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

Alicia Guemez-Gamboa, Long N. Nguyen, Hongbo Yang, Maha S. Zaki, Majdi Kara, Tawfeg Ben-Omran, Naiara Akizu, Rasim Ozgur Rosti, Basak Rosti, Eric Scott, Jana Schroth, Brett Copeland, Keith K. Vaux, Amaury Cazenave-Gassiot, Debra Q.Y. Quek, Bernice H. Wong, Bryan C. Tan, Markus R. Wenk, Murat Gunel, Stacey GabrielNeil C. Chi, David L. Silver, Joseph G. Gleeson

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

Docosahexanoic acid (DHA) is the most abundant omega-3 fatty acid in brain, and, although it is considered essential, deficiency has not been linked to disease. Despite the large mass of DHA in phospholipids, the brain does not synthesize it. DHA is imported across the blood-brain barrier (BBB) through the major facilitator superfamily domain-containing 2a (MFSD2A) protein. MFSD2A transports DHA as well as other fatty acids in the form of lysophosphatidylcholine (LPC). We identify two families displaying MFSD2A mutations in conserved residues. Affected individuals exhibited a lethal microcephaly syndrome linked to inadequate uptake of LPC lipids. The MFSD2A mutations impaired transport activity in a cell-based assay. Moreover, when expressed in mfsd2aa-morphant zebrafish, mutants failed to rescue microcephaly, BBB breakdown and lethality. Our results establish a link between transport of DHA and LPCs by MFSD2A and human brain growth and function, presenting the first evidence of monogenic disease related to transport of DHA in humans.

Original languageEnglish (US)
Pages (from-to)809-813
Number of pages5
JournalNature Genetics
Volume47
Issue number7
DOIs
StatePublished - Jun 26 2015

All Science Journal Classification (ASJC) codes

  • Genetics

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    Guemez-Gamboa, A., Nguyen, L. N., Yang, H., Zaki, M. S., Kara, M., Ben-Omran, T., Akizu, N., Rosti, R. O., Rosti, B., Scott, E., Schroth, J., Copeland, B., Vaux, K. K., Cazenave-Gassiot, A., Quek, D. Q. Y., Wong, B. H., Tan, B. C., Wenk, M. R., Gunel, M., ... Gleeson, J. G. (2015). Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome. Nature Genetics, 47(7), 809-813. https://doi.org/10.1038/ng.3311