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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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 [8]
Cites
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Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders
Sweeney, M. D., Sagare, A. P., & Zlokovic, B. V. (2018) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.188 · Cited by 3,076 · see citing works
Blood-Brain Barrier: From Physiology to Disease and Back
Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R., & Zlokovic, B. V. (2019) · Physiological Reviews · doi:10.1152/physrev.00050.2017 · Cited by 2,294 · see citing works
Establishment and Dysfunction of the Blood-Brain Barrier
Zhao, Z., Nelson, A. R., Betsholtz, C., & Zlokovic, B. V. (2015) · Cell · doi:10.1016/j.cell.2015.10.067 · Cited by 1,670 · see citing works
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Sweeney, M. D., Ayyadurai, S., & Zlokovic, B. V. (2016) · Nature Neuroscience · doi:10.1038/nn.4288 · Cited by 1,125 · see citing works
Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease
Nelson, A. R., Sweeney, M. D., Sagare, A. P., & Zlokovic, B. V. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.12.016 · Cited by 559 · see citing works
Wong, B. H., Chan, J. P., Cazenave-Gassiot, A., Poh, R. W., Foo, J. C., Galam, D. L. A., Ghosh, S., Nguyen, L. N., Barathi, V. A., Yeo, S. W., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.721340 · Cited by 155 · see citing works
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- Authors
- Alakbarzade, V., Hameed, A., Quek, D. Q. Y., Chioza, B. A., Baple, E. L., Cazenave-Gassiot, A., Nguyen, L. N., Wenk, M. R., Ahmad, A. Q., Sreekantan-Nair, A., Weedon, M. N., Rich, P., Patton, M. A., Warner, T. T., Silver, D. L., & Crosby, A. H.
- Affiliations
- University of Exeter (GB)
- Institute of Biomedical and Genetic Engineering (PK)
- National University of Singapore (SG)
- Rehabilitation Hospital of Indiana (US)
- St George's Hospital (GB)
- National Health Service (GB)
- UCL Queen Square Institute of Neurology (GB)
- Corresponding author
- Silver, David L
- Crosby, Andrew H
- ORCID
- Venue
- Nature Genetics
- Published
- 2015-05-25
- Volume
- 47
- Issue
- 7
- Pages
- 814-817
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1565002540
- Cited by
- 144
- References
- 1
- Citations by year
- 2026: 12 · 2025: 11 · 2024: 9 · 2023: 13 · 2022: 14 · 2021: 18 · 2020: 17 · 2019: 6 · 2018: 15 · 2017: 17 · 2016: 5 · 2015: 7
- FWCI
- 7.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- MFSD2A, intellectual disability, spasticity, omega-3 fatty acids, blood-brain barrier, brain development, transporter activity
- MeSH terms
- Adolescent, Animals, Base Sequence, Biological Transport, Blood-Brain Barrier, Child, Child, Preschool, Female, Humans, Infant, Lysophosphatidylcholines, Male, Microcephaly, Pedigree, Syndrome, Fatty Acids, Omega-3, Case-Control Studies, Sequence Analysis, DNA, Mutation, Missense, Tumor Suppressor Proteins, Symporters, Genetic Association Studies, HEK293 Cells
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