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

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 8

Mfsd7c-KO embryos exhibited cell death in SVZs.

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Mfsd7c-KO embryos exhibited cell death in SVZs. (A and B) Representativ...
(A and B) Representative images of coronal sections of E14.5 WT and KO embryos that were immunostained to detect activated caspase-3, a marker for cell death. The activated caspase-3+ cells were only observed in the SVZs in GEs of KO embryos as shown by arrowheads (top), but not in the cortical hem and neocortex (bottom). Dead cells were clearly localized in avascular regions in GEs. The vascular network was visualized by CD31. (C) Enlarged images in the GEs. The activated caspase-3+ cells were found in close proximity to nonendothelial cells that were also positive for CD31 in the VZs of GE. Activated caspase-3+ cells had condensed nuclei (red arrows), and the CD31-positive cells are adjacent to them (white arrows). n = 5–8 per genotype. (D) Quantification of caspase-3+ cells in the GEs. Each dot represents 1 section from 8 WT and 5 KO embryos. ***P < 0.001, 2-tailed t test.