, Volume 19, Issue 4, pp 227–235 | Cite as

Homozygous mutation in MFSD2A, encoding a lysolipid transporter for docosahexanoic acid, is associated with microcephaly and hypomyelination

  • Tamar HarelEmail author
  • Debra Q. Y. Quek
  • Bernice H. Wong
  • Amaury Cazenave-Gassiot
  • Markus R. Wenk
  • Hao Fan
  • Itai Berger
  • Dorit Shmueli
  • Avraham Shaag
  • David L. SilverEmail author
  • Orly Elpeleg
  • Shimon Edvardson
Original Article


The major facilitator superfamily domain-containing protein 2A (MFSD2A) is a constituent of the blood-brain barrier and functions to transport lysophosphatidylcholines (LPCs) into the central nervous system. LPCs such as that derived from docosahexanoic acid (DHA) are indispensable to neurogenesis and maintenance of neurons, yet cannot be synthesized within the brain and are dependent on MFSD2A for brain uptake. Recent studies have implicated MFSD2A mutations in lethal and non-lethal microcephaly syndromes, with the severity correlating to the residual activity of the transporter. We describe two siblings with shared parental ancestry, in whom we identified a homozygous missense mutation (c.1205C > A; p.Pro402His) in MFSD2A. Both affected individuals had microcephaly, hypotonia, appendicular spasticity, dystonia, strabismus, and global developmental delay. Neuroimaging revealed paucity of white matter with enlarged lateral ventricles. Plasma lysophosphatidylcholine (LPC) levels were elevated, reflecting reduced brain transport. Cell-based studies of the p.Pro402His mutant protein indicated complete loss of activity of the transporter despite the non-lethal, attenuated phenotype. The aggregate data of MFSD2A-associated genotypes and phenotypes suggest that additional factors, such as nutritional supplementation or modifying genetic factors, may modulate the severity of disease and call for consideration of treatment options for affected individuals.


MFSD2A Docosahexanoic acid Blood-brain barrier Microcephaly Lysophosphatidylcholine Lysolipid transporters 



The authors wish to thank the family for their participation in this study.

Conflict of interest

The authors declare that they have no conflict of interest.


The work was supported in part by National Research Foundation grants, Singapore NRF2016NRF-NRFI001-15 (to D.L.S.), NRFI2015-05 (to M.R.W.); by the Biomedical Research Council of A*STAR (to H. F.); and by a BMRC-SERC joint grant (BMRC-SERC 112 148 0006, to M.R.W.) from the Agency for Science, Technology and Research, Singapore.

Supplementary material

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ESM 1 (XLSX 45 kb)
10048_2018_556_MOESM2_ESM.xlsx (12 kb)
ESM 2 (XLSX 12 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Tamar Harel
    • 1
    Email author
  • Debra Q. Y. Quek
    • 2
  • Bernice H. Wong
    • 2
  • Amaury Cazenave-Gassiot
    • 3
    • 4
  • Markus R. Wenk
    • 3
    • 4
  • Hao Fan
    • 5
    • 6
    • 7
  • Itai Berger
    • 8
  • Dorit Shmueli
    • 9
  • Avraham Shaag
    • 1
    • 10
  • David L. Silver
    • 2
    Email author
  • Orly Elpeleg
    • 1
    • 10
  • Shimon Edvardson
    • 8
    • 10
  1. 1.Department of Genetic and Metabolic DiseasesHadassah-Hebrew University Medical CenterJerusalemIsrael
  2. 2.Signature Research Program in Cardiovascular and Metabolic DisordersDuke-NUS Medical SchoolSingaporeSingapore
  3. 3.Department of BiochemistryNational University of SingaporeSingaporeSingapore
  4. 4.Singapore Lipidomics Incubator (SLING), Life Sciences InstituteNational University of SingaporeSingaporeSingapore
  5. 5.Bioinformatics Institute (BII), Agency for ScienceTechnology and Research (A*STAR)SingaporeSingapore
  6. 6.Department of Biological SciencesNational University of SingaporeSingaporeSingapore
  7. 7.Centre for Computational BiologyDUKE-NUS Medical SchoolSingaporeSingapore
  8. 8.Pediatric Neurology UnitHadassah-Hebrew University Medical CenterJerusalemIsrael
  9. 9.Child Developmental Center, Clalit Health ServicesJerusalemIsrael
  10. 10.Monique and Jacques Roboh Department of Genetic ResearchHadassah-Hebrew University Medical CenterJerusalemIsrael

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