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.
View: Text | PDF
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

×

Figure 6

Deficiency in MFSD7c results in microcephaly.

Options: View larger image (or click on image) Download as PowerPoint
Deficiency in MFSD7c results in microcephaly. (A and B) Representative i...
(A and B) Representative images of coronal sections of E14.5 and E20.5 WT and KO embryos were stained with DAPI and GLUT1. Thinning of cortices were visible at E20.5. (C) Quantification of VZ and cortex thickness in E20.5 WT and KO embryos. Each dot represents 1 section. Data are represented as mean ± SD. n = 4–5 per genotype. ****P < 0.0001, 2-tailed t test. (D and E) Illustration of human MFSD7c gene and the modeled structure of human MFSD7c. Shown are missense mutations that have been reported for MFSD7c and the 2 novel mutations that occurred in the patient shown in D. (F) MRI images of the patient brain showing that the patient has microcephaly and noticeable thinning of the cortices. The enlarged ventricles in mouse embryos at E20.5 or the human patient are possibly the results of thinning of cortices. Asterisks denote enlarged ventricles in both KO embryos and the human patient. Arrowheads show the reduced frontal brain in the human patient. n = 1 patient.