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

Abstract

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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Figure 1: Mutation of MFSD2A causes non-lethal neurodevelopmental delay and microcephaly.
Figure 2: The MFSD2A p.Ser339Leu alteration results in partial loss of function.
Figure 3: Total plasma LPC concentration and concentrations of individual LPC species by lipidomic mass spectrometry.

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Acknowledgements

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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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.

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Correspondence to David L Silver or Andrew H Crosby.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Homozygosity map of affected family members.

Homozygosity plots indicate detected autozygous genomic regions shared by affected family members in each family, with the homozygous region containing the MFSD2A region indicated in red.

Supplementary Figure 2 Facial features of affected family members.

Features include microcephaly and up-slanting palpebral fissures (a, II:3; b, III:2; c, III:3; d, III:4). Published with consent.

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Supplementary Figures 1 and 2, and Supplementary Tables 1 and 2. (PDF 240 kb)

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Alakbarzade, V., Hameed, A., Quek, D. et al. A partially inactivating mutation in the sodium-dependent lysophosphatidylcholine transporter MFSD2A causes a non-lethal microcephaly syndrome. Nat Genet 47, 814–817 (2015). https://doi.org/10.1038/ng.3313

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