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 disease1,2. 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) protein3. 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.

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NCBI Reference Sequence

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Acknowledgements

This work was supported by grants from the US National Institutes of Health, including P01HD070494 (to J.G.G. and N.C.C.), R01NS048453 (to J.G.G.), K99NS089943 (to A.G.-G.), and U54HG003067 to the Broad Institute and U54HG006504 to the Yale Center for Mendelian Disorders (M.G.), grant CBRG/069/2014 from the Singapore Ministry of Health's National Medical Research Council (to D.L.S.), Singapore National Research Foundation Competitive Research Program grant 2007-04 (to M.R.W.) and the National University of Singapore's Life Sciences Institute (to M.R.W.). Sequencing was provided in part by a gift from BGI to Rady Children's Hospital, San Diego for undiagnosed patients. Human brain samples were provided by S. Roy (University of California, San Diego).

Author information

Author notes

    • Alicia Guemez-Gamboa
    • , Long N Nguyen
    •  & Hongbo Yang

    These authors contributed equally to this work.

Affiliations

  1. Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.

    • Alicia Guemez-Gamboa
    • , Naiara Akizu
    • , Rasim Ozgur Rosti
    • , Basak Rosti
    • , Eric Scott
    • , Jana Schroth
    • , Brett Copeland
    • , Keith K Vaux
    •  & Joseph G Gleeson
  2. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

    • Alicia Guemez-Gamboa
    • , Naiara Akizu
    • , Rasim Ozgur Rosti
    • , Basak Rosti
    • , Eric Scott
    • , Jana Schroth
    • , Brett Copeland
    • , Keith K Vaux
    •  & Joseph G Gleeson
  3. Signature Research Program in Cardiovascular and Metabolic Disorders, Duke–National University of Singapore Graduate Medical School, Singapore.

    • Long N Nguyen
    • , Debra Q Y Quek
    • , Bernice H Wong
    • , Bryan C Tan
    •  & David L Silver
  4. Department of Medicine, University of California, San Diego, La Jolla, California, USA.

    • Hongbo Yang
    •  & Neil C Chi
  5. Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.

    • Maha S Zaki
  6. Department of Pediatrics, Tripoli Children's Hospital, Tripoli, Libya.

    • Majdi Kara
  7. Clinical and Metabolic Genetics Division, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.

    • Tawfeg Ben-Omran
  8. Department of Biochemistry, National University of Singapore, Singapore.

    • Amaury Cazenave-Gassiot
    •  & Markus R Wenk
  9. Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology and Genetics, Yale University, School of Medicine, New Haven, Connecticut, USA.

    • Murat Gunel
  10. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Stacey Gabriel

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Contributions

M.S.Z., M.K., T.B.-O., K.K.V. and R.O.R. recruited subjects and analyzed the clinical data. E.S., J.S. and B.C. interpreted exome results. J.G.G. and D.L.S. conceived and designed the project. N.A. prepared human brain samples. M.G. and S.G. provided sequencing. A.G.-G. performed genetic analysis to identify MFSD2A mutations. L.N.N. performed lipid transport studies, lipidomics, thin-layer chromatography (TLC) and confocal microscopy. H.Y. and N.C.C. performed zebrafish morpholino studies, and A.G.-G. analyzed and interpreted the data. B.R., D.Q.Y.Q., B.H.W. and B.C.T. assisted with cloning, immunoblots and imaging. A.C.-G. and M.R.W. provided expertise in mass spectrometry. D.L.S., L.N.N., A.G.-G. and J.G.G. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to David L Silver or Joseph G Gleeson.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–13, Supplementary Tables 1–6 and Supplementary Note.

Videos

  1. 1.

    Supplementary Video 1

    Intracardiac injection of 2,000-kDa dextran into control embryos at 3 days post-fertilization (d.p.f.). Side view 0 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to brain parenchyma.

  2. 2.

    Supplementary Video 2

    Intracardiac injection of 2,000-kDa dextran into control embryos at 3 days post-fertilization (d.p.f.). Dorsal view 0 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to brain parenchyma.

  3. 3.

    Supplementary Video 3

    Intracardiac injection of 2,000-kDa dextran into control embryos at 3 days post-fertilization (d.p.f.). Side view 40 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to brain parenchyma.

