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Deficiency of MFSD7c results in microcephaly-associated vasculopathy in Fowler syndrome
Pazhanichamy Kalailingam, … , Karin Weiss, Long N. Nguyen
Pazhanichamy Kalailingam, … , Karin Weiss, Long N. Nguyen
Published May 5, 2020
Citation Information: J Clin Invest. 2020;130(8):4081-4093. https://doi.org/10.1172/JCI136727.
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Research Article Vascular biology

Deficiency of MFSD7c results in microcephaly-associated vasculopathy in Fowler syndrome

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Abstract

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.

Authors

Pazhanichamy Kalailingam, Kai Qi Wang, Xiu Ru Toh, Toan Q. Nguyen, Madhuvanthi Chandrakanthan, Zafrul Hasan, Clair Habib, Aharon Schif, Francesca Clementina Radio, Bruno Dallapiccola, Karin Weiss, Long N. Nguyen

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Figure 4

Deletion of MFSD7c does not result in ruptured CNS blood vessels and increased permeability of BBB.

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Deletion of MFSD7c does not result in ruptured CNS blood vessels and inc...
(A and B) Brain sections of E14.5 (n = 3 embryos per genotype) (A) and E16.5 (n = 4 embryos per genotype) (B). WT and Mfsd7c-KO embryos were stained with MFSD2a (a CNS endothelial cell marker, green) and Ter119 (red blood cell marker, pink). Arrows indicate clumps of erythrocytes surrounded by blood vessels in Mfsd7c-KO embryos. There was no hemorrhage in KO embryonic brains. Shown here are hindbrain regions. Scale bars: 20 μm. Experiments were repeated 3 times. (C and D) Representative coronal brain sections of E15.5 WT and KO showing that NHS-biotin was contained inside KO blood vessels. Arrows show enlarged blood vessels with strong signals of NHS-biotin. Experiments were repeated twice with n = 6 for WT or KO.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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