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

Pazhanichamy Kalailingam1, Kai Qi Wang1, Xiu Ru Toh1

  • 1Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

The Journal of Clinical Investigation
|May 6, 2020
PubMed

Insights

Mutations in FLVCR2 cause Fowler syndrome, leading to neurological defects. Mouse studies reveal Mfsd7c is crucial for central nervous system (CNS) blood vessel development, linking gene ablation to microcephaly-associated vasculopathy.

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Genetics

Background:

  • Fowler syndrome is linked to mutations in the FLVCR2 gene, causing severe neurological defects.
  • The mouse ortholog, Mfsd7c, is expressed in the blood-brain barrier, suggesting a role in CNS development.

Purpose of the Study:

  • To characterize Mfsd7c-knockout (KO) mice and compare their phenotypes to human patients with FLVCR2 mutations.
  • To investigate the role of Mfsd7c in central nervous system (CNS) blood vessel development.

Main Methods:

  • Generation and characterization of global Mfsd7c-KO mice.
  • Phenotypic analysis of Mfsd7c-KO embryos, including vascular morphology and brain development.
  • Transcriptomic analysis of Mfsd7c-KO embryonic brains.
  • Comparison with human genetic data for FLVCR2 mutations.

Main Results:

  • Mfsd7c-KO mice exhibited late-gestation lethality, likely due to CNS defects.
  • Inhibited CNS blood vessel angiogenesis, characterized by dilated and fused vascular tips (glomeruloid vessels), was observed in Mfsd7c-KO embryos.
  • Both Mfsd7c-KO embryos and humans with FLVCR2 mutations showed reduced cerebral cortical layers, enlarged ventricles, and microcephaly.
  • Transcriptomic analysis revealed upregulated glycolysis and angiogenesis genes, alongside hypoxia and neuronal cell death in Mfsd7c-KO brains.

Conclusions:

  • MFSD7c is essential for normal CNS blood vessel growth.
  • Ablation of MFSD7c leads to microcephaly-associated vasculopathy, mirroring phenotypes in human Fowler syndrome patients.
Keywords:
TransportVascular Biologyendothelial cells

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