  4. 4.

    Supplementary Video 4

    Intracardiac injection of 2,000-kDa dextran into control embryos at 3 days post-fertilization (d.p.f.). Dorsal view 40 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to brain parenchyma.

  5. 5.

    Supplementary Video 5

    Intracardiac injection of 2,000-kDa dextran into mfsd2aa morpholino (1 ng) (MO)–injected embryos at 3 days post-fertilization (d.p.f.). Side view 0 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to dextran extravasation into the brain parenchyma.

  6. 6.

    Supplementary Video 6

    Intracardiac injection of 2,000-kDa dextran into mfsd2aa morpholino (1 ng) (MO)–injected embryos at 3 days post-fertilization (d.p.f.). Dorsal view 0 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to dextran extravasation into the brain parenchyma.

  7. 7.

    Supplementary Video 7

    Intracardiac injection of 2,000-kDa dextran into mfsd2aa morpholino (1 ng) (MO)–injected embryos at 3 days post-fertilization (d.p.f.). Side view 40 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to dextran extravasation into the brain parenchyma.

  8. 8.

    Supplementary Video 8

    Intracardiac injection of 2,000-kDa dextran into mfsd2aa morpholino (1 ng) (MO)–injected embryos at 3 days post-fertilization (d.p.f.). Dorsal view 40 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to dextran extravasation into the brain parenchyma.

  9. 9.

    Supplementary Video 9

    Intracardiac injection of 2,000-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with zebrafish wild-type MFSD2A mRNA (50 ng). Side view 0 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to the absence of dextran extravasation into the brain parenchyma.

  10. 10.

    Supplementary Video 10

    Intracardiac injection of 2,000-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with zebrafish wild-type MFSD2A mRNA (50 ng). Dorsal view 0 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to the absence of dextran extravasation into the brain parenchyma.

  11. 11.

    Supplementary Video 11

    Intracardiac injection of 2,000-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with zebrafish wild-type MFSD2A mRNA (50 ng). Side view 40 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to the absence of dextran extravasation into the brain parenchyma.

  12. 12.

    Supplementary Video 12

    Intracardiac injection of 2,000-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with zebrafish wild-type MFSD2A mRNA (50 ng). Dorsal view 40 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to the absence of dextran extravasation into the brain parenchyma.

  13. 13.

    Supplementary Video 13

    Intracardiac injection of 2,000-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with human wild-type mfsd2aa mRNA (50 ng). Side view 0 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to the absence of dextran extravasation into the brain parenchyma.

  14. 14.

    Supplementary Video 14

    Intracardiac injection of 2,000-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with human wild-type mfsd2aa mRNA (50 ng). Dorsal view 0 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to the absence of dextran extravasation into the brain parenchyma.

  15. 15.

    Supplementary Video 15

    Intracardiac injection of 2,000-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with human wild-type mfsd2aa mRNA (50 ng). Side view 40 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to the absence of dextran extravasation into the brain parenchyma.

  16. 16.

    Supplementary Video 16

    Intracardiac injection of 2,000-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with human wild-type mfsd2aa mRNA (50 ng). Dorsal view 40 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to the absence of dextran extravasation into the brain parenchyma.

  17. 17.

    Supplementary Video 17

    Intracardiac injection of 2,000-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with mutated p.Ser166Leu (p.S166L) human MFSD2A mRNA (50 ng). Side view 0 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to dextran extravasation into the brain parenchyma.

  18. 18.

    Supplementary Video 18

    Intracardiac injection of 2,000-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with mutated p.Ser166Leu (p.S166L) human MFSD2A mRNA (50 ng). Dorsal view 0 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to dextran extravasation into the brain parenchyma.

  19. 19.

    Supplementary Video 19

    Intracardiac injection of 2,000-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with mutated p.Ser166Leu (p.S166L) human MFSD2A mRNA (50 ng). Side view 40 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to dextran extravasation into the brain parenchyma.

  20. 20.

    Supplementary Video 20

    Intracardiac injection of 2,000-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with mutated p.Ser166Leu (p.S166L) human MFSD2A mRNA (50 ng). Dorsal view 40 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to dextran extravasation into the brain parenchyma.

