Read Article
Related Articles
Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid.
Nguyen LN
et al.
Nature
2014
Mfsd2a Is a Transporter for the Essential ω-3 Fatty Acid Docosahexaenoic Acid (DHA) in Eye and Is Important for Photoreceptor Cell Development.
Wong BH
et al.
Journal of Biological Chemistry
2016
Lipase Treatment of Dietary Krill Oil, but Not Fish Oil, Enables Enrichment of Brain Eicosapentaenoic Acid and Docosahexaenoic Acid.
Yalagala PCR
et al.
Molecular Nutrition & Food Research
2020
Efficient Enrichment of Retinal DHA with Dietary Lysophosphatidylcholine-DHA: Potential Application for Retinopathies.
Sugasini D
et al.
Nutrients
2020
Disrupted Blood-Retina Lysophosphatidylcholine Transport Impairs Photoreceptor Health But Not Visual Signal Transduction
Ekaterina S Lobanova
et al.
The Journal of Neuroscience
2019
Dietary docosahexaenoic acid (DHA) as lysophosphatidylcholine, but not as free acid, enriches brain DHA and improves memory in adult mice
Dhavamani Sugasini
et al.
Scientific Reports
2017
Mfsd2a: A Physiologically Important Lysolipid Transporter in the Brain and Eye
Wong BH
et al.
In: Jiang XC. (eds) Lipid Transfer in Lipoprotein Metabolism and Cardiovascular Disease. Advances in Experimental Medicine and Biology
2020
Enrichment of brain docosahexaenoic acid (DHA) is highly dependent upon the molecular carrier of dietary DHA: lysophosphatidylcholine is more efficient than either phosphatidylcholine or triacylglycerol
Dhavamani Sugasini
et al.
The Journal of Nutritional Biochemistry
2019
The lysolipid transporter Mfsd2a regulates lipogenesis in the developing brain
Jia Pei Chan
et al.
PLoS Biology
2018
Blood lysophosphatidylcholine (LPC) levels and characteristic molecular species in neonates: prolonged low blood LPC levels in very low birth weight infants
Akihiro Takatera
et al.
Pediatric Research
2007
Dietary lysophosphatidylcholine-EPA enriches both EPA and DHA in the brain: potential treatment for depression
Poorna C. R. Yalagala
et al.
Journal of Lipid Research
2019
Longitudinal Metabolomic Profiling of Amino Acids and Lipids across Healthy Pregnancy
Karen L Lindsay
et al.
PLOS ONE
2015
Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome
Alicia Guemez-Gamboa 1
et al.
Nature Genetics
2015
A partially inactivating mutation in the sodium-dependent lysophosphatidylcholine transporter MFSD2A causes a non-lethal microcephaly syndrome
Vafa Alakbarzade
et al.
Nature Genetics
2015
Quantification of lysophosphatidylcholines and phosphatidylcholines using liquid chromatography-tandem mass spectrometry in neonatal serum
Akihiro Takatera
et al.
Journal of Chromatography B
2006
Insights into major facilitator superfamily domain-contaning protein-2a (Mfsd2a) in physiology and pathophysiology. What do we know so far?
Eser Ocak P
et al.
Journal of Neuroscience Research
2020
Child Head Circumference and Placental MFSD2a Expression Are Associated to the Level of MFSD2a in Maternal Blood During Pregnancy
María Sánchez-Campillo
et al.
Frontiers in Endocrinology
2020
Major facilitator superfamily domain-containing protein 2a (MFSD2A) has roles in body growth, motor function, and lipid metabolism
Justin H Berger
et al.
PLoS ONE
2012
The Lysophosphatidylcholine Transporter MFSD2A Is Essential for CD8 + Memory T Cell Maintenance and Secondary Response to Infection
Ann R Piccirillo
et al.
J Immunol
2019
Homozygous mutation in MFSD2A, encoding a lysolipid transporter for docosahexanoic acid, is associated with microcephaly and hypomyelination
Tamar Harel
et al.
Neurogenetics
2018
Lysophosphatidylcholine as a preferred carrier form of docosahexaenoic acid to the brain
M Lagarde
et al.
Journal of Molecular Neuroscience
2001
Maternal lipid levels across pregnancy impact the umbilical cord blood lipidome and infant birth weight
Jennifer L LaBarre
et al.
Scientific Reports
2020
Preferential incorporation of sn-2 lysoPC DHA over unesterified DHA in the young rat brain
F Thies
et al.
American Journal of Physiology
1994
Lysophosphatidylcholine as a carrier of docosahexaenoic acid to target tissues
M Lagarde
et al.
World Rev Nutr Diet
2001
Plasma BDNF is a more reliable biomarker than erythrocyte omega-3 index for the omega-3 fatty acid enrichment of brain
Dhavamani Sugasini
et al.
Scientific Reports
2020
Perspective: The Potential Role of Circulating Lysophosphatidylcholine in Neuroprotection against Alzheimer Disease
Richard D Semba
et al.
Advances in Nutrition
2020
Omega-3 PUFA metabolism and brain modifications during aging
Hillary Chappus-McCendie
et al.
Prog Neuropsychopharmacol Biol Psychiatry
2019
Role of phosphatidylcholine-DHA in preventing APOE4-associated Alzheimer's disease
Rhonda P Patrick
et al.
FASEB JOURNAL
2019
Carriers of an apolipoprotein E epsilon 4 allele are more vulnerable to a dietary deficiency in omega-3 fatty acids and cognitive decline
Tanya Gwendolyn Nock
et al.
Biochim Biophys Acta Mol Cell Biol Lipids.
2017
Docosahexaenoic acid prevents cognitive deficits in human apolipoprotein E epsilon 4-targeted replacement mice
Raphaël Chouinard-Watkins
et al.
Neurobiology of Aging
2017
Blood-Brain Barrier Permeability Is Regulated by Lipid Transport-Dependent Suppression of Caveolae-Mediated Transcytosis
Benjamin J Andreone
et al.
Neuron
2017
Mechanisms of DHA transport to the brain and potential therapy to neurodegenerative diseases
Amanda Lo Van
et al.
Biochimie
2016
Enhanced incorporation of dietary DHA into lymph phospholipids by altering its molecular carrier
Papasani V Subbaiah
et al.
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
2016
Mfsd2a-based pharmacological strategies for drug delivery across the blood-brain barrier
Jing-Zhang Wang
et al.
Pharmachological Research
2016
The Cellular and Molecular Landscapes of the Developing Human Central Nervous System
John C Silbereis
et al.
Neuron
2016
Efficient Docosahexaenoic Acid Uptake by the Brain from a Structured Phospholipid
Mayssa Hachem
et al.
Molecular Neurobiology
2015
A dose response randomised controlled trial of docosahexaenoic acid (DHA) in preterm infants.
C T Collins
et al.
Prostaglandins Leukot Essent Fatty Acids
2015
Blood-brain barrier: a dual life of MFSD2A?
Zhao Z
et al.
Neuron
2014
Pregnancy-induced metabolic phenotype variations in maternal plasma
Hemi Luan
et al.
Journal of Proteome Research
2014
MFSD2a, the Syncytin-2 receptor, is important for trophoblast fusion
C Toufaily
et al.
Placenta
2012
Docosahexaenoic acid (DHA) and the developing central nervous system (CNS) - Implications for dietary recommendations
Philippe Guesnet
et al.
Biochimie
2011
Lipidomics reveals a remarkable diversity of lipids in human plasma
Oswald Quehenberger
et al.
J Lipid Res.
2010
DHA deficiency and prefrontal cortex neuropathology in recurrent affective disorders
Robert K McNamara
et al.
J Nutr.
2010
A placenta-specific receptor for the fusogenic, endogenous retrovirus-derived, human syncytin-2
Cécile Esnault
et al.
Proc Natl Acad Sci USA
2008
The aging human orbitofrontal cortex: decreasing polyunsaturated fatty acid composition and associated increases in lipogenic gene expression and stearoyl-CoA desaturase activity
Robert K McNamara
et al.
Prostaglandins Leukot Essent Fatty Acids
2008
Cell survival matters: docosahexaenoic acid signaling, neuroprotection and photoreceptors
Nicolas G Bazan
et al.
Trends Neurosci
2006
The role of essential fatty acids in development
William C Heird
et al.
Annu Rev Nutr
2005
Essential fatty acid transfer and fetal development
S M Innis
et al.
Placenta
2005
Preferential transfer of 2-docosahexaenoyl-1-lysophosphatidylcholine through an in vitro blood-brain barrier over unesterified docosahexaenoic acid
N Bernoud
et al.
Journal of Neurochemistry
2002
The uptake and metabolism of plasma lysophosphatidylcholine in vivo by the brain of squirrel monkeys
D R Illingworth, O W Portman
et al.
Biochem J .
1972
Maternal DHA and the development of attention in infancy and toddlerhood
John Colombo
et al.
Child Dev.
2004
Daily Enteral DHA Supplementation Alleviates Deficiency in Premature Infants
Michelle L Baack
et al.
Lipids
2016
Neurogenetics . 2018 Dec;19(4):227-235. doi: 10.1007/s10048-018-0556-6.

