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Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly

Alicia Guemez-Gamboa1, Long N Nguyen2, Hongbo Yang3

  • 11] Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Nature Genetics
|May 26, 2015
PubMed

Insights

Mutations in MFSD2A disrupt the transport of essential docosahexaenoic acid (DHA) and lysophosphatidylcholine (LPC) lipids, causing lethal microcephaly syndrome in humans.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Docosahexaenoic acid (DHA) is a crucial omega-3 fatty acid for brain development, but the brain cannot synthesize it.
  • DHA is imported into the brain via the blood-brain barrier (BBB) by the MFSD2A protein, which transports it as lysophosphatidylcholine (LPC).

Purpose of the Study:

  • To investigate the role of MFSD2A in human brain development and function.
  • To identify genetic mutations affecting MFSD2A and their associated clinical manifestations.

Main Methods:

  • Identification of mutations in the MFSD2A gene in two families with microcephaly syndrome.
  • Assessment of MFSD2A transport activity using cell-based assays.
  • Validation of mutant MFSD2A function in a zebrafish model (mfsd2aa-morphants).

Main Results:

  • Identified mutations in conserved MFSD2A residues led to impaired LPC lipid transport.
  • Affected individuals presented with a lethal microcephaly syndrome due to insufficient LPC uptake.
  • Mutant MFSD2A failed to rescue microcephaly, BBB breakdown, and lethality in zebrafish.

Conclusions:

  • Establishes a direct link between MFSD2A-mediated transport of DHA and LPCs and human brain growth.
  • Presents the first evidence of a monogenic disease caused by impaired DHA transport.
  • Highlights the critical role of MFSD2A in maintaining brain development and function.

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