 突变的胚胎和人类均表现出皮质层减少、脑室扩大和小头畸形。Mfsd7cK-KO 胚胎大脑的转录组分析显示，参与糖酵解和血管生成的基因上调。Mfsd7c-KO 大脑表现出缺氧和神经元细胞死亡。我们的结果表明 MFSD7c 是中枢神经系统血管正常生长所必需的，并且该基因的缺失会导致小鼠和人类的小头畸形相关血管病变。