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

July 24, 2018
Tamar Harel 1, 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 10 11, David L Silver 12, Orly Elpeleg 10 11, Shimon Edvardson 8 11

1Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, POB 12000, 9112001, Jerusalem, Israel. tamarhe@hadassah.org.il.

2Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Singapore.

3Department of Biochemistry, National University of Singapore, 8 Medical Drive, Block MD 7, Singapore, 117597, Singapore.

4Singapore Lipidomics Incubator (SLING), Life Sciences Institute, National University of Singapore, 28 Medical Drive, Singapore, 117456, Singapore.

5Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), 30 Biopolis St., Matrix No. 07-01, Singapore, 138671, Singapore.

6Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore, 117543, Singapore.

7Centre for Computational Biology, DUKE-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.

8Pediatric Neurology Unit, Hadassah-Hebrew University Medical Center, 9112001, Jerusalem, Israel.

9Child Developmental Center, Clalit Health Services, Jerusalem, Israel.

10Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, POB 12000, 9112001, Jerusalem, Israel.

11Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, 9112001, Jerusalem, Israel.

12Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Singapore. david.silver@duke-nus.edu.sg.

Abstract

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.

Keywords
Blood-brain barrier
Microcephaly
Major facilitator superfamily domain containing 2a (Mfsd2a)
DHA
EPA
Polyunsaturated fatty acid (PUFA)
LPC
Lysolipids
Lysophospholipid
Plasticity
Early life
Brain
RELATED