  21. 21.

    Supplementary Video 21

    Intracardiac injection of 2,000-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with mutated p.Thr159Met (p.T159M) human MFSD2A mRNA (50 ng). Side view 0 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to dextran extravasation into the brain parenchyma.

  22. 22.

    Supplementary Video 22

    Intracardiac injection of 2,000-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with mutated p.Thr159Met (p.T159M) human MFSD2A mRNA (50 ng). Dorsal view 0 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to dextran extravasation into the brain parenchyma.

  23. 23.

    Supplementary Video 23

    Intracardiac injection of 2,000-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with mutated p.Thr159Met (p.T159M) human MFSD2A mRNA (50 ng). Side view 40 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to dextran extravasation into the brain parenchyma.

  24. 24.

    Supplementary Video 24

    Intracardiac injection of 2,000-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with mutated p.Thr159Met (p.T159M) human MFSD2A mRNA (50 ng). Dorsal view 40 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to dextran extravasation into the brain parenchyma.

  25. 25.

    Supplementary Video 25

    Intracardiac injection of 10-kDa dextran into control embryos at 3 days post-fertilization (d.p.f.). Side view 2 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to brain parenchyma.

  26. 26.

    Supplementary Video 26

    Intracardiac injection of 10-kDa dextran into control embryos at 3 days post-fertilization (d.p.f.). Dorsal view 2 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to brain parenchyma.

  27. 27.

    Supplementary Video 27

    Intracardiac injection of 10-kDa dextran into mfsd2aa morpholino (1 ng) (MO)–injected embryos at 3 days post-fertilization (d.p.f.). Side view 2 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to dextran extravasation into the brain parenchyma.

  28. 28.

    Supplementary Video 28

    Intracardiac injection of 10-kDa dextran into mfsd2aa morpholino (1 ng) (MO)–injected embryos at 3 days post-fertilization (d.p.f.). Dorsal view 2 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to dextran extravasation into the brain parenchyma.

  29. 29.

    Supplementary Video 29

    Intracardiac injection of 10-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with human wild-type MFSD2A mRNA (50 ng). Side view 2 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to the absence of dextran extravasation into the brain parenchyma.

  30. 30.

    Supplementary Video 30

    Intracardiac injection of 10-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with human wild-type MFSD2A mRNA (50 ng). Dorsal view 2 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to the absence of dextran extravasation into the brain parenchyma.

  31. 31.

    Supplementary Video 31

    Intracardiac injection of 10-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with zebrafish wild-type mfsd2aa mRNA (50 ng). Side view 2 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to the absence of dextran extravasation into the brain parenchyma.

  32. 32.

    Supplementary Video 32

    Intracardiac injection of 10-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with zebrafish wild-type mfsd2aa mRNA (50 ng). Dorsal view 2 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to the absence of dextran extravasation into the brain parenchyma.

  33. 33.

    Supplementary Video 33

    Intracardiac injection of 10-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with mutated p.Ser166Leu (p.S166L) human MFSD2A mRNA (50 ng). Side view 2 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to dextran extravasation into the brain parenchyma.

  34. 34.

    Supplementary Video 34

    Intracardiac injection of 10-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with mutated p.Ser166Leu (p.S166L) human MFSD2A mRNA (50 ng). Dorsal view 2 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to dextran extravasation into the brain parenchyma.

  35. 35.

    Supplementary Video 35

    Intracardiac injection of 10-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with mutated p.Thr159Met (p.T159M) human MFSD2A mRNA (50 ng). Side view 2 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to dextran extravasation into the brain parenchyma.

  36. 36.

    Supplementary Video 36

    Intracardiac injection of 10-kDa dextran into mfsd2aa morpholino (MO)–injected embryos at 3 days post-fertilization (d.p.f.). mfsd2aa MO (1 ng) was coinjected with mutated p.Thr159Met (p.T159M) human MFSD2A mRNA (50 ng). Dorsal view 2 min after dextran injection. Colocalization of dextran (green) and cranial blood vessels (red). Arrow pointing to dextran extravasation into the brain parenchyma.

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https://doi.org/10.1038/ng.3311