Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome
Open accessAbstract
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.
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Inactivating mutations in MFSD2A gene lead to development of microcephaly syndrome in humans associated with loss of neurons and intellectual disability, and in the case of some mutations lethal microcephaly.
“Inactivating mutations in MFSD2A gene, encoding the sodium-dependent endothelial transporter that transports essential omega-3 fatty acids into the brain (430) and regulates caveolae-mediated transcellular trafficking across the BBB (21, 62, 684), lead to development of microcephaly syndrome in humans associated with loss of neurons and intellectual disability, and in case of some mutations lethal”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [218]
The clinical findings in our copy (section labelled Abstract; page unavailable) link two MFSD2A variants to microcephaly, intellectual disability, and death within the first few years. The paper reports brain hypoplasia and atrophy, but does not establish loss of neurons specifically. Both variants described in these families were associated with a lethal syndrome; the paper does not distinguish lethal from nonlethal mutations. (LLM, conf=0.88)
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- Authors
- 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., Gabriel, S., Chi, N. C., Silver, D. L., & Gleeson, J. G.
- Affiliations
- National University of Singapore (SG)
- University of California San Diego (US)
- National Research Centre (EG)
- Howard Hughes Medical Institute (US)
- Broad Institute (US)
- Corresponding author
- Silver, David L
- Gleeson, Joseph G
- ORCID
- Venue
- Nature Genetics
- Published
- 2015-05-25
- Volume
- 47
- Issue
- 7
- Pages
- 809-813
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC4547531
- OpenAlex
- W2166500841
- Cited by
- 225
- References
- 23
- Citations by year
- 2026: 21 · 2025: 10 · 2024: 11 · 2023: 19 · 2022: 25 · 2021: 25 · 2020: 25 · 2019: 14 · 2018: 26 · 2017: 25 · 2016: 14 · 2015: 9
- FWCI
- 13.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- National University of Singapore (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (1s10od018521-01)
- National Human Genome Research Institute (U54HG006504, U54HG003067)
- National Institute of Neurological Disorders and Stroke (R01NS048453, K99NS089943)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD070494)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- MFSD2A, microcephaly, docosahexaenoic acid, lysophosphatidylcholine, major facilitator superfamily, blood-brain barrier, brain growth, monogenic disorders, loss-of-function mutations
- MeSH terms
- Adolescent, Animals, Biological Transport, Blood-Brain Barrier, Brain, Child, Child, Preschool, Consanguinity, Female, Genes, Lethal, Humans, Infant, Male, Microcephaly, Syndrome, Zebrafish, Fatty Acids, Omega-3, Case-Control Studies, Mice, Knockout, Mutation, Missense, Tumor Suppressor Proteins, Symporters, Genetic Association Studies, HEK293 Cells
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