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 5

Deficiency of MFSD7c results in glomeruloid vessel structures.

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Deficiency of MFSD7c results in glomeruloid vessel structures. (A) Repre...
(A) Representative images of GLUT1 staining in hindbrain (left) and GLUT1 and MFSD7c costaining in thalamus regions (right) of E16.5 and E18.5 WT and KO embryos, respectively. Arrows show enlarged blood vessels in KO embryos. Experiments were repeated at least 3 times (n = 6 embryos per genotype). (B) Costaining of MFSD7c and GLUT1 in coronal brain sections of E18.5 WT and KO embryos. In the absence of MFSD7c, glomeruloid blood vessels were observed in brain sections of KO embryos. Arrowheads show the glomeruloid structures at the tips of blood vessels in KO embryos. Experiments were repeated at least 3 times (n = 6 embryos per genotype). (C) Enlarged images of a glomeruloid structure from E18.5 KO brain sections with erythrocytes (GLUT1 is present in both endothelial cells and erythrocytes, red signals). MFSD7c, green; GLUT1, red. Arrows show endothelial cells. Asterisks show erythrocytes. (D) H&E staining of brain sections from a human patient with S203Y homozygous mutation. Glomeruloid blood vessel structures were also observed in the brain sections of the patient. (E) Immunostaining of the human patient brain sections with GLUT1, MFSD7c, and DAPI. Arrows show glomeruliod structures that are positive with GLUT1 and MFSD7c. Arrowheads show the staining of GLUT1 with erythrocytes. n = 1 patient.