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A partially inactivating mutation in the sodium-dependent lysophosphatidylcholine transporter MFSD2A causes a non-lethal microcephaly syndrome

Nature Genetics volume 47, pages 814817 (2015) | Download Citation


The major pathway by which the brain obtains essential omega-3 fatty acids from the circulation is through a sodium-dependent lysophosphatidylcholine (LPC) transporter (MFSD2A), expressed in the endothelium of the blood-brain barrier. Here we show that a homozygous mutation affecting a highly conserved MFSD2A residue (p.Ser339Leu) is associated with a progressive microcephaly syndrome characterized by intellectual disability, spasticity and absent speech. We show that the p.Ser339Leu alteration does not affect protein or cell surface expression but rather significantly reduces, although not completely abolishes, transporter activity. Notably, affected individuals displayed significantly increased plasma concentrations of LPCs containing mono- and polyunsaturated fatty acyl chains, indicative of reduced brain uptake, confirming the specificity of MFSD2A for LPCs having mono- and polyunsaturated fatty acyl chains. Together, these findings indicate an essential role for LPCs in human brain development and function and provide the first description of disease associated with aberrant brain LPC transport in humans.

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We are grateful to the families for participating in this research. The work was supported by UK Medical Research Council grants G1002279, G0900205 and G1001931 and by the Newlife Foundation for disabled children (to A.H.C., M.A.P. and E.L.B.), the Singapore Ministry of Health's National Medical Research Council grant CBRG/069/2014 (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.).

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Author notes

    • Vafa Alakbarzade
    • , Abdul Hameed
    • , Debra Q Y Quek
    • , Barry A Chioza
    •  & Emma L Baple

    These authors contributed equally to this work.


  1. Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Wellcome Wolfson Centre, Exeter, UK.

    • Vafa Alakbarzade
    • , Barry A Chioza
    • , Emma L Baple
    • , Ajith Sreekantan-Nair
    • , Michael N Weedon
    • , Michael A Patton
    •  & Andrew H Crosby
  2. Reta Lila Weston Institute of Neurological Studies, Department of Molecular Neurosciences, University College London Institute of Neurology, London, UK.

    • Vafa Alakbarzade
    •  & Thomas T Warner
  3. Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan.

    • Abdul Hameed
  4. Signature Research Program in Cardiovascular and Metabolic Disorders, Duke–National University of Singapore Graduate Medical School, Singapore.

    • Debra Q Y Quek
    • , Long N Nguyen
    •  & David L Silver
  5. Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.

    • Emma L Baple
  6. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.

    • Emma L Baple
  7. Life Sciences Institute, National University of Singapore, Singapore.

    • Amaury Cazenave-Gassiot
    •  & Markus R Wenk
  8. Department of Physical Medicine and Rehabilitation, Indiana University–Purdue University Indianapolis (IUPUI), Indianapolis, Indiana, USA.

    • Arshia Q Ahmad
  9. Rehabilitation Hospital Indiana, Indianapolis, Indiana, USA.

    • Arshia Q Ahmad
  10. Department of Neuroradiology, St. George's Hospital, London, UK.

    • Phil Rich
  11. Southwest Thames Regional Genetics Service, St George's Healthcare National Health Service (NHS) Trust, London, UK.

    • Michael A Patton


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A.H.C. and D.L.S. conceived, designed and supervised the project. V.A., D.Q.Y.Q., B.A.C., A.C.-G., L.N.N., M.R.W. and M.N.W. performed experiments. A.H. aided in family recruitment. A.H., A.Q.A., T.T.W., M.A.P., P.R. and E.L.B. aided in assessment of clinical data. A.S.-N. was involved in the genetic studies. A.H.C., D.L.S. and E.L.B. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to David L Silver or Andrew H Crosby.

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