Cited by 225Barrier Structure and Function StudiesFatty Acid Research and HealthDrug Transport and Resistance Mechanisms

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Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome

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Guemez-Gamboa, Alicia, Nguyen, Long N, Yang, Hongbo, Zaki, Maha S, Kara, Majdi, Ben-Omran, Tawfeg, Akizu, Naiara, Rosti, Rasim Ozgur, Rosti, Basak, Scott, Eric, Schroth, Jana, Copeland, Brett, Vaux, Keith K, Cazenave-Gassiot, Amaury, Quek, Debra Q Y, Wong, Bernice H, Tan, Bryan C, Wenk, Markus R, Gunel, Murat, Gabriel, Stacey, Chi, Neil C, Silver, David L, Gleeson, Joseph G·2015·Nature Genetics

DOI 10.1038/ng.3311PMC PMC4547531

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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 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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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: Nguyen, Long N
Yang, Hongbo
Zaki, Maha S
Kara, Majdi
Akizu, Naiara
Scott, Eric
Copeland, Brett
Vaux, Keith K
Cazenave-Gassiot, Amaury
Wong, Bernice H
Tan, Bryan C
Wenk, Markus R
Gabriel, Stacey
Silver, David L
Gleeson, Joseph G
Venue: Nature Genetics
Publisher: Springer Science and Business Media LLC
Published: 2015-05-25
Volume: 47
Issue: 7
Pages: 809-813
ISSN: 1061-4036 (ISSN-L)
1546-1718
DOI: 10.1038/ng.3311
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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Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome

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